RNA Splicing Modulation

JOINT RESEARCH AGREEMENT STATEMENT

This application is subject to a Joint Research Agreement between Applicant, The General Hospital Corporation, and Co-Applicant, PTC Therapeutics, Inc., which was in effect on or before the Jan. 2, 2020 filing date of U.S. Provisional Application Ser. No. 62/956,616.

SEQUENCE LISTING

This application contains a Sequence Listing submitted electronically in ASCII format, the entire contents of which is hereby incorporated by reference in its entirety.

INTRODUCTION

One aspect described herein is use of a compound to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell. Another aspect described herein is use of a compound in a method to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell.

BACKGROUND

Splicing is a key control point in human gene expression. Disturbances in splicing due to mutation or aberrant splicing regulatory networks lead to dysregulated protein expression and to a substantial fraction of human diseases. These disturbances represent a promising opportunity for therapeutic intervention. Several classes of active and selective small molecule splicing modulator compounds (SMCs) have recently been identified validating pre-mRNA splicing as a viable intervention point. However, to date there have been few examples of SMCs that effectively target splicing defects and ameliorate pathogenesis.

RNA splicing is a complex and tightly regulated process that removes introns from pre-mRNA transcripts to generate mature mRNA. Differential processing of pre-mRNA is one of the principal mechanisms generating diversity in different cell and tissue types. This process can give rise to functionally different proteins or, can also generate mRNAs with different localization, stability and efficiency of translation through alternative splicing of UTRs. RNA splicing requires the widely conserved spliceosome machinery along with multiple splicing factors^1-2. The splicing reaction is directed by specific sequences, including the 5′ and 3′ splice sites, the intron branch site, and splice site enhancers and silencers found in both exons and introns^1-2. Changes in the sequences of these elements, through inherited or sporadic mutations, can result in deficient or aberrant splice site recognition by the spliceosome and lead to mis-splicing of the pre-mRNA transcript. Disruption of splicing regulatory elements can generate aberrant transcripts through complete or partial exon skipping, intron inclusion or mis-regulation of alternative splicing, the outcome of which often generates premature termination codons (PTCs) that lead to nonsense-mediated mRNA decay (NMD) of the transcript or the production of a truncated protein. Conversely, mutations in the UTRs may affect transcript localization, stability or efficiency of translation. Mutations that alter mRNA splicing are known to lead to many human monogenic diseases including spinal muscular atrophy (SMA), neurofibromatosis type 1 (NF1), cystic fibrosis (CF), familial dysautonomia (FD), Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM), as well as steer to complex diseases such as cancer and diabetes^3-18.

The development of drugs that can increase the amount of normal transcript in patients is a new, precisely targeted treatment approach aimed directly at the primary molecular disease mechanism without altering the genome. The development of splicing modulation therapies for DMD (EXONDYS 51™) and SMA (Nusinersen, Risdiplam, Branaplam)^42-43has validated the utility of splicing modification as a valuable therapeutic strategy for human disorders.

New therapeutic approaches aimed at identifying and correcting pre-mRNA splicing defects have shown significant promise in many diseases^19-55. Small molecule SMCs are attractive therapeutic options because they can be orally administered and are typically systemic and therefore distributed in all tissues. Advances in precision medicine and the capability to discover patient-specific mutations have provided a strong impetus to develop new methods to predict drug selectivity to a target disease gene of interest while improving the drug development process and enhancing patient safety in a personalized medicine paradigm.

SUMMARY

One aspect described herein is a compound for use in a method to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with the compound, and wherein the compound is 2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, having the formula of Compound (I):

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Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a wildtype gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is Compound (I) for use in the method, wherein the 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a mutant gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is Compound (I) for use in the method, wherein the 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, and wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I).

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the subject is human.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein one or more of the mature RNA isoforms produce a functional protein.

Another aspect described herein is a pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, excipient, or diluent for use in a method of treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof, wherein the compound is 2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine having the formula of Compound (I):

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wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from a gene transcript in a cell.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Table 14 and 15.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Table 14.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is other than the gene selected from the group consisting of Table 15.

One aspect described herein is use of a compound to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with the compound 2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, having the formula of Compound (I):

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Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein one or more of the mature RNA isoforms produce a functional protein.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript.

Another aspect described herein is use of Compound (I), wherein a gene having the mutated transcript is selected from the group consisting of Table 14 and 15.

Another aspect described herein is use of Compound (I), wherein a gene having the mutated transcript is selected from the group consisting of Table 14.

Another aspect described herein is use of Compound (I), wherein a gene having the mutated transcript is other than the gene selected from the group consisting of Table 15.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C: Differences Between Compound (I) and Kinetin

FIG. 1A shows the structure of kinetin compared with Compound (I).

FIG. 1B provides a representation of the dual-reporter minigene used to test splicing modulation activity of kinetin and Compound (I). Rluc and Fluc indicate Renilla and Firefly luciferase, respectively. A/C indicates the start codon mutation in Fluc and gtaagC (SEQ ID NO: 104) indicates the location of the mutation that results in exclusion of Exon 20. Dose response curves for kinetin and Compound (I) are shown for the dual-luciferase assay in Rluc-FD-Fluc transfected HEK293T cells treated for 24 hours with kinetin or Compound (I). Exon 20 inclusion, measured by normalized relative luciferase units (RLU), is plotted as a function of compound concentration. Normalized RLU refers to the ratio between firefly and Renilla luciferase and provides a measure of exon 20 inclusion. Assays were run in triplicate and curves were created by nonlinear regression using Prism4 (GraphPad Software Inc.).

FIG. 1C shows Compound (I) splicing modulation activity in human FD fibroblasts. Cells were treated for 24 hours at the concentrations indicated. The experiment was performed in triplicate.

FIGS. 2A-2G: Transcriptome Changes in Response to Compound (I).

FIG. 2A provides a representation of an exon triplet. Exon U is upstream of Exon X, which is upstream of Exon D. R₁, R₂and R₃represent RNA sequencing (RNASeq) reads spanning the regions between two adjacent exons. UI₁, I₁X, XI₂and I₂D are four regions flanking the four splice sites of the exon-triplet. Each flanking region consists of 25 exonic base pairs and 75 intronic base pairs.

FIG. 2B provides a volcano plot showing the ψ (PSI: Percent Spliced-In) changes in splicing after treatment with Compound (I). Each dot represents one of the 161,097 expressed exon triplets in human fibroblasts. The x axis represents the ψ changes after treatment and the y axis represents the False Discovery Rate (FDR) (log 10 transformed). The two vertical dashed lines indicate ψ changes of 0.1 and −0.1 as thresholds for exclusion and inclusion, respectively. The horizontal dashed line indicates an FDR of 0.1. The dots on the right side of the right vertical dashed line and above the horizontal dashed line represent the exon-triplets with an increase for Exon X inclusion (Δψ≥0.1 and FDR<0.1) while the dots on left side of the left vertical dashed line and above the horizontal dashed line represent an increase for Exon X exclusion (Δψ≤−0.1 and FDR<0.1). Black dots in-between the two vertical dashed lines represent exon-triplets unchanged from the treatment.

FIG. 2C shows independent RT-PCR validation of splicing changes of twenty randomly selected candidates after three independent experiments run in duplicate. For each validated exon-triplet, ψ change measured by RNASeq (x axis) is plotted against the splicing changes measured by RT-PCR (y axis). The R²value indicates the coefficient of Pearson correlation. The solid line shows the estimated linear regression. The grey zone indicates the 95% confidence interval for predictions from the estimated linear regression.

FIGS. 2D-2G shows RT-PCR results comparing Compound (I) (Cpd(I)) and kinetin for the splicing response of the four highlighted genes in FIG. 2C: LPINJ (FIG. 2D), HSD17B4 (FIG. 2E), SLC4A7 (FIG. 2F) and CRYZ (FIG. 2G) in human fibroblasts. The upper bands indicate the isoform in which Exon X is included while the lower bands indicate the isoform in which Exon X is skipped.

FIGS. 3A-3G: Convolutional Neural Network (CNN) Prediction of Compound (I) Response

FIGS. 3A1-3A2 show a heatmap of 12 Motifs, with FIG. 3A1 showing CNN Motifs ranked according to predicted contribution in the CNN Model toward the inclusion Class (Motifs 25, 49 and 18), and Motifs ranked according to predicted contribution in the Model toward the exclusion Class (Motifs 47, 21, 29, 9 and 10), whereas FIG. 3A2 shows the Motifs predicted to contribute toward an unchanged response Class (Motifs 01, 22, 27 and 37). The gradience bar indicates the directional contribution of each Motif used to build the dendrogram rows and columns representing the predicted response of each Motif to treatment. The right domain (progressively darker shaded range from 0 to +1) indicates a Motifs predicted positive contribution while the left domain indicates a Motifs predicted negative contribution in a progressively darker shaded range from 0 to −1. The LOGO plot for each Motif is shown on the left side of the heatmap with the corresponding Motif number shown on the right.

FIG. 3A3 shows a heatmap of positional importance for each of the 12 Motifs from FIGS. 3A1-3A2 within the XI₂region of the 5′ splice site of Exon X. The thick vertical line shows the exon-intron boundary. The gradience bar indicates positional importance, as measured by positional activation in the first layer of the CNN Model, where the right positive domain (shadowed-no slash) suggests the necessity of the Motif and the left domain (shadowed-slash) suggests the absence of the Motif.

FIGS. 3B1-3B2 show a heatmap of 13 Motifs, with FIG. 3B1 showing the Motifs ranked according to predicted contribution in the CNN Model toward the inclusion Class (Motifs 25 and 49), and Motifs ranked according to predicted contribution in the model toward the exclusion Class (Motifs 10, 21, 47, 9 and 40), whereas FIG. 3B2 shows the Motifs ranked according to predicted contribution in the model toward an unchanged response Class (Motifs 16, 33, 27, 35, 22 and 37). The gradience bar indicates the directional contribution of each Motif used to build the dendrogram rows and columns representing the predicted response of each Motif to treatment. The right domain (progressively darker shaded range from 0 to +1) indicates a Motifs predicted positive contribution while the left domain (in a progressively darker shaded range from 0 to −1) indicates a Motifs predicted negative contribution. The LOGO plot for each Motif is shown on the left side of the heatmap with the corresponding Motif number shown on the right.

FIG. 3B3 shows a heatmap of positional importance for each of the 13 Motifs from FIGS. 3B1-3B2 within the XI₂region of the 5′ splice site of Exon X. The thick vertical line shows the exon-intron boundary. The gradience bar indicates positional importance, as measured by positional activation in the first layer of the CNN model, where the right positive domain (shadowed) suggests the necessity of the Motif and the left domain (progressively less shadowed) suggests the absence of the Motif.

FIG. 3C shows box plots indicating splicing strength for each splice junction along the exon triplets for inclusion (light grey), exclusion (dark grey) and unchanged (black) group, as defined by the RNASeq data based on positional importance as shown in FIGS. 3A3 and 3B3. The middle lines inside the boxes indicate the median and the lower and upper hinges correspond to the first and third quartiles. Each box extends to 1.5 times inter-quartile range (IQR) from upper and lower hinges respectively. Outliers are not shown. Only comparisons with significant difference are marked by stars (two-tailed, unpaired Welch's t test with Bonferroni correction).

FIG. 3D shows the LOGO plot results of Enrichment Motifs from a 5-mer enrichment analysis in adjacent nucleotides from the −3 to +7 position of the 5′ splice sites of the middle exon, and shows their most similar CNN Motifs from the CNN Model having the same Class Effect (e.g. inclusion, exclusion and unchanged) beneath them. Enrichment Motifs AAGGT (SEQ ID NO: 110) and AGTAA (SEQ ID NO: 109) were enriched in inclusion Class sequences detected in the 5-mer enrichment analysis. These Enrichment Motifs looked similar to inclusion Class sequences for CNN Motif 25 (AAGGT) (SEQ ID NO: 43) and CNN Motif 49 (CTGTA) (SEQ ID NO: 63) identified by the CNN model, respectively. Similarly, Enrichment Motif TTACA (SEQ ID NO: 105) was enriched in exclusion Class sequences detected in the 5-mer enrichment analysis. This Enrichment Motif looked similar to the exclusion Class sequence for CNN Motif 29 (TCGTG) (SEQ ID NO: 47) identified by the CNN model. Enrichment Motif AGGTA (SEQ ID NO: 106) was enriched in unchanged Class sequences detected in the 5-mer enrichment analysis. This Enrichment Motif looked similar to the unchanged Class sequence for CNN Motif 22 (AGGAN)(SEQ ID NO: 41) identified by the CNN model.

FIGS. 3E-3G Upper row: The length of the exon triplets cloned into minigenes constructs are shown. The flanking sequences of the 5′ splice sites of Exon X are shown in LOGO plots. The height of each nucleotide was estimated using in silico saturated mutagenesis, with the corresponding closely matched CNN Motifs indicated below the plots. The CPSF7 Minigene in FIG. 3E shows the wildtype 5′ splice site −6 to +6 sequence GATTAAgtgggt (SEQ ID NO: 2), correlated with Motif 25: AAGGT (SEQ ID NO: 43) and compared with the mutated 5′ splice site −6 to +6 sequence GATTAAGTAGGT (SEQ ID NO: 10), correlated with Motif 25: AAGGT (SEQ ID NO: 43) and Motif 49: CTGTA (SEQ ID NO: 63). The SETD5 Minigene in FIG. 3F shows the wildtype 5′ splice site −6 to +6 sequence CACTAGgtgaga (SEQ ID NO: 3), correlated with Motif 10: TGAGC (SEQ ID NO: 32) and Motif 21: GAGAG (SEQ ID NO: 40) and compared with the mutated 5′ splice site −6 to +6 sequence CACTAGgtgagc (SEQ ID NO: 11), correlated with Motif 10: TGAGC (SEQ ID NO: 32). The PARP6 Minigene in FIG. 3G shows the wildtype 5′ splice site −3 to +7 sequence CCAgtgagga (SEQ ID NO: 4), correlated with Motif 26: GATTA (SEQ ID NO: 44) and compared with the mutated 5′ splice site −3 to +7 sequence CCAgttagga (SEQ ID NO: 12), correlated with Motif 32: TTAAA (SEQ ID NO: 49). Middle row: Splicing changes for Exon X in both wildtype and mutated exon triplets, predicted by the CNN model (left) and measured by RT-PCR of the minigene (right). The RT-PCR experiments were performed in duplicate and independently repeated three times for each minigene to make the bar plots (two-tailed, unpaired Student's t test). Bottom row: Example of splicing changes induced by treatment with Compound (I) in the minigene splicing assays. The percentage for Exon X inclusion is indicated beneath each lane, from treated and untreated conditions in both wildtype and mutated minigenes. The upper bands indicate the isoforms in which Exon X is included while the lower bands indicate the isoforms in which Exon X is skipped. The statistical significance, as shown in FIGS. 3E-3G, was determined via two-tailed, unpaired Student's test: *p<0.05; **p<0.01; ***p<0.001.

FIGS. 4A-4F Identification of Compound (I) Targets

FIG. 4A shows the workflow for identification of potential therapeutic targets for Compound (I) as derived from ClinVar pathogenic mutations (CV-pMUTs). SpliceAI was applied to identify all ClinVar pathogenic mutations (CV-pMUTs) and the CNN model was used to determine whether counts per million (CPMs) disrupting annotated splice sites would be rescued by Compound (I) treatment (left). The bar plot shows the percentage of each filtered result out of the total number of disrupting annotated splice sites (right).

FIG. 4B shows the violin plot of the distance from either all CV-pMUTs or the CV-pMUTs disrupting annotated splicing to the closest splice junction. The y axis is in a log₁₀-transformed scale. Each violin shape shows the distribution of distance. The horizontal dashed line indicates 75 nucleotides from the closest splice junction. The significance of difference is determined using the Kolmogorov-Smirnov (K-S) test.

FIGS. 4C-4F Upper row: The sequences at the 5′ splice site of Exon X in patient cells and minigene constructs are shown (FIGS. 4C-4F). The sequences around the 5′ splice site of Exon X are shown in LOGO plots, with the closely matched CNN motifs indicated beneath the plots. The LIPA patient cell minigene in FIG. 4C shows the cell line mutated 5′ splice site −6 to +6 sequence AGCCAAgtaggc (SEQ ID NO: 107), correlated with Motif 25: AAGGT (SEQ ID NO: 43) and Motif 49: CTGTA (SEQ ID NO: 63). The CFTR patient cell minigene in FIG. 4D shows the cell line mutated 5′ splice site −6 to +6 sequence ATCCAAgtatgt (SEQ ID NO: 14), correlated with Motif 25: AAGGT (SEQ ID NO: 43) and Motif 49: CTGTA (SEQ ID NO: 63). The MLH1 patient cell minigene in FIG. 4E shows the cell line mutated 5′ splice site −5 to +6 sequence CTGAAGtcagt (SEQ ID NO: 15), correlated with Motif 18: AAGCT (SEQ ID NO: 38). The MAPT patient cell minigene in FIG. 4F shows the cell line mutated 5′ splice site −3 to +16 sequence AGTgtgagtccttcacat (SEQ ID NO: 108), correlated with Motif 44: NTGNN (SEQ ID NO: 56) and Motif 38: TATGT (SEQ ID NO: 54). The bar plots demonstrate the CNN model prediction of Compound (I) response for the mutated sequences. Middle row: RT-PCR experiments validated treatment responses in patient cell lines carrying specific splice site mutations. The upper bands indicate the isoform in which the middle Exon X is included while the lower bands indicate the isoform in which the middle Exon X is skipped. Each set of gels is one of the triplicates used to generate the bar plots beneath. Bottom row: The bar plots demonstrate the splicing change promoted by Compound (I) treatment. The statistical significance, as shown in FIGS. 4C-4F, was determined via two-tailed, unpaired Student's test: *p<0.05; **p<0.01; ***p<0.001.

FIGS. 5A-5C CNN Model Training Process

FIGS. 5A1-5A2 show details of the CNN model workflow. For each exon-triplet, as shown in FIG. 5A1, the sequences from UI₁, I₁X, XI₂and I₂D are concatenated and then one-hot coded. In the model, two rounds of convolution were applied before the hidden layer. Each round of convolution consists of a convolution layer of fifty filters, a ReLU activation layer and a max pooling layer of size 2. After two rounds of convolution, the output is converted connected to a hidden layer with 90% dropout rate. The output from the hidden layer shown in FIG. 5A2 is ReLU transformed again and is then linearly transformed into a vector of three, representing three different treatment responses. The final sigmoid nonlinearity maps each element in the vector to a value between 0 and 1, considered as the probability of Compound (I) responsiveness.

FIG. 5B shows the training progress of the CNN model. The x axis represents the number of Epochs iterated during training. The leftmost y axis shows loss score measured by binary entropy while the rightmost y axis shows the average AUC of prediction from three classes. The vertical dashed midline at approximately 12 Epochs on the x axis indicates the stop of training to avoid overfitting. The light grey negative slope plot line shows training loss and the darker grey negative slope plot line shows validation loss respectively along the growth of Epochs shown on the x-axis. The positive slope black plot line shows the improvement of AUC along the growth of Epochs shown on the x-axis.

FIG. 5C shows the AUC curves of prediction for each class using the test set. The x axis represents specificity while the y axis represents sensitivity. The grey negative slope diagonal line indicates the boundary beneath which the prediction is no better than a random guess. The AUC for inclusion, exclusion and unchanged response are shown as the rightmost grey plot line, the middle darker grey plot line and the leftmost black plot line adjacent to the grey diagonal line, respectively.

FIGS. 6A-6B: Motifs Identified by the CNN Model

FIGS. 6A1-6A7 show a heatmap of all CNN Motifs identified by the CNN Model. The color of the Drug Response Contribution in the gradience bar indicates the directional contribution of each motif. The right side domain (progressively shaded in the darker range from 0 to +1) indicates positive contribution while the left side domain (progressively shaded in the lighter range from 0 to −1) indicates negative contribution. The LOGO plot of each motif is shown on the left side of the heatmap, with the motif number shown on the right. The motif response is built in three columns.

FIGS. 6A1-6A2 indicate a Class Effect, having contribution toward the inclusion Class (darker positive range in left column).

FIGS. 6A3-6A5 indicate a Class Effect, having contribution toward the exclusion Class (darker positive range in middle column).

FIGS. 6A6-6A7 indicate a Class Effect, having contribution toward an unchanged Class (darker positive range in right column).

FIGS. 6B1-6B4 show a heatmap of motif importance at each 100 nucleotides in the UI₁, I₁X, XI₂and I₂D regions, each of which consists of 25 nucleotides in the exon and 75 nucleotides in the intron. Each thick vertical line shows the exon-intron boundary. The gradience bar indicates positional importance, as measured by positional activation in the first layer of the CNN model, where the right positive domain (shadowed) suggests the necessity of the motif and the left negative domain (shadowed) suggests the absence of the motif. Only the top twelve motifs are shown according to FIGS. 3A1-3A2. The motifs are grouped based on their response classification, representing inclusion (Motifs 18, 25 and 49), exclusion (Motifs 09, 10, 21, 29 and 47) and unchanged (Motifs 01, 22, 27 and 37).

FIGS. 7A-7G show the relative expression of full-length (FL) and Δ20 ELP1 mRNA (left panel), and ELP1 protein quantification (right panel) in brain (FIG. 7A) and liver (FIG. 7B) after oral doses of Compound (I) ranging from 10 to 100 mg/kg in adult transgenic TgFD9 mouse (n=4-6 mice in each treatment group). Comparisons were done within the same group, against the vehicle-treated mice. In the figure, *p<0.05; **p<0.01; ***p<0.001.

FIGS. 7C-E show the relative expression of full-length (FL) and Δ20 ELP1 mRNA (left graphs), and ELP1 protein quantification (right graphs) in kidney (FIG. 7C), heart (FIG. 7D) and skin (FIG. 7E) after oral doses of Compound (I) ranging from 10 to 100 mg/kg in adult transgenic TgFD9 mouse (n=4-6 mice in each treatment group). Comparisons were done within the same group, against the vehicle-treated mice. FIG. 7F shows weight assessment of TgFD9 mice in different treatment groups. FIG. 7G shows Compound (I) distribution in the brain, liver, kidney and plasma. The levels of compound were measured using mass spectrometry. In the figure, *p<0.05; **p<0.01; ***p<0.001.

FIG. 8A shows a western blot analysis of LIPA protein in patient fibroblasts carrying the c.894G>A mutation. The top and bottom panels show the blot probed with anti-LIPA and anti-β-Actin antibody, respectively.

FIG. 8B shows a bar chart providing a densitometric analysis of the western blot expressed as percentage of wild-type (WT). LIPA was normalized to β-Actin. To generate the bar plot, the experiment was performed in duplicate and independently repeated three times. The statistical significance is determined via two-tailed, unpaired Student's test: where * p<0.05; ** p<0.01; *** p<0.001.

FIG. 9A shows a western blot analysis of CFTR protein in 293-Flpin cells stably expressing WT-EMG-i14-il8 or c.2988G>A-EMG-i14-il8. 293Flpin cells with no endogenous expression of CFTR protein served as negative control. The top and bottom panels show the blot probed with anti-CFTR and anti-Na+K+ATPase antibody, respectively.

FIG. 9B shows a bar plot providing a densitometric analysis of the western blot expressed as percentage of mature CFTR protein, Band C. The amount of mature CFTR protein was normalized to Na+K+ATPase. To generate the bar plot, the experiment was performed in duplicate and independently repeated three times. the statistical significance is determined via two-tailed, unpaired Student's test: where * p<0.05; ** p<0.01; *** p<0.001.

FIG. 9C shows CFTR chloride channel analysis in CFBE-Flpin cells stably expressing c.2988G>A-EMG-i14-i18 with a representative tracing of short-circuit current (Isc) measurements recorded in Ussing chambers after treatment of cells with either DMSO (vehicle) or variable doses of Compound (I) for 72 h, as indicated by the labeled dose levels for the treatment response. Cells were mounted on Ussing chambers to measure CFTR mediated chloride channel. After stabilization of the basal current, forskolin (10 μM) was added to the basolateral chambers followed by CFTR potentiator, Ivacaftor (10 μM), and CFTR Inhibitor 172 (10 μM) added to the apical chambers.

FIG. 9D shows a stacked bar graph indicating recovery of CFTR function upon treatment of cells with Compound (I). Change in Isc (ΔIsc), a measure of CFTR function, was defined as the current inhibited by Inh-172 after sustained Isc responses were achieved upon stimulation with forskolin alone, indicated by a dark stack within each bar or sequentially with ivacaftor, indicated by a white stack within each bar (n=2 Isc measurements per treatment). The statistical significance is determined via one-way ANOVA when compared with forskolin stimulated CFTR function in DMSO (vehicle) treated cells: where * p<0.05; ** p<0.01; *** p<0.001.

FIGS. 10A-10F show the results of an in silico saturation mutagenesis analysis on selected 100-mer portions of interrogated 400-mer sequences of interest. The indices of the selected sequences in the XI₂boundary are provided. Each plot includes three parts: 1. The wild-type sequence where letter heights indicate the importance of each nucleotide: The taller the letter, the more important the wild-type nucleotide; 2. A heatmap showing the changes of prediction score (probability of drug response) from the CNN Model when a nucleotide is mutated into the other three nucleotide alternatives: the darker the color, the stronger the change of the prediction score; and, 3. A curve plot demonstrating the highest gain (black line) and loss (grey line) of prediction score (probability of drug response) at each position. FIGS. 10A and 10B represent the XI₂regions of two Motif sequences known to have an inclusion Class drug response, respectively. FIGS. 10C and 10D represent the XI₂regions of two Motif sequences known to have an exclusion Class drug response, respectively. FIGS. 10E and 10F represent the XI₂regions of two Motif sequences known to have an unchanged Class drug response, respectively. The results of this analysis on sequences known to have a particular Class Effect confirm the usefulness of the CNN Model to accurately predict and identify sequences capable of splicing modulation by a small molecule SMC.

FIG. 11 shows a heatmap of Pearson correlation between the Enrichment Motif (each row) in adjacent nucleotides from the −3 to +7 position of the 5′ splice sites of the middle exon and 39 CNN motifs (each column). The range for positive and negative correlation is from 0 to 0.5 and from 0 to −0.5, respectively, where the lightest color indicates a neutral correlation and the progressively darker color toward a positive or negative correlation indicates a progressively stronger correlation. For example, Enrichment Motif AAGGT (SEQ ID NO: 110), known to have an exon inclusion Effect, has the highest average Positive correlation to CNN Motifs (18, 25, 26, 28, 32 and 49) that have a predictive contribution toward an exon inclusion Effect. Enrichment Motif TTACA (SEQ ID NO: 105), known to have an exon exclusion Effect, has the highest average Positive correlation to CNN Motifs (01, 02, 03, 04, 05, 09, 10, 12, 17, 20, 21, 29, 38, 40, 41, 42, 43, 44 and 47) that have a predictive contribution toward an exon exclusion Effect. Enrichment Motif AGGTA (SEQ ID NO: 106), enriched in sequences known to have an unchanged exon Effect against drug treatment, has the highest average correlation with CNN motifs (06, 14, 15, 16, 22, 23, 27, 31, 33, 34, 35, 37, 46 and 48) for no treatment response. Comparatively, Enrichment Motif AGTAA (SEQ ID NO: 109), known to have an exon inclusion Effect, has the highest average correlation with CNN motifs that are responsible for no drug response. This result suggests a potentially false-positive Enrichment Motif detected during the enrichment analysis, where evenly distributed nucleotides A, C, T and G were used as background. Notably, the human genome is biased towards the presence of GTAA (SEQ ID NO: 169), in the +1 to +4 position of the 5′ splice site, thus suggesting Enrichment Motif AGTAA (SEQ ID NO: 109) is close to random. These observations suggest the CNN Model is more capable of efficiently identifying motifs amenable to splicing modulation in the presence of a small molecule SMC, with additional prediction power, than slower classical methods.

FIG. 12A shows the AUCs for the different treatment responses obtained from 1,000 random-initiated CNN models. The diamond indicates the performance of the CNN Model described herein.

FIG. 12B shows the distribution of Pearson correlation between the Motifs shown in FIGS. 3B1-3B2 in the CNN Model described herein and predictive motifs having similar rates of probability in each of the 1,000 random-initiated CNN models.

DETAILED DESCRIPTION

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(SEQ ID NO: 1)

CAAgtaagt,

(SEQ ID NO: 2)

GATTAAgtgggt,

(SEQ ID NO: 3)

CACTAGgtgaga,

and

(SEQ ID NO: 4)

CCAgtgagga.

Another aspect described herein is Compound (I) for use in the method, wherein the 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of:

(SEQ ID NO: 5)

CAAguaagu,

(SEQ ID NO: 6)

GAUUAAgugggu,

(SEQ ID NO: 7)

CACUAGgugaga,

and

(SEQ ID NO: 8)

CCAgugagga.

(SEQ ID NO: 9)

CAAgtaagc,

(SEQ ID NO: 10)

GATTAAgtaggt,

(SEQ ID NO: 11)

CACTAGgtgagc,

(SEQ ID NO: 12)

CCAgttagga,

(SEQ ID NO: 13)

AGCCAAgtatgt,

(SEQ ID NO: 14)

ATCCAAgtatgt,

(SEQ ID NO: 15)

CTGAAgtcagt,

and

(SEQ ID NO: 16)

AGTgtaagta.

Another aspect described herein is Compound (I) for use in the method, wherein the 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of:

(SEQ ID NO: 17)

CAAguaagc,

(SEQ ID NO: 18)

GAUUAAguaggu,

(SEQ ID NO: 19)

CACUAGgugagc,

(SEQ ID NO: 20)

CCAguuagga,

(SEQ ID NO: 21)

AGCCAAguaugu,

(SEQ ID NO: 22)

AUCCAAguaugu,

(SEQ ID NO: 23)

CUGAAgucagu,

and

(SEQ ID NO: 24)

AGUguaagua.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

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wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from a gene transcript in a cell.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Table 14 and 15.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Table 14.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is other than the gene selected from the group consisting of Table 15.

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Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from comprises, a sequence the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence s nucleotide sequences of the predicted gene transcript are the 5′ splice site of Exon 2 is selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 14 and 15.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 14.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is other than the gene selected from the group consisting of Table 15.

Methods of Modulating Wildtype Gene Isoforms

One aspect described herein is Compound (I) for use in a method to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Table 1 lists wildtype genes identified by RNA sequencing and mutated genes predicted by SpliceAI scores and the CNN model, as described herein, which may be modulated by Compound (I) toward either or both exon inclusion and exon exclusion.

TABLE 1

A1BG-AS1, AAAS, ABCA1, ABCA4, ABCA6,

ABCA9, ABCB6, ABCC3, ABCC9,

ABHD14A-ACY1, ABI1, ABI2, ABI3BP, AC024560.3,

AC027612.6, AC037459.4, ACAA1,

ACACA, ACAD10, ACADSB, ACBD4, ACBD5,

ACIN1, ACLY, ACOX1, ACSL3, ACSL4,

ACTN1, ACY1, AD000671.6, ADA, ADAM10,

ADAM33, ADAMTSL4, ADARB1, ADK,

AFMID, AGK, AHI1, AKAP11, AKAP13, AKIP1,

AKR1A1, AL163636.6, ALDH3A2,

ALDH3B1, ALDH4A1, ALKBH1, ALKBH3,

ALMS1, AMMECR1L, AMPD2, ANK2,

ANKRD10, ANKRD11, ANKRD36, ANO6,

ANTXR2, ANXA2, AP1G1, AP2M1, APBB2,

APC, APOL1, APP, ARHGAP12, ARHGAP23,

ARHGEF10, ARHGEF10L, ARHGEF12,

ARHGEF25, ARID4B, ARIH2, ARMC9,

ARSK, ASAH1, ASAP2, ASCC2, ASL, ASPH,

ASPM, ASUN, ASXL1, ATG10, ATG16L1,

ATG7, ATG9A, ATM, ATP2C1, ATP5SL,

ATPAF1, ATRX, ATXN1, ATXN3, AUP1,

AUTS2, AVL9, B3GALNT1, BAG6, BANP,

BAX, BAZ1A, BBS4, BBS5, BBX, BCAR1, BCOR,

BFSP1, BIN1, BIRC6, BLOC1S6,

BMP2K, BMPR2, BOK, BPTF, BRCA1,

BRCA2, BRD8, BRIP1, BROX, BTBD19,

C11orf30, C11orf70, C12orf29, C16orf13,

C1orf85, C1RL, C2CD5, C3orf18, C5orf42,

C5orf45, C8orf59, C9orf156, C9orf85, CA5A,

CA5BP1, CALU, CAMK2D, CAMTA1,

CAPN3, CAPN7, CAPRIN2, CARD8,

CARKD, CASP3, CAST, CCBL2, CCDC25,

CCDC90B, CCNDBP1, CCNL1, CD3D, CD44,

CD46, CD55, CD99P1, CDAN1, CDC14B,

CDC16, CDH1, CDH23, CDK16, CEP290, CERKL,

CFTR, CHD3, CHD7, CHEK2, CHKB,

CKLF, CLASP1, CLCN1, CLCN6, CLK1,

CLMP, CLN3, CMC1, CNGB3, CNOT10, COG6,

COL11A1, COL12A1, COL16A1, COL3A1,

COL4A3, COL4A5, COL5A2, COL6A1,

COL6A3, COL7A1, COPB2, COPS7A, COPS8,

COQ6, COX20, CPEB2, CPSF7, CPT1C,

CRAT, CREBBP, CRLS1, CRNDE, CRYZ,

CSAD, CSTB, CTDSPL, CTNS, CTSK, CTU2,

CUBN, CUTC, CWC25, CWC27, CYB561D2,

CYBB, CYLD, CYP20A1, DAB2, DBT,

DCAF10, DCAF11, DCAF17, DCAF8, DCP1A,

DCUN1D5, DCX, DCX, DDB2, DGKA,

DGKE, DGUOK, DHRSX, DIMT1, DIS3,

DLG1, DMD, DMTF1, DNAH5, DNAH9,

DNAJC19, DNAJC2, DNM1L, DNMT1,

DOCK5, DOCK7, DPH3, DPY19L4, DRAM2,

DSCR3, DTNBP1, DUSP11, DUSP22, DYNC2H1,

DYNC2LI1, EBF3, EBP, EBPL, EDC3,

EDEM2, EDRF1, EFEMP1, EHBP1, EHMT2,

EIF4A2, EIF4E2, EIF4H, ELK1, ELN,

ELOVL1, ENC1, ENOSF1, EP300, EPB41L1,

EPB41L2, ERBB2IP, ERCC6, ERLEC1,

ERMAP, ETHE1, EVC, EVI5L, F10, F13A1, F8,

FAM104A, FAM111A, FAM134C,

FAM149B1, FAM172A, FAM204A, FAM211A-

AS1, FAM21C, FAP, FBN1, FBXL12,

FBXL3, FBXO25, FBXW11, FGF5, FGFR1OP,

FHL2, FIG4, FIP1L1, FLAD1, FLNA, FLT3,

FN1, FNBP4, FNIP2, FOXN3, FRYL, FUT8,

FXR2, FYN, G6PC, GAA, GAB1, GABPB2,

GABRE, GABRG2, GALNS, GCK, GFPT2,

GGCT, GIT2, GK, GLA, GLS, GNB5,

GNPTAB, GOLGA4, GOLGB1, GOLT1B,

GPR133, GPR143, GPR180, GPX4, GRHPR,

GRIPAP1, GRN, GTF2I, GTF3A, GUCY2C, GUF1,

GUSB, GYPA, HACL1, HAUS7, HBB,

HCFC1R1, HDAC10, HDAC7, HECTD3,

HERC3, HFE, HIPK3, HMGXB4, HNRNPA2B1,

HNRNPD, HNRNPDL, HPS1, HSD17B4, HSF2,

HUWE1, IDH1, IFT57, IFT88, IGF2BP2,

IL15RA, IL36RN, INF2, ING4, INO80E, INPP1,

IP6K2, IPO8, IQCB1, IRAK4, ISOC2,

IST1, ITGB1BP1, KATNBL1, KDM4C,

KDM5A, KDSR, KIAA0100, KIAA0586,

KIAA1109, KIF14, KIF3A, KIT, KITLG, KLC1,

KMT2D, KRIT1, KTN1, L3HYPDH,

LACC1, LAMB3, LAMTOR3, LAS1L, LDLR,

LENG8, LETMD1, LGALS8, LHCGR,

LINC00963, LIPA, LMAN2L, LMNA, LMO7,

LONRF1, LOXL3, LPHN2, LPIN1, LRCH3,

LRRC28, LRRC32, LSM1, LTA4H, LTBP1,

LTBP3, LTBP4, LUC7L, LYPLAL1, LYRM7,

LZTFL1, MACF1, MADD, MAGOHB,

MAN2C1, MAP3K3, MAP4K4, MAPK11,

MAPK12, MAPKAP1, MAPT, MARK3,

MBD5, MBNL1, MBOAT2, MCFD2, ME3,

MED13, MED15, MEG3, MEGF6, METAP1,

METTL14, MFF, MFSD12, MGEA5, MGST2,

MINK1, MIR22HG, MKS1, MLF1, MLH1,

MLLT6, MLST8, MMAB, MMP19, MORF4L2,

MOSPD1, MPC1, MPDZ, MPI, MPV17,

MRPL33, MSH2, MSRB3, MTCH2, MTM1,

MTMR2, MTMR3, MTMR6, MTRR, MTSS1L,

MYBL1, MYBPC3, MYCBP2, MYEF2,

MYLK, MYNN, MYO18A, MYO19, MYO1B,

MYO5A, MYO7A, NABP1, NADK2, NAE1,

NBN, NEK1, NEO1, NEXN, NF1, NF2,

NFE2L1, NIPA2, NIPBL, NLRC5, NLRX1,

NPEPPS, NPHP1, NPR2, NPRL3, NR3C2,

NRG1, NSD1, NSFL1C, NSMCE2, NSUN4,

NT5C2, NUB1, NUP43, NUP62, NUPL2,

NUTM2A-AS1, OARD1, OCA2, OCRL, ODF2,

ODF2L, OFD1, OGT, OPTN, ORC6, ORMDL1,

OS9, OSBPL8, OTC, OTOGL, PACRGL,

PAFAH1B1, PAH, PAM, PARD3, PARL, PARN,

PARP11, PARP6, PATL1, PCBP2, PCID2,

PCM1, PCNXL2, PCNXL4, PCYT2, PDCD10,

PDE4DIP, PDLIM2, PDZD11, PEAK1,

PEX1, PEX11A, PEX5, PFDN1, PFDN6, PFKM,

PHC3, PHKG2, PHLDB1, PI4KB, PIGG,

PIGN, PIGT, PIK3C2A, PIKFYVE, PILRB,

PIN1, PKIG, PLA2G12A, PLA2R1, PLAGL1,

PLBD2, PMS2, PMS2P3, PNPLA8, PODNL1,

POLG, POLR3GL, POMGNT1, PPAP2A,

PPFIBP1, PPIL3, PPIP5K2, PPM1M, PPP1R12A,

PPP1R21, PPP2R3C, PPP3CB, PPP3CC,

PPP4C, PPP6R2, PPRC1, PPT1, PREB, PREPL,

PRKAG1, PRMT2, PRMT7, PRPF39,

PRPF40B, PRR16, PRR4, PRRX1, PRUNE,

PSME4, PTEN, PTPN13, PTPN21, PTPN23,

PTPN4, PTPRA, PVR, PXDN, QTRTD1, R3HCC1L,

R3HDM4, RAB11FIP2, RABEPK,

RAD1, RAD51B, RAD51C, RALGPS2, RALY,

RB1, RBBP9, RBCK1, RBM41, RCOR3,

REPS1, REV3L, RFWD2, RGL2, RGN, RHAG,

RHBDD2, RHOBTB1, RHOT1, RIF1,

RIPK2, RNASE4, RNF146, RNF170, RNF214,

RNF216, RNF34, RNFT1, ROBO1, RP11-

1055B8.7, RP11-14N7.2, RP11-274B21.1,

RP11-33B1.1, RP11-383H13.1, RP11-773D16.1,

RP13-279N23.2, RPAIN, RPL7L1, RPP14,

RPS6KB2, RRBP1, RSU1, RTEL1, RTEL1-

TNFRSF6B, RTTN, RUFY2, RWDD1, RWDD2B,

RWDD4, SBF1, SCMH1, SCN1A,

SCN5A, SDCCAG8, SDHD, SEC31B, SECISBP2L,

SEMA4F, SENP1, SENP6, SERAC1,

SETD5, SETX, SFXN4, SGSM3, SH3D19,

SHMT2, SIPA1L1, SLC10A7, SLC12A1,

SLC15A4, SLC22A17, SLC25A17, SLC25A32,

SLC25A36, SLC35A1, SLC35A3,

SLC35D2, SLC37A3, SLC38A2, SLC38A6,

SLC4A11, SLC4A7, SLC5A6, SLC7A6,

SLC9B2, SLIT2, SLMAP, SLMO1, SLTM,

SMAD5, SMARCA1, SMARCD1, SMC5,

SMEK2, SMPDL3A, SMS, SMURF2, SNAPC5,

SNED1, SNHG14, SNHG15, SNRNP70,

SNRPA1, SNRPG, SNX10, SNX14, SNX21,

SPAST, SPATA20, SPATA7, SPDL1, SPG11,

SPPL2A, SPTA1, SPTAN1, SPTB, SRD5A2,

ST6GALNAC6, ST7, STARD3NL, STARD5,

STAT6, STK11, STK16, STK19, STK40,

STRA13, STRADA, STRN3, STX16, STX16-

NPEPL1, STX3, STXBP1, STXBP3, STYXL1,

SUCO, SUGP2, SUGT1, SULF1, SUN2,

SUPT20H, SYNGAP1, SYNRG, TAF1, TAF2,

TANGO2, TARBP2, TAS2R14, TAZ,

TBC1D14, TBC1D17, TBC1D25, TBC1D5,

TBCK, TBPL1, TBX15, TCERG1, TCIRG1,

TEAD2, TECTA, TEP1, TFDP1, TFDP2,

TFPI, TFR2, TGFBR2, THAP6, THAP9-AS1,

THBS3, THOC2, TIA1, TIAL1, TIMM17B,

TIMM21, TJP2, TM7SF3, TMCO4, TMEM11,

TMEM120A, TMEM126B, TMEM138,

TMEM18, TMEM194A, TMEM234, TMEM260,

TMEM39B, TMEM62, TMOD2, TMPRSS6,

TMUB2, TMX3, TOM1, TP53, TP53INP1,

TP53TG1, TPD52L1, TPD52L2, TPO, TPRA1,

TPT1-AS1, TRAPPC12, TRAPPC2, TREX2,

TRIM16, TRIM37, TRIM65, TRIO, TRIP10,

TRIP12, TROVE2, TRPC1, TRPM4, TRPT1,

TSEN15, TSR1, TSTD3, TUBG2, TULP3,

TXNDC11, TXNL4A, TYR, U2AF1L4, UACA,

UBA7, UBE2A, UBE2D1, UBN2, UBP1,

UBQLN1, UFD1L, UNC5B, URGCP, UROD,

USMG5, USP24, USP25, USP33, USP53,

USP8, VAMP7, VCAN, VEZT, VMA21, VPS13B,

VPS29, WBP1, WDFY2, WDR35, WDR73, XDTP53,

XPC, YEATS2, YIPF1, YME1L1,

YY1AP1, ZBTB8OS, ZC2HC1A, ZC3H11A,

ZCCHC6, ZCCHC8, ZDHHC16, ZDHHC20,

ZDHHC7, ZFAND1, ZFAND5, ZFAS1, ZMIZ1,

ZMYM4, ZMYM5, ZNF160, ZNF207,

ZNF248, ZNF280D, ZNF384, ZNF512,

ZNF516, ZNF532, ZNF720, and ZZZ3.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a wildtype gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a mutant gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a wildtype gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a wildtype gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a mutant gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a mutant gene transcript comprising, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) increases exon inclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) increases exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

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wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from a gene transcript in a cell, and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 1.

One aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 1.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 1.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 1.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 1.

Table 2 lists wildtype genes identified by RNA sequencing and mutated genes predicted by SpliceAI scores and the CNN model, as described herein, which may be modulated by Compound (I) toward both exon inclusion and exon exclusion.

TABLE 2

ASPH, BBS4, BPTF, BRCA1, BRIP1, CD46,

CDC14B, COL6A3, DIS3, DMD, DNM1L,

DRAM2, DYNC2H1, FAM172A, FBN1, FIP1L1,

GIT2, GLS, KLC1, LMAN2L, LPHN2,

MACF1, MAPT, MEG3, MFF, MLH1, MOSPD1,

MSRB3, MTMR2, MYLK, MYNN, MYO5A, OPTN, OTC,

RPAIN, SDCCAG8, SIPA1L1, SLC38A6, SUPT20H, TBCK,

TSEN15, and ZNF207.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in a method to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in a method to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof, wherein the method comprises, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 2.

Another aspect described herein is Compound (I) for use in a method to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof, wherein the method comprises, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 2.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 2.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 2.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 2.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 2.

Table 3 lists wildtype genes identified by RNA sequencing, as described herein, that may be modulated by Compound (I) toward either or both exon inclusion and exon exclusion.

TABLE 3

A1BG-AS1, AAAS, ABCA1, ABCA6, ABCA9,

ABCB6, ABCC3, ABHD14A-ACY1, ABI1,

ABI2, ABI3BP, AC024560.3, AC027612.6,

AC037459.4, ACAA1, ACACA, ACAD10,

ACBD4, ACBD5, ACIN1, ACLY, ACOX1, ACSL3,

ACSL4, ACTN1, ACY1, AD000671.6,

ADA, ADAM33, ADAMTSL4, ADARB1, ADK,

AFMID, AHI1, AKAP11, AKAP13,

AKIP1, AKR1A1, AL163636.6, ALDH3B1, ALDH4A1,

ALKBH1, ALKBH3, AMMECR1L,

AMPD2, ANK2, ANKRD10, ANKRD11,

ANKRD36, ANO6, ANXA2, AP1G1, AP2M1,

APBB2, APOL1, APP, ARHGAP12, ARHGAP23,

ARHGEF10, ARHGEF10L, ARHGEF12,

ARHGEF25, ARID4B, ARIH2, ARSK,

ASAP2, ASCC2, ASL, ASPH, ASUN, ASXL1,

ATG10, ATG16L1, ATG7, ATG9A, ATP2C1,

ATP5SL, ATPAF1, ATXN1, ATXN3, AUP1,

AUTS2, AVL9, B3GALNT1, BAG6, BANP,

BAX, BAZ1A, BBS4, BBS5, BBX, BCAR1,

BCOR, BIN1, BIRC6, BLOC1S6, BMP2K,

BOK, BPTF, BRD8, BROX, BTBD19, C11orf30,

C11orf70, C12orf29, C16orf13, C1orf85, C1RL,

C2CD5, C3orf18, C5orf42, C5orf45,

C8orf59, C9orf156, C9orf85, CA5BP1,

CALU, CAMK2D, CAMTA1, CAPN7, CAPRIN2,

CARD8, CARKD, CASP3, CAST, CCBL2,

CCDC25, CCDC90B, CCNDBP1, CCNL1,

CD44, CD46, CD55, CD99P1, CDC14B,

CDC16, CDK16, CEP290, CHD3, CHEK2, CHKB,

CKLF, CLASP1, CLCN6, CLK1, CMC1,

CNOT10, COL12A1, COL16A1, COL6A3,

COPB2, COPS7A, COPS8, COQ6, COX20,

CPEB2, CPSF7, CPT1C, CRAT, CREBBP,

CRLS1, CRNDE, CRYZ, CSAD, CTDSPL,

CUTC, CWC25, CYB561D2, CYLD, CYP20A1,

DAB2, DBT, DCAF10, DCAF11, DCAF17,

DCAF8, DCP1A, DCUN1D5, DDB2, DGKA,

DHRSX, DIMT1, DIS3, DLG1, DMD, DMTF1,

DNAJC19, DNAJC2, DNM1L, DNMT1,

DOCK5, DOCK7, DPH3, DPY19L4, DRAM2,

DSCR3, DTNBP1, DUSP11, DUSP22,

DYNC2H1, EBPL, EDC3, EDEM2, EDRF1,

EFEMP1, EHBP1, EHMT2, EIF4A2, EIF4E2,

EIF4H, ELK1, ELN, ELOVL1, ENC1,

ENOSF1, EPB41L1, EPB41L2, ERBB2IP, ERLEC1,

ERMAP, ETHE1, EVC, EVI5L, FAM104A,

FAM111A, FAM134C, FAM149B1, FAM172A,

FAM204A, FAM211A-AS1, FAM21C, FAP,

FBXL12, FBXL3, FBXO25, FBXW11, FGF5,

FGFR1OP, FHL2, FIP1L1, FLAD1, FLNA, FN1,

FNBP4, FNIP2, FOXN3, FRYL, FUT8,

FXR2, FYN, GAB1, GABPB2, GABRE, GALNS,

GFPT2, GGCT, GIT2, GK, GLS,

GOLGA4, GOLGB1, GOLT1B, GPR133,

GPR180, GRIPAP1, GTF2I, GTF3A, GUF1,

GUSB, HACL1, HAUS7, HCFC1R1, HDAC10,

HDAC7, HECTD3, HERC3, HIPK3,

HMGXB4, HNRNPA2B1, HNRNPD, HNRNPDL,

HPS1, HSD17B4, HSF2, HUWE1, IFT88,

IGF2BP2, IL15RA, INF2, ING4, INO80E, INPP1,

IP6K2, IPO8, IQCB1, IRAK4, ISOC2,

IST1, ITGB1BP1, KATNBL1, KDM4C,

KDM5A, KIAA0100, KIF3A, KITLG, KLC1,

KTN1, L3HYPDH, LACC1, LAMTOR3, LAS1L,

LENG8, LETMD1, LGALS8, LINC00963,

LMAN2L, LMO7, LONRF1, LOXL3,

LPHN2, LPIN1, LRCH3, LRRC28, LRRC32, LSM1,

LTA4H, LTBP1, LTBP3, LTBP4, LUC7L,

LYPLAL1, LYRM7, LZTFL1, MACF1, MADD,

MAGOHB, MAN2C1, MAP3K3, MAP4K4,

MAPK11, MAPK12, MAPKAP1, MARK3,

MBD5, MBNL1, MBOAT2, ME3, MED13,

MED15, MEG3, MEG3, MEGF6, METAP1,

METTL14, MFF, MFSD12, MGEA5,

MGST2, MINK1, MIR22HG, MKS1, MLF1, MLH1,

MLLT6, MLST8, MMP19, MORF4L2, MOSPD1,

MPDZ, MPI, MPV17, MRPL33, MSRB3,

MSRB3, MTCH2, MTMR2, MTMR3,

MTMR6, MTRR, MTSS1L, MYBL1, MYCBP2,

MYEF2, MYLK, MYNN, MYO18A, MYO19,

MYO1B, MYO5A, NABP1, NADK2, NAE1,

NBN, NEK1, NEO1, NEXN, NF2, NFE2L1,

NIPA2, NLRC5, NLRX1, NPEPPS, NPR2,

NPRL3, NRG1, NSFL1C, NSMCE2, NSUN4,

NT5C2, NUB1, NUP43, NUP62, NUPL2,

NUTM2A-AS1, OARD1, OCRL, ODF2,

ODF2L, OFD1, OPTN, ORMDL1, OS9, OSBPL8,

PACRGL, PAM, PARD3, PARL, PARP11,

PARP6, PATL1, PCBP2, PCID2, PCM1,

PCNXL2, PCNXL4, PCYT2, PDE4DIP,

PDLIM2, PDZD11, PEAK1, PEX1, PEX11A,

PEX5, PFDN1, PFDN6, PFKM, PHC3, PHKG2,

PHLDB1, PI4KB, PIGG, PIGN, PIGT,

PIK3C2A, PIKFYVE, PILRB, PIN1, PKIG,

PLA2G12A, PLA2R1, PLAGL1, PLBD2,

PMS2P3, PNPLA8, PODNL1, POLR3GL, PPAP2A,

PPFIBP1, PPIL3, PPIP5K2, PPM1M,

PPP1R12A, PPP1R21, PPP2R3C, PPP3CB, PPP3CC,

PPP4C, PPP6R2, PPRC1, PREB,

PREPL, PRKAG1, PRMT2, PRPF39, PRPF40B,

PRR16, PRR4, PRRX1, PRUNE, PSME4,

PTPN13, PTPN21, PTPN23, PTPN4, PTPRA, PVR,

PXDN, QTRTD1, R3HCC1L, R3HDM4,

RAB11FIP2, RABEPK, RAD1, RALGPS2,

RALY, RBBP9, RBCK1, RBM41, RCOR3,

REPS1, REV3L, RFWD2, RGL2, RGN, RHBDD2,

RHOBTB1, RHOT1, RIF1, RIPK2,

RNASE4, RNF146, RNF170, RNF214, RNF34,

RNFT1, ROBO1, RP11-1055B8.7, RP11-

14N7.2, RP11-274B21.1, RP11-33B1.1, RP11-

383H13.1, RP11-773D16.1, RP13-279N23.2,

RPAIN, RPL7L1, RPP14, RPS6KB2, RRBP1,

RSU1, RTEL1, RTEL1-TNFRSF6B, RUFY2,

RWDD1, RWDD2B, RWDD4, SBF1, SCMH1,

SDCCAG8, SEC31B, SECISBP2L,

SEMA4F, SENP1, SENP6, SERAC1, SETD5,

SETX, SFXN4, SGSM3, SH3D19, SHMT2,

SIPA1L1, SLC15A4, SLC22A17, SLC25A17,

SLC25A32, SLC25A36, SLC35A1, SLC35A3,

SLC35D2, SLC37A3, SLC38A2, SLC38A6, SLC4A7,

SLC5A6, SLC7A6, SLC9B2, SLIT2,

SLMAP, SLMO1, SLTM, SMAD5, SMARCA1,

SMARCD1, SMC5, SMEK2, SMPDL3A,

SMURF2, SNAPC5, SNED1, SNHG14, SNHG15,

SNRNP70, SNRPA1, SNRPG, SNX14,

SNX21, SPATA20, SPATA7, SPDL1,

SPPL2A, SPTAN1, ST6GALNAC6, ST7,

STARD3NL, STARD5, STAT6, STK16, STK19,

STK40, STRA13, STRADA, STRN3,

STX16, STX16-NPEPL1, STX3, STXBP3,

STYXL1, SUCO, SUGP2, SUGT1, SULF1,

SUN2, SUPT20H, SYNRG, TAF1, TAF2,

TANGO2, TARBP2, TAS2R14, TAZ, TBC1D14,

TBC1D17, TBC1D25, TBC1D5, TBCK, TBPL1,

TBX15, TCERG1, TEAD2, TEP1, TFDP1,

TFDP2, TFPI, TGFBR2, THAP6, THAP9-AS1,

THBS3, THOC2, TIA1, TIAL1, TIMM17B,

TIMM21, TM7SF3, TMCO4, TMEM11,

TMEM120A, TMEM126B, TMEM18,

TMEM194A, TMEM234, TMEM260, TMEM39B,

TMEM62, TMOD2, TMUB2, TMX3,

TOM1, TP53INP1, TP53TG1, TPD52L1,

TPD52L2, TPRA1, TPT1-AS1, TRAPPC12,

TREX2, TRIM16, TRIM65, TRIO, TRIP10,

TRIP12, TROVE2, TRPC1, TRPM4, TRPT1,

TSEN15, TSR1, TSTD3, TUBG2, TULP3,

TXNDC11, TXNL4A, U2AF1L4, UACA, UBA7,

UBE2A, UBE2D1, UBN2, UBP1, UBQLN1,

UFD1L, UNC5B, URGCP, USMG5, USP24,

USP25, USP33, USP53, USP8, VAMP7, VCAN,

VEZT, VPS29, WBP1, WDFY2, YEATS2,

YIPF1, YME1L1, YY1AP1, ZBTB8OS,

ZC2HC1A, ZC3H11A, ZCCHC6, ZCCHC8,

ZDHHC16, ZDHHC20, ZDHHC7, ZFAND1,

ZFAND5, ZFAS1, ZMIZ1, ZMYM4, ZMYM5,

ZNF160, ZNF207, ZNF248, ZNF280D, ZNF384,

ZNF512, ZNF516, ZNF532, ZNF720, and ZZZ3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO: 2), and CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CTGAAgtcagt (SEQ ID NO: 15), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from CUGAAgucagu (SEQ ID NO: 23), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 3.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 3.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO: 2), and CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CTGAAgtcagt (SEQ ID NO: 15), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from CUGAAgucagu (SEQ ID NO: 23), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 3.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 3.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 3.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 3.

Methods of Modulating Mutated Gene Isoforms

Table 4 lists mutated genes predicted by SpliceAI scores and the CNN Model, as described herein, that may be modulated by Compound (I) toward either or both exon inclusion and exon exclusion.

TABLE 4

ABCA4, ABCC9, ACADSB, ADAM10, AGK,

ALDH3A2, ALMS1, ANTXR2, APC,

ARMC9, ASAH1, ASPM, ATM, ATRX, BBS4,

BFSP1, BMPR2, BRCA1, BRCA2, BRIP1,

CA5A, CAPN3, CD3D, CDAN1, CDH1, CDH23,

CERKL, CFTR, CHD7, CLCN1, CLMP,

CLN3, CNGB3, COG6, COL11A1, COL3A1,

COL4A3, COL4A5, COL5A2, COL6A1,

COL7A1, CSTB, CTNS, CTSK, CTU2, CUBN,

CWC27, CYBB, DCX, DGKE, DGUOK,

DMD, DNAH5, DNAH9, DYNC2H1, DYNC2LI1,

EBF3, EBP, EP300, ERCC6, F10, F13A1,

F8, FBN1, FIG4, FLT3, FUT8, G6PC, GAA,

GABRG2, GCK, GLA, GNB5, GNPTAB,

GPR143, GPX4, GRHPR, GRN, GUCY2C,

GYPA, HBB, HFE, IDH1, IFT57, IL36RN,

KDSR, KIAA0586, KIAA1109, KIF14, KIT,

KMT2D, KRIT1, LAMB3, LDLR, LHCGR,

LIPA, LMNA, MAPT, MCFD2, MLH1, MMAB,

MPC1, MSH2, MTM1, MYBPC3,

MYO7A, NF1, NIPBL, NPHP1, NR3C2, NSD1,

OCA2, OFD1, OGT, ORC6, OTC, OTOGL,

PAFAH1B1, PAH, PARN, PDCD10, PIGN,

PMS2, POLG, POMGNT1, PPT1, PRMT7,

PTEN, RAD51B, RAD51C, RB1, RHAG, RNF216,

RTTN, SCN1A, SCN5A, SDCCAG8,

SDHD, SLC10A7, SLC12A1, SLC4A11, SMS,

SNX10, SPAST, SPG11, SPTA1, SPTB,

SRD5A2, STK11, STXBP1, SYNGAP1,

TCIRG1, TECTA, TFR2, TGFBR2, TJP2,

TMEM138, TMPRSS6, TP53, TPO, TRAPPC2,

TRIM37, TYR, UROD, VMA21, VPS13B,

WDR35, WDR73, and XPC.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 4.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 4.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 4.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 4.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 4.

Methods of Modulating Wildtype Gene Isoforms

Table 5 lists wildtype genes identified by RNA sequencing, as described herein, that may be modulated by Compound (I) toward exon inclusion.

TABLE 5

ABI1, ABI2, AC027612.6, ACBD5, ACIN1,

ACLY, ACOX1, ACSL3, AFMID, AHI1,

AKAP13, AL163636.6, ANKRD11, ANXA2,

AP1G1, ARHGAP12, ARHGEF10, ARSK,

ASAP2, ASPH, ATG10, ATP2C1, ATP5SL,

B3GALNT1, BANP, BBX, BPTF, BROX,

C11orf30, C12orf29, C2CD5, C3orf18, C5orf45,

C8orf59, C9orf156, CA5BP1, CALU,

CAMTA1, CASP3, CCBL2, CD44, CD46,

CDC14B, CDK16, CEP290, CLASP1, CLK1,

CMC1, COL12A1, COL6A3, COPB2, COPS8,

CPSF7, CREBBP, CYLD, DAB2, DCAF8,

DCP1A, DCUN1D5, DIS3, DNAJC19, DNM1L,

DOCK5, DPH3, DRAM2, EDEM2,

EFEMP1, EIF4H, ENC1, EPB41L2, FAM172A,

FAM21C, FBXL3, FGFR1OP, FIP1L1,

FNBP4, FRYL, FUT8, FXR2, GGCT, GIT2,

GLS, GTF2I, HNRNPA2B1, HNRNPDL,

HSD17B4, HSF2, IL15RA, INF2, INO80E,

INPP1, IP6K2, IQCB1, ITGB1BP1, KATNBL1,

KDM5A, KLC1, KTN1, L3HYPDH, LGALS8,

LMAN2L, LONRF1, LPHN2, LPIN1,

LRCH3, LSM1, MACF1, MAGOHB, MAPKAP1,

MARK3, MBNL1, ME3, MEG3,

METAP1, MFF, MOSPD1, MSRB3, MTMR2,

MYEF2, MYLK, MYNN, MYO18A,

MYO1B, MYO5A, NABP1, NEO1, NF2, NPEPPS,

NRG1, NSMCE2, NUP62, OCRL,

OFD1, OPTN, OSBPL8, PARP6, PDE4DIP,

PDZD11, PHC3, PHLDB1, PIGN, PIN1,

PNPLA8, PPP3CB, PPP3CC, PREPL, PRPF39,

PRRX1, PRUNE, QTRTD1, R3HCC1L,

RALY, RBBP9, RBM41, REV3L, RFWD2,

RNASE4, RNF34, RP11-14N7.2, RP11-

274B21.1, RPAIN, RRBP1, RWDD1, SDCCAG8,

SETX, SH3D19, SIPA1L1, SLC15A4,

SLC35A3, SLC38A6, SLTM, SMARCA1,

SNRNP70, SPATA7, SPDL1, SPPL2A,

ST6GALNAC6, STARD3NL, STK40, STRN3,

SUCO, SUGP2, SUPT20H, SYNRG, TAF2,

TBCK, TBPL1, TGFBR2, THAP9-AS1, TIA1,

TIAL1, TIMM17B, TM7SF3, TMEM126B,

TMEM18, TMEM234, TPD52L1, TPT1-AS1,

TRIM16, TRIM65, TRIP12, TROVE2,

TSEN15, TXNL4A, UBP1, USP33, USP8,

VEZT, VPS29, ZC2HC1A, ZC3H11A,

ZDHHC20, ZNF207, ZNF516, and ZNF532.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO: 2), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO: 6), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 5.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 5.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO: 2), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO: 6), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 5.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 5.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 5.

Table 6 lists wildtype genes identified by RNA sequencing, as described herein, that may be modulated by Compound (I) toward exon exclusion.

TABLE 6

A1BG-AS1, AAAS, ABCA1, ABCA6, ABCA9,

ABCB6, ABCC3, ABHD14A-ACY1,

ABI3BP, AC024560.3, AC037459.4, ACAA1,

ACACA, ACAD10, ACBD4, ACSL4,

ACTN1, ACY1, AD000671.6, ADA, ADAM33,

ADAMTSL4, ADARB1, ADK, AKAP11,

AKIP1, AKR1A1, ALDH3B1, ALDH4A1,

ALKBH1, ALKBH3, AMMECR1L, AMPD2,

ANK2, ANKRD10, ANKRD36, ANO6,

AP2M1, APBB2, APOL1, APP, ARHGAP23,

ARHGEF10L, ARHGEF12, ARHGEF25,

ARID4B, ARIH2, ASCC2, ASL, ASPH, ASUN,

ASXL1, ATG16L1, ATG7, ATG9A, ATPAF1,

ATXN1, ATXN3, AUP1, AUTS2, AVL9,

BAG6, BAX, BAZ1A, BBS4, BBS5, BCAR1,

BCOR, BIN1, BIRC6, BLOC1S6, BMP2K,

BOK, BPTF, BRD8, BTBD19, C11orf70, C16orf13,

C1orf85, C1RL, C5orf42, C9orf85,

CAMK2D, CAPN7, CAPRIN2, CARD8, CARKD,

CAST, CCDC25, CCDC90B, CCNDBP1,

CCNL1, CD46, CD55, CD99P1, CDC14B, CDC16,

CHD3, CHEK2, CHKB, CKLF, CLCN6,

CNOT10, COL16A1, COL6A3, COPS7A,

COQ6, COX20, CPEB2, CPT1C, CRAT, CRLS1,

CRNDE, CRYZ, CSAD, CTDSPL, CUTC, CWC25,

CYB561D2, CYP20A1, DBT, DCAF10,

DCAF11, DCAF17, DDB2, DGKA, DHRSX,

DIMT1, DIS3, DLG1, DMD, DMTF1,

DNAJC2, DNM1L, DNMT1, DOCK7, DPY19L4,

DRAM2, DSCR3, DTNBP1, DUSP11,

DUSP22, DYNC2H1, EBPL, EDC3, EDRF1,

EHBP1, EHMT2, EIF4A2, EIF4E2, ELK1,

ELN, ELOVL1, ENOSF1, EPB41L1, ERBB2IP,

ERLEC1, ERMAP, ETHE1, EVC, EVI5L,

FAM104A, FAM111A, FAM134C, FAM149B1,

FAM172A, FAM204A, FAM211A-AS1,

FAP, FBXL12, FBXO25, FBXW11, FGF5,

FHL2, FIP1L1, FLAD1, FLNA, FN1, FNIP2,

FOXN3, FYN, GAB1, GABPB2, GABRE,

GALNS, GFPT2, GIT2, GK, GLS, GOLGA4,

GOLGB1, GOLTIB, GPR133, GPR180, GRIPAP1,

GTF3A, GUF1, GUSB, HACL1,

HAUS7, HCFC1R1, HDAC10, HDAC7,

HECTD3, HERC3, HIPK3, HMGXB4, HNRNPD,

HPS1, HUWE1, IFT88, IGF2BP2, ING4, IPO8,

IRAK4, ISOC2, IST1, KDM4C, KIAA0100,

KIF3A, KITLG, KLC1, LACC1, LAMTOR3,

LAS1L, LENG8, LETMD1, LINC00963,

LMAN2L, LMO7, LOXL3, LPHN2, LRRC28,

LRRC32, LTA4H, LTBP1, LTBP3, LTBP4,

LUC7L, LYPLAL1, LYRM7, LZTFL1, MACF1,

MADD, MAN2C1, MAP3K3, MAP4K4,

MAPK11, MAPK12, MBD5, MBOAT2,

MED13, MED15, MEG3, MEGF6, METTL14,

MFF, MFSD12, MGEA5, MGST2, MINK1,

MIR22HG, MKS1, MLF1, MLH1, MLLT6,

MLST8, MMP19, MORF4L2, MOSPD1,

MPDZ, MPI, MPV17, MRPL33, MSRB3, MTCH2,

MTMR2, MTMR3, MTMR6, MTRR, MTSS1L,

MYBL1, MYCBP2, MYLK, MYNN,

MYO19, MYO5A, NADK2, NAE1, NBN,

NEK1, NEXN, NFE2L1, NIPA2, NLRC5,

NLRX1, NPR2, NPRL3, NSFL1C, NSUN4,

NT5C2, NUB1, NUP43, NUPL2, NUTM2A-

AS1, OARD1, ODF2, ODF2L, OPTN, ORMDL1,

OS9, PACRGL, PAM, PARD3, PARL,

PARP11, PATL1, PCBP2, PCID2, PCM1,

PCNXL2, PCNXL4, PCYT2, PDLIM2, PEAK1,

PEX1, PEX11A, PEX5, PFDN1, PFDN6, PFKM,

PHKG2, PI4KB, PIGG, PIGT, PIK3C2A,

PIKFYVE, PILRB, PKIG, PLA2G12A,

PLA2R1, PLAGL1, PLBD2, PMS2P3, PODNL1,

POLR3GL, PPAP2A, PPFIBP1, PPIL3, PPIP5K2,

PPM1M, PPP1R12A, PPP1R21, PPP2R3C,

PPP4C, PPP6R2, PPRC1, PREB, PRKAG1,

PRMT2, PRPF40B, PRR16, PRR4, PSME4,

PTPN13, PTPN21, PTPN23, PTPN4,

PTPRA, PVR, PXDN, R3HDM4, RAB1 1FIP2,

RABEPK, RAD1, RALGPS2, RBCK1, RCOR3,

REPS1, RGL2, RGN, RHBDD2,

RHOBTB1, RHOT1, RIF1, RIPK2, RNF146,

RNF170, RNF214, RNFT1, ROBO1, RP11-

1055B8.7, RP11-33B1.1, RP11-383H13.1,

RP11-773D16.1, RP13-279N23.2, RPAIN,

RPL7L1, RPP14, RPS6KB2, RSU1,

RTEL1, RTEL1-TNFRSF6B, RUFY2, RWDD2B,

RWDD4, SBF1, SCMH1, SEC31B, SECISBP2L,

SEMA4F, SENP1, SENP6, SERAC1,

SETD5, SFXN4, SGSM3, SHMT2, SIPA1L1,

SLC22A17, SLC25A17, SLC25A32,

SLC25A36, SLC35A1, SLC35D2,

SLC37A3, SLC38A2, SLC38A6, SLC4A7, SLC5A6,

SLC7A6, SLC9B2, SLIT2, SLMAP, SLMO1,

SMAD5, SMARCD1, SMC5, SMEK2,

SMPDL3A, SMURF2, SNAPC5, SNED1,

SNHG14, SNHG15, SNRPA1, SNRPG, SNX14,

SNX21, SPATA20, SPTAN1, ST7, STARD5,

STAT6, STK16, STK19, STRA13, STRADA,

STX16, STX16-NPEPL1, STX3, STXBP3,

STYXL1, SUGT1, SULF1, SUN2, SUPT20H,

TAF1, TANGO2, TARBP2, TAS2R14, TAZ,

TBC1D14, TBC1D17, TBC1D25, TBC1D5,

TBCK, TBX15, TCERG1, TEAD2, TEP1,

TFDP1, TFDP2, TFP1, THAP6, THBS3, THOC2,

TIMM21, TMCO4, TMEM11, TMEM120A,

TMEM194A, TMEM260, TMEM39B,

TMEM62, TMOD2, TMUB2, TMX3,

TOM1, TP53INP1, TP53TG1, TPD52L2, TPRA1,

TRAPPC12, TREX2, TRIO, TRIP10,

TRPC1, TRPM4, TRPT1, TSEN15, TSR1, TSTD3,

TUBG2, TULP3, TXNDC11, U2AF1L4,

UACA, UBA7, UBE2A, UBE2D1, UBN2,

UBQLN1, UFD1L, UNC5B, URGCP, USMG5,

USP24, USP25, USP53, VAMP7, VCAN,

WBP1, WDFY2, YEATS2, YIPF1, YME1L1,

YY1AP1, ZBTB80S, ZCCHC6, ZCCHC8,

ZDHHC16, ZDHHC7, ZFAND1, ZFAND5,

ZFAS1, ZMIZ1, ZMYM4, ZMYM5, ZNF160,

ZNF207, ZNF248, ZNF280D, ZNF384,

ZNF512, ZNF720, and ZZZ3.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CACTAGgtgaga (SEQ ID NO: 3), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CACUAGgugaga (SEQ ID NO: 7), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CACTAGgtgagc (SEQ ID NO: 11), and CTGAAgtcagt (SEQ ID NO: 15), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CACUAGgugagc (SEQ ID NO: 19), and CUGAAgucagu (SEQ ID NO: 23), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 6.

Another aspect described herein is Compound (I) for use in the method, wherein the method treats a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 6.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CACTAGgtgaga (SEQ ID NO: 3), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CACUAGgugaga (SEQ ID NO: 7), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CACTAGgtgagc (SEQ ID NO: 11), and CTGAAgtcagt (SEQ ID NO: 15), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CACUAGgugagc (SEQ ID NO: 19), and CUGAAgucagu (SEQ ID NO: 23), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 6.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a wildtype gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 6.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 6.

Methods of Modulating Mutated Gene Isoforms

Table 7 lists mutated genes predicted by SpliceAI scores and the CNN Model, as described herein, that may be modulated by Compound (I) toward exon inclusion.

TABLE 7

ABCA4, ABCC9, ACADSB, ADAM10, AGK,

ALDH3A2, ALMS1, ANTXR2, APC,

ARMC9, ASAH1, ASPM, ATM, ATRX, BBS4,

BFSP1, BMPR2, BRCA1, BRCA2, CA5A,

CAPN3, CD3D, CDH1, CDH23, CERKL, CFTR,

CHD7, CLCN1, CLMP, CLN3, CNGB3,

COG6, COL11A1, COL3A1, COL4A3, COL4A5,

COL5A2, CSTB, CTNS, CTU2, CUBN,

CWC27, CYBB, DCX, DGKE, DGUOK, DMD,

DNAH5, DNAH9, DYNC2H1, DYNC2LI1,

EBF3, EP300, F10, F13A1, FBN1, FUT8, G6PC,

GAA, GABRG2, GCK, GLA, GNB5,

GNPTAB, GPR143, GPX4, GRHPR, GRN, GUCY2C,

GYPA, HBB, IDH1, IFT57, IL36RN,

KDSR, KIAA0586, KIAA1109, KIF14, KIT,

KMT2D, KRIT1, LAMB3, LDLR, LIPA,

LMNA, MCFD2, MLH1, MMAB, MPC1, MSH2,

MTM1, MYBPC3, MYO7A, NF1, NIPBL,

NPHP1, NR3C2, NSD1, OCA2, OFD1, OGT,

ORC6, OTC, OTOGL, PAFAH1B1, PAH,

PARN, PDCD10, PIGN, PMS2, POLG, POMGNT1,

PPT1, PRMT7, PTEN, RAD51B,

RAD51C, RB1, RHAG, RNF216, RTTN, SCN1A,

SLC10A7, SLC12A1, SLC4A11, SMS,

SPAST, SPG11, SPTA1, SPTB, SRD5A2, STXBP1,

SYNGAP1, TGFBR2, TJP2, TMEM138,

TMPRSS6, TP53, TPO, TRAPPC2, TRIM37,

TYR, UROD, VMA21, VPS13B, WDR35,

WDR73, and XPC.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein a the use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof, wherein the method comprises, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 7.

embedded image

Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 7.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 7.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, modulating the production of one or more mature RNA isoforms from a gene transcript by administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 7.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 7.

Table 8 lists mutated genes predicted by SpliceAI scores and the CNN Model, as described herein, that may be modulated by Compound (I) toward exon exclusion.

TABLE 8

BRCA1, BRIP1, CDAN1, CLN3, COL6A1,

COL7A1, CTSK, EBP, ERCC6, F8, FBN1,

FIG4, FLT3, GLA, HFE, LHCGR, MAPT,

OTC, SCN5A, SDCCAG8, SDHD, SNX10,

STK11, TCIRG1, TECTA, TFR2, and TP53.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 8.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutated wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the non-mutated wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 8.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 8.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 8.

Methods of Modulating Wildtype and Mutated Gene Isoforms

One aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for increasing exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for increasing exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

One aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for increasing exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for increasing exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, modulating the production of one or more mature RNA isoforms from a gene transcript by administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Methods of Modulating Wildtype Gene Isoforms

Table 9 lists wildtype genes identified by RNA sequencing, as described herein, that may be unchanged by Compound (I) toward either or both exon inclusion and exon exclusion.

TABLE 9

AAMDC, ABCA2, ABCC3, ABCD4, ABHD16A,

ABI3BP, ACAD10, ACAP3, ACCS,

ACOT9, ACTN1, ADAM15, AFTPH, AK4,

AMBRA1, AMDHD2, AMIGO2, AMOTL1,

AMZ2P1, ANAPC11, ANKRD17, ANO6,

AOX1, ARHGEF10, ARID5A, ARIH2, ARMC10,

ARSJ, ASCC2, ATG12, ATG13, ATG4B, ATP5C1,

ATP6C, B3GALNT1, BAZ2A, BCL2L2,

BEND6, BIRC6, BLOC1S6, BRD8, BTBD3,

BTF3L4, C10orf118, C11orf30, C11orf57,

C14orf159, C2orf76, C9orf156, CACNA1C,

CAMK2G, CAMSAP1, CAPN10, CARF,

CCDC126, CCDC136, CCDC25, CCNL2,

CCNT1, CCNYL1, CD27-AS1, CDC42BPA,

CDCA7L, CDK5RAP2, CEP164, CIRBP,

CLASP2, CPNE1, CSDE1, CSNK1A1, CTIF,

CTSB, DCAF8, DCTD, DGUOK, DLGAP1-AS1,

DMKN, DMWD, DNAAF2, DNAJC14,

DNAJC24, DPH7, DPM1, DUS2, ECHDC2,

EHBP1L1, EIF4G2, ELMOD3, EMC4, ENC1,

EP400, EPS15L1, ERMARD, EVA1A, FAM114A1,

FAM13B, FAM160B2, FAM173A,

FAM175A, FAM208B, FAM35A, FAM45A,

FDPS, FGFR1, FHOD3, FLNB, FNBP1,

FOSL1, FOXRED2, FRS2, GAS7, GBP3,

GEMIN8, GLIS3, GLRB, GLT8D1, GNAS,

GPATCH8, GPBP1, GRB10, HDAC9, HMCN1,

HNRNPK, HSCB, IL17RA, IL17RC, IL6,

INTS9, IP6K2, KANSL3, KAT6A, KCTD20,

KIAA0232, KIAA0368, KIAA0753,

KIAA1551, KIAA1586, KIAA1731, KIFC3,

KLHL12, KTN1, LBR, LDB2, LRP12, MADD,

MAP2K5, MAP7D1, MAPK9, MAZ, MBD1,

MCCC2, MECR, MED23, MEGF6, MEIS1,

METTL10, METTL21A, MGLL, MICU3,

MKNK2, MLLT10, MPPE1, MRI1, MRPL55,

MTIF2, MXI1, MXRA7, MYCBP2, MYO18A,

MYO5A, N6AMT2, NCK2, NCOR2,

NEDD1, NIN, NPRL3, NTMT1, NTPCR,

NUBP2, NUMB, NUP98, NUTF2, OPN3, OSER1-

AS1, P4HA2, PARD3, PCNXL2, PDGFC,

PDP1, PDPR, PDXDC2P, PEAK1, PFDN5,

PHLPP2, PIGF, PIGP, PIGQ, PINX1, PLD3,

PLSCR4, PPP1R18, PPP6R3, PRDM5,

PRRC2B, PRUNE, PTAR1, PTPRG, PTPRS,

PUF60, PUM2, R3HDM1, RAD51D, RAF1,

RAPH1, RBM10, RBM27, RBM4, RBM5,

RCC1, RFC2, RGL1, RIF1, RILP, RILPL2,

RNF14, RNF8, RNGTT, RP11-705C15.2,

RP1-178F15.4, RPAIN, RPP38, RPS24, RPUSD1,

RRNAD1, RTN2, RUNX1, SCRN3, SEC13,

SEC31A, SETD2, SEZ6L2, SGSM2, SIKE1,

SLAIN2, SLC30A6, SLC38A9, SLC39A9,

SLFN11, SLMAP, SLTM, SMEK2, SMG7,

SMURF2, SNHG14, SPEN, SPIDR, SRSF2,

STAG1, STAG2, STARD3, STARD4, STK38L,

STOML1, STXBP5, SUOX, SYNE1, SYNJ2BP,

TAMM41, TBC1D32, TBCE, TBCEL,

TCF20, TCF7L2, TENM2, TET2, TFB2M,

TFDP2, TGIF1, THADA, THTPA, THTPA,

TJAP1, TJP1, TLK2, TMEM119, TMEM161B,

TMEM175, TMEM230, TMUB2,

TOR1AIP2, TOR3A, TP53BP2, TRA2A,

TRIM37, TRMU, TROVE2, TSPAN5, TULP3,

U2AF1, UCHL5, UPF3A, UPP1, USP3, VDR,

VEGFA, VIPAS39, VPS13D, WARS,

WDR27, WHSC1, WNK1, XIAP, XPNPEP3,

YTHDF2, YWHAB, ZBTB38, ZCCHC6,

ZEB1, ZFAT, ZFX, ZMYM1, ZNF140,

ZNF217, ZNF260, ZNF266, ZNF3, ZNF346,

ZNF37A, ZNF419, ZNF426, ZNF529, ZNF585B, ZNF638,

ZNF655, ZNF75A, ZNF767, and ZSCAN32.

Another aspect described herein is Compound (I) for use in a method to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript is transcribed from a gene other than a gene selected from Table 9.

One aspect described herein is Compound (I) for use in a method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 9a.

Table 9a lists wildtype genes identified by RNA sequencing and mutated genes predicted by SpliceAI scores and the CNN model, as described herein, which may be modulated by Compound (I) toward either or both exon inclusion or exon exclusion and toward remaining unchanged.

TABLE 9a

ABCC3, ABI3BP, ACAD10, ACTN1, ANO6,

ARHGEF10, ARIH2, ASCC2, B3GALNT1,

BIRC6, BLOC1S6, BRD8, C11orf30, C9orf156,

CCDC25, DCAF8, DGUOK, ENC1, IP6K2,

KTN1, MADD, MEGF6, MYO18A, MYO5A,

NPRL3, PARD3, PCNXL2, PEAK1, PRUNE,

RIF1, RPAIN, SLMAP, SLTM, SMEK2,

SMURF2, SNHG14, TFDP2, TMUB2, TRIM37,

TROVE2, TULP3, and ZCCHC6.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Table 9a.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene is selected from Table 9a.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Table 9a.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene is selected from Table 9a.

Another aspect described herein is use of Compound (I), wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 9a.

One aspect described herein is Compound (I) for use in a method to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Table 10 lists wildtype genes identified by RNA sequencing, modulated by kinetin toward either or both exon inclusion and exon exclusion⁹³.

TABLE 10

ANKRD10, BRD8, C2CD5, CAPRIN2, CHD3,

CRYZ, CYLD, DUSP11, EDEM2,

HSD17B4, IKBKAP, KIF3A, KLC1, L3HYPDH,

LETMD1, MORF4L2, NABP1, NEK1,

NEXN, PLA2G12A, PPFIBP1, PPIP5K2,

RHOT1, RPL7L1, RUFY2, SBF1, SDCCAG8,

SECISBP2L, SLC4A7, SNX14, STARD4, STX16,

SUCO, SUPT20H, TEAD2, TEP1, TIA1,

ZFAND1, and ZNF207.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene other than a gene selected from Table 10.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is selected from the group consisting of Table 10.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having a mutation in a gene transcript thereof is a gene other than the gene selected from the group consisting of Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 10.

One aspect described herein is Compound (I) for use in a method to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Table 11.

Table 11 lists wildtype genes identified by RNA sequencing, modulated by kinetin toward exon inclusion⁹³.

TABLE 11

CYLD, EDEM2, HSD17B4, IKBKAP, KLC1,

L3HYPDH, NABP1, SDCCAG8, SUCO,

SUPT20H, TIA1, and ZNF207.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 11.

Table 12 lists wildtype genes identified by RNA sequencing, modulated by kinetin toward exon exclusion⁹³.

TABLE 12

ANKRD10, BRD8, C2CD5, CAPRIN2, CHD3,

CRYZ, DUSP11, KIF3A, LETMD1,

MORF4L2, NEK1, NEXN, PLA2G12A, PPFIBP1,

PPIP5K2, RHOT1, RPL7L1, RUFY2,

SBF1, SECISBP2L, SLC4A7, SNX14, STARD4,

STX16, SUPT20H, TEAD2, TEP1,

ZFAND1, and ZNF207.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 12.

Table 13 lists wildtype genes identified by RNA sequencing, as described in International Application No. PCT/US2016/013553, filed on Jan. 15, 2016, and published as International Publication No. WO2016/115434 on Jul. 21, 2016, the entire contents which are incorporated herein by reference, that may be modulated by Compound (I) toward exon inclusion.

TABLE 13

ABI2, ARFGEF2, ARHGEF6, BMP2K, C19orf12,

CACNA1S, CC2D2A, CDKL5, CHD2,

CHD7, CHD8, CHRNA4, COL6A3, CUL4B,

DEPDC5, DES, DMD, DNAJC6, DYNC2H1,

FBN1, FIG4, FKTN, FMR1, GOSR2, GRIN2A,

HDAC8, IGHMBP2, IKBKAP, KDM5C,

LAMA2, LRRK2, LRSAM1, MBD5, MECP2,

MICU1, MTM1, NEB, OPHN1, PGAP1,

PLEC, RB1, RYR1, SBF2, SCN1A, SCN9A,

SLC35A3, SLC6A8, SLC9A9, SMCHD1,

STXBP1, SYNGAP1, SZT2, TSC1, TSC2, and WDR45.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 13.

Preparation of Compound (I)

The small molecule splicing modulator compound described herein as Compound (I) has been disclosed in International Publication No. WO2016/115434 as Compound 100. Compound (I) can be prepared using the methods provided in International Publication WO2016/155434 and as described herein.

Preparation of Compound (I) (2-chloro-N-(4-pyridylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine)

In brief, 4-(aminomethyl)pyridine (2, 3420 mg, 3.20 mL, 31.6 mmol, 1.19 eq.) was added to a stirred suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (5001 mg, 26.60 mmol, 1.000 eq.) (obtained from AstaTech Inc., Bristol, Pa.) in 1,4-dioxane (50.0 mL) followed by addition of N,N-diisopropylethylamine (4450 mg, 6.00 mL, 34.1 mmol, 1.28 eq.) at room temperature. The reaction mixture was then heated to 90° C. and stirred at 90° C. overnight.

The reaction progress was monitored by LC-MS analysis of an aliquot of the reaction mixture. After about 12 h, approximately 6% of starting material was detected by LC-MS. The reaction was quenched by water resulting in an emulsion. The mixture was filtered through Celite and washed with EtOAc (3×80 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic phases were washed with brine (50 mL) and then dried over sodium sulfate

The volatiles were removed under reduced pressure to produce a crude product as a dark brown solid. EtOAc (100 mL) was added to the crude solid and the mixture was heated at reflux for 15 min before slowly cooled to room temperature. The resulting precipitate was collected by filtration, washed with cold EtOAc (30 mL) and diethyl ether (100 mL). The solid was dried under high vacuum overnight to produce 2-chloro-N-(4-pyridylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Compound (I) as a light brown solid (3450 mg, 13.3 mmol, 50% yield.)

LC-MS: 0.63 min (254 nm), m/z 260.3, 262.3 [M+H]⁺, 258.2, 260.2 [M−H]⁻; ¹H NMR (DMSO-d₆) δ: 11.65-11.85 (m, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.45-8.50 (m, 1H), 7.28-7.40 (m, 2H), 7.09-7.21 (m, 1H), 6.53-6.74 (m, 1H), 4.61-4.81 (m, 2H).

As used herein, Compound (I) may have a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In certain aspects described herein, the form of Compound (I) is a free acid, free base or salt form thereof.

In certain aspects described herein, Compound (I) is a salt form.

In certain aspects described herein, the salt form of Compound (I) is a pharmaceutically acceptable salt.

In certain aspects described herein, Compound (I) is isolated for use.

The term “pharmaceutically acceptable salt(s)”, as used herein, means a salt of Compound (I) that is safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and possesses biological activity, although other salts may be found useful. A salt of Compound (I) may be formed, for example, by reacting Compound (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. In certain aspects, acid addition salts may include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrochloride, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate and the like. Certain aspects of acid addition salts may further include acetate, bromide, chloride, dichloride, trichloride, hydrochloride, dihydrochloride, formate or trifluoroacetate salts.

All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of Compound (I).

The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.

Another aspect, described herein includes Compound (I) selected from a polymorphic crystalline and amorphous form of Compound (I) and a salt, solvate, hydrate or ester of Compound (I).

Nomenclature for Compound (I) may differ slightly from other chemical names known to those skilled in the art; however, such differences will be recognized by one skilled in the art as equivalents for the structure of Compound (I) provided herein.

Terminology

As used herein, the singular forms “a,” “an,” and “the,” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

The phrase “and/or,” as used herein and in the claims, is understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one aspect, to A only (optionally including elements other than B); in another aspect, to B only (optionally including elements other than A); in yet another aspect, to both A and B (optionally including other elements); etc

As used herein and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one aspect, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another aspect, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another aspect, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below those numerical values. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%, 10%, 5%, or 1%. In certain aspects, the term “about” is used to modify a numerical value above and below the stated value by a variance of 10%. In certain aspects, the term “about” is used to modify a numerical value above and below the stated value by a variance of 5%. In certain aspects, the term “about” is used to modify a numerical value above and below the stated value by a variance of 1%.

As used herein, the term “substantial change” in the context of the amount of one or more RNA transcripts, an alternative splice variant thereof or an isoform thereof, or one or more proteins thereof, each expressed as the product of one or more of genes, means that the amount of such products changes by a statistically significant amount such as, in a nonlimiting example, a p value less than a value selected from 0.1, 0.01, 0.001, or 0.0001.

As used herein, the terms “subject” and “patient” are used interchangeably to refer to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Non-limiting examples include members of the human, equine, porcine, bovine, rattus, murine, canine and feline species. In some aspects, the subject is a mammal or a warm-blooded vertebrate animal. In certain aspects, the subject is a non-human animal. In specific aspects, the subject is a human.

When a range of values is listed herein, it is intended to encompass each value and sub-range within that range. For example, “1-5 ng” or a range of “1 ng to 5 ng” is intended to encompass 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 1-2 ng, 1-3 ng, 1-4 ng, 1-5 ng, 2-3 ng, 2-4 ng, 2-5 ng, 3-4 ng, 3-5 ng, and 4-5 ng.

It will be further understood that the terms “comprises,” “comprising,” “includes,” and/or “including,” when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

As used herein, the terms “treat,” “treatment,” “treating” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a disorder. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disorder is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable. The term “treatment” of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

As used herein, the terms “subject” and “patient” are used interchangeably to refer to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Non-limiting examples include members of the human, equine, porcine, bovine, rattus, murine, canine and feline species. In one aspect, the subject is a mammal or a warm-blooded vertebrate animal. In another aspect, the subject is a non-human animal. In another aspect, the subject is a human.

As used herein, the term “RNA” means a molecule comprising at least one ribonucleotide residue. By “ribonucleotide” is meant a nucleotide with a hydroxyl group at the 2′ position of a beta-D-ribo-furanose moiety. The terms include double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. RNAs can be synthesized in a cell by RNA polymerase I, II or III.

The term “mRNA” refers to any RNA that is produced in a cell by RNA polymerase II transcription of a gene. In one aspect, the mRNA of the disclosure is capped and polyadenylated. In one aspect, an mRNA of the disclosure encodes one or more proteins. In one aspect, the mRNA does not encode a protein. In another aspect, mRNA can refer to processed or unprocessed pre-mRNA. In another aspect, the mRNA of this disclosure includes, but is not limited to, pre-mRNA, spliced mRNA, partially spliced mRNA and alternatively spliced mRNA. In one aspect, the mRNA of the disclosure is a transcript that undergoes nonsense-mediated decay (NMD) in the presence of a compound as described herein.

Splicing is a natural biological mechanism that may occur within human cells. Splicing processes primary messenger ribonucleic acid (mRNA) that has been transcribed from deoxyribonucleic acid (DNA) before the mRNA is translated into a protein. Splicing involves removing one or more contiguous segments of mRNA and is directed, in part, by a spliceosome. The segments that are removed are often referred to as introns, but the spliceosome may remove segments that contain both introns and exons.

As used herein, the term “functional protein” refers to a form of a protein that retains a certain biological function or the functions of a full length protein or protein isoform encoded by a gene. As used herein, in the context of the use of Compound (I) to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I) to produce a functional protein, wherein the amount of functional protein produced in the absence of Compound (I) is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% less than the amount of functional protein produced in the presence of Compound (I).

As used herein, in the context of Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I) to produce a functional protein, and wherein the amount of functional protein produced in the absence of Compound (I) is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% less than the amount of functional protein produced in the presence of Compound (I).

As used herein, the term “exon” refers to any part of a gene that is a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term “exon” refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts.

As used herein, the term “intron” refers to both the DNA sequence within a gene and the corresponding sequence in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing either shortly after or concurrent with transcription.

As used herein, the term “isolated” means the physical state of Compound (I) after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.

As used herein, the term “exon triplet” refers to three consecutive exons in a gene transcript, each separated by adjacent introns. One aspect described herein includes a gene transcript of interest comprising an exon triplet for interrogation by the CNN model as described herein.

As used herein, the term “5-mer enrichment analysis” refers to 5-mer sets of nucleotides identified as adjacent nucleotides from the −3 to +7 position in a splice site junction known by those skilled in the art to have an observed frequency of Class Effect greater than mere chance toward modulating the splicing reaction. Such 5-mer sets of nucleotides having a frequency p value<0.05 toward a particular Class Effect were deemed to be enriched.

As used herein, the term “LOGO plot” refers to the presentation of a nucleotide sequence known by those skilled in the art to show an alignment of nucleotides having a particular Class Effect. In one aspect described herein, the representation of nucleotides in a LOGO plot sequence may show only one nucleotide in a LOGO plot position. In another aspect described herein, the representation of nucleotides in a LOGO plot sequence may show one or more nucleotides having differing heights in a LOGO plot position. In another aspect described herein, the representation of nucleotides in a LOGO plot sequence may show no visible nucleotide in a LOGO plot position. Accordingly, nucleotides shown in a LOGO plot position represent potential variability for the nucleotide to be in that position. It is assumed by those skilled in the art that the probability for each one of the four possible nucleotides to be present in any one position is assumed to be equally random, at least 25% of the time. As used herein, the term “constant,” in reference to a nucleotide in a particular LOGO plot position having only one nucleotide, indicates that the probability of the nucleotide to be present in that position is predicted to be 100%. In a LOGO plot presented herein, the constant nucleotide is shown by a capital letter representing the corresponding nucleotide. As used herein, the term “most dominant,” in reference to a nucleotide in a particular LOGO plot position having no clear constant nucleotide, where more than one nucleotide is present as shown in a vertical nucleotide stack, indicates that the probability of one or more nucleotides to be present in that position is predicted to be less than 100%. In a LOGO plot presented herein, the most dominant nucleotide is taken to be the topmost nucleotide in the LOGO plot position and is shown by a capital letter representing the corresponding nucleotide. In other instances, where no visible nucleotide appears in a LOGO plot position, the position is shown by the capital letter “N”.

As used herein, the term “Class” refers to exclusion or inclusion of an exon in an mRNA splicing reaction in the presence of a small molecule splicing compound to produce one or more mature RNA isoforms that are unlike an isoform produced by the wildtype or mutant gene transcript. In another aspect described herein, the effect may be the production of one or more mature RNA isoforms unchanged from the wildtype or mutant spliced isoform.

As used herein, the term “Class Effect” refers to the production of one or more mature RNA isoforms from a wildtype or mutant gene transcript in the presence of a 5-mer nucleotide sequence identified or predicted to have an effect toward exclusion or inclusion of an exon in an mRNA splicing reaction while in the presence of a small molecule splicing compound. In another aspect described herein, the predicted effect may be the production of one or more mature RNA isoforms unchanged from the wildtype or mutant spliced isoform.

As used herein, the terms “Active Class” and “Active Class Effect” refer to a set of 5-mer nucleotide sequences having a Class Effect on mRNA splicing in the presence of a small molecule splicing compound toward exclusion or inclusion of an exon in an mRNA splicing reaction in the presence of a small molecule splicing compound to produce one or more mature RNA isoforms from the wildtype or mutant gene transcript.

As used herein, the terms “Unchanged Class” and “Unchanged Class Effect” refer to a set of 5-mer nucleotide sequences having a Class Effect toward exclusion or inclusion of an exon in an mRNA splicing reaction in the presence of a small molecule splicing compound to produce one or more mature RNA isoforms that are unchanged from those produced by the wildtype or mutant gene transcript in the absence of the small molecule splicing compound.

As used herein, the term “Enrichment Motif” refers to a 5-mer nucleotide sequence identified in an enrichment analysis as described herein are known to have a certain Class Effect on mRNA splicing in the presence of a small molecule splicing compound. In one aspect described herein, an Enrichment Motif relates to a set of 5-mer nucleotide sequences identified as having an Active Class Effect. In another aspect described herein, an Enrichment Motif relates to a set of 5-mer nucleotide sequences identified as having an Unchanged Class Effect. In another aspect described herein, all nucleotides in an Enrichment Motif are assumed to contribute to the frequency of the Enrichment Motif as a unit toward a particular Class Effect. In another aspect described herein, LOGO plots for Enrichment Motifs may show nucleotides having varying heights, where the nucleotide in the position may have either a greater or lesser frequency toward having a certain Class Effect. In another aspect described herein, Constant nucleotides or More Dominant nucleotides shown in Enrichment Motif LOGO plots indicate those single nucleotides have a greater frequency toward having an Active Class Effect. In another aspect described herein, positions absent a nucleotide shown in the Enrichment Motif LOGO plot indicate nucleotides in those positions have an Unchanged Class Effect, having no frequency contribution toward an Active Class Effect.

As used herein, the term “CNN Motif” refers to a 5-mer nucleotide sequence identified and predicted by the CNN model described herein to have a Class Effect on mRNA splicing in the presence of a small molecule splicing compound. In one aspect described herein, the CNN Model was taught to convolute 400-mer sequences containing Enrichment Motifs into separate elements, where the position of each element could be analyzed as to whether the element in that position could contribute to a correct prediction toward a particular Class Effect. In another aspect described herein, once built, the CNN Model was used to weight the predictive contribution of every five nucleotides (5-mer) in the 400-mer through a convolution process. Each position within a 5-mer was individually weighted according to potential contribution to a correct prediction toward a particular Class Effect. As a result, certain 5-mer nucleotide positions having a more predictive effect were identified, enabling these 5-mer positions to be more preferentially weighted. In another aspect described herein, without being limited in any way by theory in any aspect of the CNN Model, the positional analysis convoluted by the CNN Model suggested that nucleotides in the −3 to +2 region of the splice junction were more heavily weighted. In another aspect described herein, the convoluted, highly weighted 5-mer nucleotide positions were extracted from the CNN model and converted into CNN motifs according to the weight at each position. In another aspect described herein, multiple CNN Motifs may be convoluted using the CNN Model described herein to weight nucleotides in a gene sequence of interest to predict whether a Class Effect will occur. For each CNN Motif, a single overall Class Effect for the CNN Motif was calculated, ranking the statistical probability of the CNN Motif to correctly predict a single overall Class Effect based on the statistical probability resulting from the particular analytical method used. In another aspect described herein, the frequency of an Enrichment Motif to have a particular Class Effect may be compared with the probability of a similar or dissimilar CNN motif to correctly predict a particular Class Effect using a Pearson Correlation. In one aspect described herein, a CNN Motif relates to a set of 5-mer nucleotide sequences identified as having an Active Class Effect. In one aspect described herein, a CNN Motif relates to a set of 5-mer nucleotide sequences identified as having an Unchanged Class Effect. In another aspect described herein, LOGO plots for CNN Motifs may show nucleotides having varying heights, where the nucleotide in the position may have either a greater or lesser positional importance toward a predicting a certain Class Effect. In another aspect described herein, Constant nucleotides and More Dominant nucleotides in a CNN Motif identified by the CNN model may be expected to have a positional importance toward a Class Effect. In another aspect described herein, one or more of either or both Constant nucleotides and More Dominant nucleotides in a deconvoluted CNN Motif LOGO plot may influence prediction toward a variety of Active Class Effects, the convoluted CNN Motif may have a greater positional importance toward predicting a single overall Active Class Effect. In another aspect described herein, positions absent a nucleotide shown in the CNN Motif LOGO plot indicate single nucleotides in those positions have an Unchanged Class Effect, where the open positions have no positional importance toward predicting an overall Active Class Effect.

As used herein, the term “Pearson Correlation” refers to a statistical correlation comparing the Class Effect of an Enrichment Motif with a CNN Motif. The Pearson Correlation compares the overall Class Effect predicted by an individual CNN Motif with the frequency of Class Effect for an individual Enrichment Motif. In another aspect described herein, the Pearson Correlation for an Enrichment Motif may show a Positive or Negative Correlation to a Class Effect for a similar or dissimilar CNN Motif.

As used herein, the phrase “predicted wildtype or mutant gene transcript” refers to a gene transcript containing a 5-mer nucleotide sequence identified as having a predicted Class Effect toward exclusion or inclusion of an exon in an mRNA splicing reaction in the presence of a small molecule splicing compound to produce one or more mature RNA isoforms from the wildtype or mutant gene transcript. In one aspect described herein, the predicted effect of the 5-mer nucleotide sequence may be identified using a CNN model or equivalents thereof which are within the scope of one skilled in the art to design. In another aspect described herein, the predicted effect of the 5-mer nucleotide sequence may be identified in an enrichment analysis using methods known to those skilled in the art.

Pharmaceutical Compositions and Modes of Administration

When administered to a patient, Compound (I) is preferably administered as a component of a composition that optionally comprises a pharmaceutically acceptable carrier, excipient or diluent. The composition can be administered orally, or by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa) and may be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, and can be used to administer the compound.

Methods of administration include, but are not limited to, parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intraocular, intratumoral, intracerebral, intravaginal, transdermal, ocularly, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of a compound into the bloodstream, tissue or cell(s). In a specific aspect, a compound is administered orally.

The amount of Compound (I) that will be effective in the treatment of a disease resulting from an aberrant amount of mRNA transcripts depends, e.g., on the route of administration, the disease being treated, the general health of the subject, ethnicity, age, weight, and gender of the subject, diet, time, and the severity of disease progress, and should be decided according to the judgment of the practitioner and each patient's or subject's circumstances.

In specific aspects, an “effective amount” in the context of the administration of Compound (I), or composition or medicament thereof refers to an amount of Compound (I) to a patient which has a therapeutic effect and/or beneficial effect. In certain specific aspects, an “effective amount” in the context of the administration of Compound (I), or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom(s) associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and/or (xiii) inhibits of the progression of a symptom associated with a disease. In certain aspects, an effective amount of Compound (I) is an amount effective to restore the amount of a RNA transcript of a gene to the amount of the RNA transcript detectable in healthy patients or cells from healthy patients. In other aspects, an effective amount of Compound (I) is an amount effective to restore the amount an RNA isoform and/or protein isoform of gene to the amount of the RNA isoform and/or protein isoform detectable in healthy patients or cells from healthy patients.

In certain aspects, an effective amount of Compound (I) is an amount effective to decrease the aberrant amount of an RNA transcript of a gene which associated with a disease. In certain aspects, an effective amount of Compound (I) is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene. In some aspects, an effective amount of Compound (I) is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., mRNA transcript), alternative splice variant or isoform.

In certain aspects, an effective amount of Compound (I) is an amount effective to increase or decrease the amount of an RNA transcript (e.g., an mRNA transcript) of gene which is beneficial for the prevention and/or treatment of a disease. In certain aspects, an effective amount of Compound (I) is an amount effective to increase or decrease the amount of an alternative splice variant of an RNA transcript of gene which is beneficial for the prevention and/or treatment of a disease. In certain aspects, an effective amount of Compound (I) is an amount effective to increase or decrease the amount of an isoform of gene which is beneficial for the prevention and/or treatment of a disease. Non-limiting examples of effective amounts of Compound (I) are described herein.

For example, the effective amount may be the amount required to prevent and/or treat a disease associated with the aberrant amount of an mRNA transcript of gene in a human subject.

In general, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day for a patient having a weight in a range of between about 1 kg to about 200 kg. The typical adult subject is expected to have a median weight in a range of between about 70 and about 100 kg.

Within the scope of the present description, the “effective amount” of Compound (I) for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method for preventing and/or treating a disease in a human subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 35,000 mg.

The compositions described herein are formulated for administration to the subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.

Aspects described herein include the use of Compound (I) in a pharmaceutical composition. In a specific aspect, described herein is the use of Compound (I) in a pharmaceutical composition for preventing and/or treating a disease in a human subject in need thereof comprising administering an effective amount of Compound (I) in admixture with a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the human subject is a patient with a disease associated with the aberrant amount of an mRNA transcript(s).

Compound (I) may optionally be in the form of a composition comprising the compound or a form thereof and an optional carrier, excipient, or diluent. Other aspects provided herein include pharmaceutical compositions comprising an effective amount of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific aspect, the pharmaceutical compositions are suitable for veterinary and/or human administration. The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject.

In a specific aspect and in this context, the term “pharmaceutically acceptable carrier, excipient or diluent” means a carrier, excipient or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

Typical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising Compound (I) as described herein. The compositions and single unit dosage forms can take the form of solutions or syrups (optionally with a flavoring agent), suspensions (optionally with a flavoring agent), emulsions, tablets (e.g., chewable tablets), pills, capsules, granules, powder (optionally for reconstitution), taste-masked or sustained-release formulations and the like.

Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets, caplets, capsules, granules, powder, and liquids. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.

Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

In another aspect, the method for modulating the amount of one, two, three or more RNA transcripts of a gene described herein, comprising contacting a cell with Compound (I) includes a cell in a cell culture. In other aspects, the cell is contacted with Compound (I) in a subject (e.g., a non-human animal subject or a human subject).

In certain aspects described herein, the cell(s) is contacted or cultured with Compound (I) with Compound (I) for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In other aspects described herein, the cell(s) is contacted or cultured with Compound (I) with Compound (I) for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.

In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of Compound (I), wherein the certain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In other aspects described herein, the cell(s) is contacted or cultured with a certain concentration of Compound (I), wherein the certain concentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In some aspects described herein, the cell(s) is contacted or cultured with a certain concentration of Compound (I), wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of Compound (I), wherein the certain concentration is between 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM. In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of Compound (I) that results in a substantial change in the amount of an RNA transcript (e.g., an mRNA transcript), an alternatively spliced variant, or an isoform of a gene (e.g., a gene described herein, infra).

In another aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, comprising administering to a human or non-human subject Compound (I), or a pharmaceutical composition comprising Compound (I) and a pharmaceutically acceptable carrier, excipient or diluent.

In one aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene described herein, the methods comprising administering to a human or non-human subject Compound (I), or a pharmaceutical composition comprising Compound (I) and a pharmaceutically acceptable carrier, excipient or diluent.

In certain aspects, Compound (I) contacted or cultured with a cell(s) or administered to a subject is a compound as described herein.

Compound (I) Use in a Method

(SEQ ID NO: 1)

CAAgtaagt,

(SEQ ID NO: 2)

GATTAAgtgggt,

(SEQ ID NO: 3)

CACTAGgtgaga,

and

(SEQ ID NO: 4)

CCAgtgagga.

(SEQ ID NO: 5)

CAAguaagu,

(SEQ ID NO: 6)

GAUUAAgugggu,

(SEQ ID NO: 7)

CACUAGgugaga,

and

(SEQ ID NO: 8)

CCAgugagga.

Another aspect described herein is Compound (I) for use in the method, wherein the 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of:

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

(SEQ ID NO: 5)

CAAguaagu,

(SEQ ID NO: 6)

GAUUAAgugggu,

(SEQ ID NO: 7)

CACUAGgugaga,

and

(SEQ ID NO: 8)

CCAgugagga.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I).

embedded image

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Table 14 and 15.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Table 14.

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is other than the gene selected from the group consisting of Table 15.

Use of Compound (I)

One aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I), wherein a gene having the mutated transcript is selected from the group consisting of Table 14 and 15.

Another aspect described herein is use of Compound (I), wherein a gene having the mutated transcript is selected from the group consisting of Table 14.

Another aspect described herein is use of Compound (I), wherein a gene having the mutated transcript is other than the gene selected from the group consisting of Table 15.

Compound (I) Use in a Method

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), GCAGA (SEQ ID NO: 69), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), GAGAG (SEQ ID NO: 79), AGGAN (SEQ ID NO: 80), AGACC (SEQ ID NO: 81), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), GGGAA (SEQ ID NO: 94), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), CAGGC (SEQ ID NO: 97), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

(SEQ ID NO: 1)

CAAgtaagt,

(SEQ ID NO: 2)

GATTAAgtgggt,

(SEQ ID NO: 3)

CACTAGgtgaga,

and

(SEQ ID NO: 4)

CCAgtgagga.

(SEQ ID NO: 5)

CAAguaagu,

(SEQ ID NO: 6)

GAUUAAgugggu,

(SEQ ID NO: 7)

CACUAGgugaga,

and

(SEQ ID NO: 8)

CCAgugagga.

Another aspect described herein is Compound (I) for use in a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof, wherein the method comprises, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the subject is human.

Another aspect described herein is Compound (I) for use in a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof, wherein the method comprises, modulating the production of one or more mature RNA isoforms from a gene transcript by administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript.

Methods for Modulating Isoform Production

One aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is a method for increasing exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I).

Another aspect described herein is a method for increasing exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I).

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein one or more of the mature RNA isoforms produce a functional protein.

Compound (I) Use in a Method

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates exon inclusion or exon exclusion to produce one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

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Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from the group consisting of Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Methods for Modulating Isoform Production

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to increase exon inclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to increase exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the subject is human, and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Compound (I) Use in a Method

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell, wherein the method comprises, contacting the cell in vivo or in vitro with Compound (I), and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

embedded image

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13. METHODS FOR MODULATING ISOFORM PRODUCTION

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

One aspect described herein is a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating exon inclusion or exon exclusion in one or more mature RNA isoforms from a gene transcript in a cell comprising, contacting the cell in vivo or in vitro with Compound (I), wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the gene transcript is transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Methods for Treating a Disease

One aspect described herein is Compound (I) for use in a method, wherein the method treats a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the disease is selected from Table 14 or 15.

embedded image

Another aspect described herein is Compound (I) for use in the method, wherein a gene having the mutated transcript is selected from Table 14 or 15.

One aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein the disease is selected from Table 14 or 15.

Another aspect described herein is use of Compound (I) to treat a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the subject is human, wherein the disease is selected from Table 14 or 15.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering Compound (I) to the subject, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, wherein one or more of the mature RNA isoforms produce a functional protein, and wherein the disease is selected from Table 14 or 15.

Another aspect described herein is a method for treating a disease associated with or mediated by a mutation in a gene transcript in a subject in need thereof comprising, administering to the subject a pharmaceutical composition of Compound (I) and a pharmaceutically acceptable carrier, excipient, or diluent, wherein exon inclusion or exon exclusion is modulated in one or more mature RNA isoforms produced from the gene transcript, and wherein the disease is selected from Table 14 or 15.

Table 14 lists diseases associated with genes having a mutated transcript identified by Clin VAR SpliceAI scores and the CNN Model, as described herein, that are predicted to be modulated by Compound (I) toward either or both exon exclusion and exon inclusion.

TABLE 14

Gene
Disease

ABCA4
Stargardt disease 1

ABCC9
Hypertrichotic osteochondrodysplasia;

Dilated cardiomyopathy 1O

ACADSB
Deficiency of 2-methylbutyryl-CoA dehydrogenase

ADAM10
Reticulate acropigmentation of Kitamura

AGK
Inborn genetic diseases; Sengers syndrome;

Cataract, autosomal recessive congenital 5

ALDH3A2
Sjögren-Larsson syndrome

ALMS1
not provided

ANTXR2
Hyaline fibromatosis syndrome

APC
Hereditary cancer-predisposing syndrome;

Familial adenomatous polyposis 1

ARMC9
Joubert Syndrome 30; ARMC9-related

Joubert syndrome

ASAH1
Farber disease

ASPM
Microcephaly; Primary autosomal

recessive microcephaly 5

ATM
Ataxia-telangiectasia syndrome; Familial cancer

of breast; Hereditary cancer-predisposing syndrome

ATRX
ATR-X syndrome

BBS4
Bardet-Biedl syndrome

BFSP1
Cataract 33, multiple types

BMPR2
Primary pulmonary hypertension

BRCA1
Hereditary breast and ovarian cancer

syndrome; Hereditary cancer-predisposing

syndrome; Breast-ovarian cancer, familial 1

BRCA2
Tracheoesophageal fistula; Medulloblastoma;

Malignant tumor of prostate;

Hereditary breast and ovarian cancer

syndrome; Familial cancer of breast;

Hereditary cancer-predisposing syndrome;

Fanconi anemia, complementation

group D1; Breast-ovarian cancer, familial

2; Breast and/or ovarian cancer;

Glioma susceptibility 3; Pancreatic

cancer 2; Wilms tumor 1

BRIP1
Hereditary cancer-predisposing syndrome;

Familial cancer of breast; Fanconi

anemia, complementation group J

CA5A
Carbonic anhydrase VA deficiency,

hyperammonemia due to

CAPN3
Muscle weakness; Muscular Diseases;

Absent Achilles reflex

CD3D
Immunodeficiency 19

CDAN1
Congenital dyserythropoietic anemia, type I

CDH1
Hereditary cancer-predisposing syndrome

CDH23
Usher syndrome, type 1D

CERKL
Retinitis pigmentosa; Retinitis pigmentosa 26

CFTR
Inborn genetic diseases; Cystic fibrosis;

Hereditary pancreatitis

CHD7
Inborn genetic diseases

CLCN1
Congenital myotonia, autosomal recessive

form; Congenital myotonia,

autosomal dominant form

CLMP
Intestinal pseudo-obstruction

CLN3
Juvenile neuronal ceroid lipofuscinosis

CNGB3
Achromatopsia 3

COG6
Congenital disorder of glycosylation type 2L

COL11A1
Connective tissue disorder

COL3A1
Ehlers-Danlos syndrome, type 4

COL4A3
Alport syndrome, autosomal recessive

COL4A5
Alport syndrome 1, X-linked recessive

COL5A2
Ehlers-Danlos syndrome, classic type

COL6A1
Bethlem myopathy 1

COL7A1
Transient bullous dermolysis of the newborn

CSTB
Unverricht-Lundborg syndrome

CTNS
Nephropathic cystinosis

CTSK
Pyknodysostosis

CTU2
Microcephaly, facial dysmorphism, renal

agenesis, and ambiguous genitalia syndrome

CUBN
Megaloblastic anemia due to inborn

errors of metabolism

CWC27
Retinitis pigmentosa with or without

skeletal anomalies

CYBB
Chronic granulomatous disease, X-linked

DCX
Heterotopia

DGKE
Hemolytic-uremic syndrome

DGUOK
not provided

DMD
Becker muscular dystrophy

DNAH5
Ciliary dyskinesia

DNAH9
Ciliary dyskinesia, primary, 40

DYNC2H1
Jeune thoracic dystrophy; Short-rib thoracic

dysplasia 3 with or without polydactyly

DYNC2LI1
Short-rib thoracic dysplasia 15 with polydactyly

EBF3
Hypotonia, ataxia, and delayed

development syndrome

EBP
Chondrodysplasia punctata 2 X-linked

dominant; MEND syndrome

EP300
Rubinstein-Taybi syndrome 2

ERCC6
Cockayne syndrome B

F10
Factor X deficiency

F13A1
Factor XIII subunit A deficiency

F8
Hereditary factor VIII deficiency disease

FBN1
Marfan syndrome; Cardiovascular phenotype

FIG4
Polymicrogyria, Amyotrophic lateral

sclerosis 11, Charcot-Marie-Tooth

disease, type 4J, Yunis-Varon syndrome

FLT3
Acute myeloid leukemia

FUT8
Congenital disorder of glycosylation

with defective fucosylation 1

G6PC
Glycogen storage disease type 1A

GAA
Glycogen storage disease, type II

GABRG2
Rolandic epilepsy

GCK
Maturity-onset diabetes of the young, type 2

GLA
Fabry disease; Fabry disease, cardiac variant

GNB5
Intellectual developmental disorder

with cardiac arrhythmia

GNPTAB
Pseudo-Hurler polydystrophy; I cell disease;

Mucolipidosis III alpha/beta, atypical

GPR143
Ocular albinism, type I

GPX4
Spondylometaphyseal dysplasia Sedaghatian type

GRHPR
Nephrocalcinosis; Nephrolithiasis

GRN
Frontotemporal dementia

GUCY2C
Meconium ileus

GYPA
BLOOD GROUP ERIK

HBB
beta Thalassemia

HFE
Hemochromatosis type 1

IDH1
Hepatocellular carcinoma; Medulloblastoma;

Acute myeloid leukemia;

Transitional cell carcinoma of the bladder;

Multiple myeloma; Astrocytoma;

Brainstem glioma; Lung adenocarcinoma;

Neoplasm of brain; Neoplasm of the

breast; Neoplasm of the large intestine;

Malignant melanoma of skin; Adenoid

cystic carcinoma; Glioblastoma; Myelodysplastic

syndrome; Adenocarcinoma of prostate

IFT57
Orofaciodigital Syndrome XVIII

IL36RN
Pustular psoriasis, generalized

KDSR
Erythrokeratodermia variabilis et progressiva 4

KIAA0586
Short-rib thoracic dysplasia 14 with polydactyly

KIAA1109
Alkuraya-Kucinskas Syndrome

KIF14
Microcephaly 20, primary, autosomal recessive

KIT
Partial albinism

KMT2D
Kabuki syndrome 1

KRIT1
not provided

LAMB3
Adult junctional epidermolysis bullosa

LDLR
Familial hypercholesterolemia

LHCGR
Leydig cell agenesis

LIPA
Lysosomal acid lipase deficiency

LMNA
Cardiovascular phenotype; Benign scapuloperoneal

muscular dystrophy with cardiomyopathy

MAPT
Frontotemporal dementia

MCFD2
Factor v and factor viii, combined deficiency of, 2

MLH1
Hereditary nonpolyposis colon cancer;

Hereditary cancer-predisposing

syndrome; Lynch syndrome

MMAB
Methylmalonic aciduria cblB type

MPC1
Mitochondrial pyruvate carrier deficiency

MSH2
Hereditary cancer-predisposing syndrome

MTM1
Severe X-linked myotubular myopathy

MYBPC3
Hypertrophic cardiomyopathy

MYO7A
Usher syndrome, type 1

NF1
Multiple cafe-au-lait spots; Hereditary

cancer-predisposing syndrome;

Neurofibromatosis, type 1

NIPBL
Cornelia de Lange syndrome 1

NPHP1
Nephronophthisis; Nephronophthisis 1

NR3C2
Pseudohypoaldosteronism type 1 autosomal dominant

NSD1
Beckwith-Wiedemann syndrome

OCA2
Tyrosinase-positive oculocutaneous albinism

OFD1
Oral-facial-digital syndrome

OGT
Mental retardation, X-Linked 106

ORC6
Meier-Gorlin syndrome 3

OTC
not provided

OTOGL
Deafness, autosomal recessive 84b

PAFAH1B1
Lissencephaly 1

PAH
Phenylketonuria

PARN
Dyskeratosis congenita, autosomal recessive 6

PDCD10
Cerebral cavernous malformations 3

PIGN
Multiple congenital anomalies-

hypotonia-seizures syndrome 1

PMS2
Hereditary nonpolyposis colon cancer;

Hereditary cancer-predisposing

syndrome; Lynch syndrome; Turcot syndrome

POLG
Seizures; Progressive sclerosing poliodystrophy

POMGNT1
Congenital muscular dystrophy-

dystroglycanopathy with brain and eye

anomalies, type A3; Muscle eye brain disease

PPT1
Ceroid lipofuscinosis neuronal 1

PRMT7
Short stature, brachydactyly, intellectual

developmental disability, and seizures

PTEN
Hereditary cancer-predisposing syndrome; PTEN

hamartoma tumor syndrome; Cowden syndrome 1

RAD51B
Hereditary breast and ovarian cancer syndrome;

Hereditary cancer-predisposing syndrome

RAD51C
Hereditary cancer-predisposing syndrome;

Fanconi anemia, complementation

group O; Breast-ovarian cancer, familial 3

RB1
Hereditary cancer-predisposing syndrome;

Retinoblastoma

RHAG
Rh-null, regulator type

RNF216
Hypogonadotropic hypogonadism 7 with

or without anosmia; Leukodystrophy

RTTN
Congenital microcephaly; Microcephaly,

short stature, and polymicrogyria with

or without seizures

SCN1A
Severe myoclonic epilepsy in infancy

SCN5A
Brugada syndrome 1

SDCCAG8
Senior-Loken syndrome 7

SDHD
Pheochromocytoma; Hereditary cancer-

predisposing syndrome; Paraganglioma

and gastric stromal sarcoma; Paragangliomas

1; Cowden syndrome 3

SLC10A7
Short stature, amelogenesis imperfecta,

and skeletal dysplasia with scoliosis

SLC12A1
Bartter syndrome, type 1, antenatal

SLC4A11
Corneal endothelial dystrophy

SMS
Snyder Robinson syndrome

SNX10
Osteopetrosis, autosomal recessive 8

SPAST
Spastic paraplegia 4, autosomal dominant

SPG11
Spastic paraplegia 11, autosomal recessive

SPTA1
Congenital hemolytic anemia; Hereditary

pyropoikilocytosis; Spherocytosis type 3

SPTB
Spherocytosis type 2

SRD5A2
3-Oxo-5 alpha-steroid delta

4-dehydrogenase deficiency

STK11
Peutz-Jeghers syndrome

STXBP1
Inborn genetic diseases

SYNGAP1
Mental retardation, autosomal dominant 5

TCIRG1
Osteopetrosis autosomal recessive 1

TECTA
Nonsyndromic hearing loss and deafness

TFR2
Hemochromatosis type 3

TGFBR2
Loeys-Dietz syndrome 2

TJP2
Progressive familial intrahepatic cholestasis 4

TMEM138
Joubert syndrome 16

TMPRSS6
Microcytic anemia

TP53
Hereditary cancer-predisposing

syndrome; Li-Fraumeni syndrome

TPO
Deficiency of iodide peroxidase

TRAPPC2
Spondyloepiphyseal dysplasia tarda

TRIM37
Mulibrey nanism syndrome

TYR
Tyrosinase-negative oculocutaneous albinism

UROD
Familial porphyria cutanea tarda

VMA21
Inborn genetic diseases; Myopathy,

X-linked, with excessive autophagy

VPS13B
not provided

WDR35
Short rib polydactyly syndrome 5

WDR73
Galloway-Mowat syndrome 1

XPC
Xeroderma pigmentosum, group C

Table 15 lists diseases associated with mutated genes that may be modulated toward exon inclusion, as disclosed in International Publication No. WO2016/115434.

TABLE 15

GeneBank

Gene
Gene Name
Associated Diseases
Acc. No.

ARFGEF2
ADP-
Periventricular
NG 011490.1

ribosylation
heterotopia

factor guanine
with microcephaly

nucleotide-

exchange

factor 2

(brefeldin

A-inhibited)

ARHGEF6
RHO guanine
Mental retardation,
NG 008873.1

nucleotide
X-linked 46

exchange

factor 6

CACNA1S
Calcium
Hypokalemic
NG 009816.1

channel,
periodic paralysis,

voltage-
type 1; Malignant

dependent,
hyperthermia

L Type, alpha-
susceptibility 5;

IS subunit
Thyrotoxic periodic

paralysis,

susceptibility to, 1

CC2D2A
Coiled-coil
COACH syndrome;
NG 013035.1

and C2
Joubert syndrome

domain-
9; Meckel syndrome 6

containing

protein 2A

CDKL5
Cyclin-
Angelman syndrome-like;
NG 008475.1

dependent
Epileptic encephalopathy,

kinase-like 5
early infantile, 2

CHD2
Chromodomain
Epileptic encephalopathy,
NG 012826.1

helicase DNA-
childhood-onset

binding protein 2

CHD7
Chromodomain
CHARGE syndrome;
NG 007009.1

helicase DNA-
Hypogonadotropic

binding protein 7
hypogonadism 5 with

or without anosmia;

Scoliosis, idiopathic 3

CHD8
Chromodomain
Autism, susceptibility
NG 021249.1

helicase DNA-

binding protein 8

CHRNA4
Cholinergic
Epilepsy, nocturnal
NG 011931.1

receptor,
frontal lobe, 1; Nicotine

neuronal
addiction, susceptibility to

nicotinic, alpha

polypeptide 4

Cl9orfl2
Chromosome
Spastic paraplegia 43,
NG 031970.1

10 open
autosornal recessive;

reading frame 12
Neurodegeneration with

brain iron accumulation 4

COL6A3
Collagen type
Bethlem myopathy;
NG 008676.1

VI, alpha-3
Ullrich congenital

muscular dystrophy

CUL4B
Cullin 4b
Mental retardation,
NG 009388.1

X-linked,

syndromic 15

(Cabezas type)

DEPDC5
DEP domain-
Epilepsy, familial focal,
NG 034067.1

containing
with variable foci

protein 5

DES
Desmin
Muscular dystrophy,
NG 008043.1

limb-girdle, type 2R;

Cardiomyopathy,

dilated, 11; Myopathy,

myofibrillar, 1;

Scapuloperoneal

syndrome,

neurogenic, Kaeser type

DMD
Dystrophin
Becker muscular
NG 012232.1

dystrophy;

Cardiomyopathy,

dilated, 3B; Duchenne

muscular dystrophy

DNAJC6
DNAJ/HSP40
Parkinson disease 19,
NG 033843.1

homology
juvenile-onset

subfamily

C member6

DYNC2H1
Dynein,
Short-rib thoracic
NG 016423.1

cytoplasmic 2
dysplasia 3 with or

heavy chain 1
without polvdactvlv

FBN1
Fibrillin 1
Acromicric
NG 008805.2

dysplasia; Aortic

aneurysm, ascending,

and dissection; Ectopia

lentis, familial; Marfan

syndrome;

MASS syndrome;

Stiff skin syndrome;

Weill-Marchesani

syndrome

2, dominant

FIG4
SAC domain-
Polymicrogyria, bilateral
NG 007977.1

containing
temporooccipital,

inositol
Amyotrophic lateral

phosphatase 3
sclerosis 11,

Charcot-Marie-Tooth

disease, type 4J,

Yunis-Varon syndrome

FKTN
Fukutin
Cardiomyopathy, dilated,
NG 008754.1

IX; Muscular dystrophy-

dystroglycanopathy

(congenital with brain

and eye anomalies),

type A4, B4 and C4

FMR1
Fragile X mental
Fragile X syndrome;
NG 007529.1

retardation
Fragile X

protein
tremor/ataxia syndrome;

Premature ovarian

failure 1

GOSR2
Golgi SNAP
Epilepsy, progressive
NG 031806.1

receptor
myoclonic 6

complex

member 2

GRIN2A
Glutamate
Epilepsy, focal,
NG 011812.1

receptor,
with speech disorder

ionotropic,
and with or without

N-methyl-
mental retardation

D-aspartate,

subunit 2A

HDAC8
Histone
Cornelia de Lange
NG 015851.1

deacetylase 8
syndrome 5;

Wilson-Turner svndrome

IGHMBP2
Immunoglobin 2
Charcot-Marie-Tooth
NG 007976.1

MU-binding
disease, axonal, type 2S;

protein2
Neuronopathy, distal

hereditary motor, type VI

IKBKAP
Inhibitor of
Dysautonomia, familial
NG 008788.1

kappa light

polypeptide gene

enhancer

in B cells,

kinase complex-

associated

protein

KDM5C
Lysine-specific
Mental retardation,
NG 008085.1

demethylase 5C
X-linked, syndromic,

Claes-Jensen type

LAMA2
Laminin alpha-2
Muscular dystrophy,
NG 008678.1

congenital

merosin-deficient;

Muscular dystrophy,

congenital, due

to partial

LAMA2 deficiency

LRRK2
Leucine-rich
Parkinson disease 8
NG 011709.1

repeat kinase 2

LRSAM1
Leucine-rich
Charcot-Marie-Toothe
NG 032008.1

repeat-and
disease, axonal, type 2P

sterile

alpha motif-

containing 1

MBD5
Methyl-CpG-
Mental retardation,
NG 017003.1

binding
autosomal dominant 1

domain protein 5

MECP2
Methyl-CpG-
Angelman syndrome;
NG 007107.2

binding
Encephalopathy,

protein 2
neonatal severe;

Mental retardation,

X-linked syndromic,

Lubs type; Mental

retardation, X-linked,

syndromic 13; Rett

syndrome; Rett syndrome,

preserved speech

variant; Autism

susceptibility, X-linked 3

MICU1
Mitochondrial
Myopathy with
NG 033179.1

calcium
extrapyramidal signs

uptake protein 1

MTM1
Myotubularin 1
Myotubular mvopathv,
NG 008199.1

X-linked

NEB
Nebulin
Nemaline myopathy 2,
NG 009382.2

autosomal recessive

OPHN1
Oligophreninl
Mental retardation,
NG 008960.1

X-linked, with

cerebellar hypoplasia and

distinctive facial

appearance

PGAP1
Post-GPI
Mental retardation,
NC 000002.12

attachment to
autosomal
Range:

proteins 1
recessive 42
196833004

19692 6995

PLEC
Plectin
Epidermolysis bullosa
NG 012492.1

simplex with

pyloric atresia;

Epidermolysis bullosa

simplex, Ogna type;

Muscular dystrophy with

epidermolysis

bullosa simplex;

Muscular dystrophy,

limb-girdle, type 2Q

RBI
Retinoblastoma
Bladder cancer,
NG 009009.1

1
somatic; Osteosarcoma,

somatic; Retinoblastoma;

Retinoblastoma,

trilateral; Small cell

cancer of the

lung, somatic

RYR1
Ryanodine
Central core disease;
NG 008866.1

receptor 1
King-Denbo rough

syndrome; Minicore

myopathy with external

ophthalmoplegia;

Neuromuscular disease,

congenital, with uniform

type 1 fiber;

Malignant hyperthermia

susceptibility 1

SBF2
SET-binding
Charcot-Marie-Tooth
NG 008074.1

factor 2
disease, type 4B2

SCN9A
Sodium channel,
Epilepsy, generalized,
NG 012798.1

voltage-
with febrile seizures

gated, type
plus, type 7;

IX, alpha subunit
Erythermalgia,

primary; Febrile seizures,

familial, 3B; HSAN2D,

autosomal recessive;

Paroxysmal extreme

pain disorder, Small

fiber neuropathy; Dravet

syndrome, modifier of

SCN1A
Sodium channel,
Dravet syndrome;
NG 011906.1

neuronal type 1,
Epilepsy, generalized,

alpha subunit
with febrile seizures

plus, type 2;

Febrile seizures,

familial, 3A; Migraine,

familial hemiplegic, 3

SLC35A3
Solute carrier
Arthrogryposis, mental
NG 033857.1

family 35
retardation, and seizures

(UDP-N-

acetylglucos-

amine

transporter)

member 3

SLC6A8
Solute carrier
Cerebral creatine
NG 012016.1

family 6
deficiency syndrome 1

(neurotransmitter

transporter

creatine)

member 8

SLC9A9
Solute carrier
Autism susceptibility
NG 017077.1

family 9

(sodium/

hydrogen

exchanger)

member 9

SMCHD1
Structural
Fascioscapulohumer al
NG 031972.1

maintenance of
muscular

chromosomes
dystrophy 2, digenic

flexible hinge

domain-

containing

protein 1

STXBP1
Syntaxin-binding
Epileptic encephalopathy,
NG 016623.1

protein 1
early infantile, 4

SYNGAP1
Synaptic RAS-
Mental retardation,
NG 016137.1

GTPase-
autosomal dominant 5

activating

protein 1

SZT2
Seizure
Epileptic encephalopathy,
NG 029091.1

threshold 2
early infantile, 18

TSC2
Tuberin
Lymphangioleiomyo
NG 005895.1

matosis, somatic;

Tuberous sclerosis-2

TSC1
Hamartin
Focal cortical dysplasia,
NG 012386.1

Taylor balloon cell type;

Lymphangioleiomyo

matosis;

Tuberous sclerosis-I

WDR45
WD40 repeat-
Neurodegeneration with
NG 033004.1

containing
brain iron accumulation 5

protein 45

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from Table 14 or 15.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from Table 14.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from Table 15.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is other than a disease selected from Table 14 or 15.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is other than a disease selected from Table 14.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is other than a disease selected from Table 15.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from the group consisting of: 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency, Absent Achilles reflex, Achromatopsia 3, Acute myeloid leukemia, Adenocarcinoma of prostate, Adenoid cystic carcinoma, Adult junctional epidermolysis bullosa, Alkuraya-kucinskas syndrome, Alport syndrome (Autosomal recessive), Alport syndrome 1 (X-linked recessive), Ambiguous genitalia syndrome, Amelogenesis imperfecta (Short stature and skeletal dysplasia with scoliosis), Amyotrophic lateral sclerosis, Astrocytoma, Ataxia, Ataxia-telangiectasia syndrome, ATR-X syndrome, Autism spectrum disorders, Autism, Bardet-Biedl syndrome, Bartter syndrome (Type 1, antenatal), Becker muscular dystrophy, Beckwith-Wiedemann syndrome, Benign scapuloperoneal muscular dystrophy with cardiomyopathy, Beta thalassemia, Bethlem myopathy 1, Blood group ERIK, Brainstem glioma, Breast cancer (familial), Breast-ovarian cancer (familial 1), Breast-ovarian cancer (familial 2), Breast-ovarian cancer (Familial 3), Breast-ovarian cancer, Brugada syndrome 1, Carbonic anhydrase VA deficiency (hyperammonemia due to), Cardiovascular phenotype, Cataract (autosomal recessive congenital 5), Cataract 33 (multiple types), Cerebral cavernous malformations 3, Ceroid lipofuscinosis neuronal 1, Charcot-Marie-Tooth disease, CHARGE syndrome, Chondrodysplasia punctata 2 (X-linked dominant), Chronic granulomatous disease (X-linked), Ciliary dyskinesia (Primary 40), Ciliary dyskinesia, Cockayne syndrome B, Congenital disorder of glycosylation (Type 2L), Congenital disorder of glycosylation with defective fucosylation, Congenital dyserythropoietic anemia (Type I), Congenital hemolytic anemia, Congenital microcephaly, Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (Type A3), Congenital myotonia (Autosomal dominant form), Congenital myotonia (Autosomal recessive form), Connective tissue disorder, Corneal endothelial dystrophy, Cornelia de Lange syndrome 1, Cowden syndrome 1, Cowden syndrome 3, Cystic fibrosis (Atypical), Cystic fibrosis, Deafness (Autosomal recessive 84b), Deficiency of 2-methylbutyryl-CoA dehydrogenase, Deficiency of iodide peroxidase, Delayed development syndrome, Dementia, Dilated cardiomyopathy 10, Dyskeratosis congenita (Autosomal recessive 6), Ehlers-Danlos syndrome (Classic type), Ehlers-Danlos syndrome (Type 4), Epilepsy, Epileptic encephalopathy, Erythrokeratodermia variabilis et progressiva 4, Fabry disease (Cardiac variant), Fabry disease, Facial dysmorphism, Factor v and Factor viii (combined deficiency of, 2), Factor X deficiency, Factor XIII subunit A deficiency, Familial adenomatous polyposis 1, Familial cancer of breast, Familial dysautonomia, Familial hypercholesterolemia, Familial isolated growth hormone deficiency type II, Familial porphyria cutanea tarda, Fanconi anemia (complementation group D1), Fanconi anemia (complementation group J), Fanconi anemia (Complementation group O), Farber disease, Frasier syndrome, Frontotemporal dementia, Galloway-Mowat syndrome 1, Glioblastoma, Glioma susceptibility 3, Glycogen storage disease (Type 1A), Glycogen storage disease (Type II), Hemochromatosis (Type 1), Hemochromatosis (Type 3), Hemolytic-uremic syndrome, Hepatocellular carcinoma, Hereditary breast and ovarian cancer syndrome, Hereditary cancer-predisposing syndrome, Hereditary factor VIII deficiency disease, Hereditary nonpolyposis colon cancer, Hereditary pancreatitis, Hereditary pyropoikilocytosis, Heterotopia, Huntington's disease, Hyaline fibromatosis syndrome, Hypertrichotic osteochondrodysplasia, Hypertrophic cardiomyopathy, Hypogonadotropic hypogonadism 7 with anosmia, Hypogonadotropic hypogonadism 7 without anosmia, Hypotonia, I cell disease, Immunodeficiency 19, Inborn genetic diseases, Intellectual developmental disability (with short stature, brachydactyly and seizures), Intellectual developmental disorder (Cardiac arrhythmia), Intestinal pseudo-obstruction, Jeune thoracic dystrophy, Joubert syndrome (Armc9-related), Joubert syndrome 16, Joubert syndrome 30, Juvenile neuronal ceroid lipofuscinosis, Kabuki syndrome 1, Leukodystrophy, Leydig cell agenesis, Li-Fraumeni syndrome, Lissencephaly 1, Loeys-Dietz syndrome 2, Lung adenocarcinoma, Lynch syndrome, Lysosomal acid lipase deficiency, Malignant melanoma of skin, Malignant tumor of prostate, Marfan syndrome (Cardiovascular phenotype), Marfan syndrome, Maturity-onset diabetes of the young (Type 2), Meconium ileus, Medulloblastoma, Megaloblastic anemia due to inborn errors of metabolism, Meier-Gorlin syndrome 3, MEND syndrome, Menkes disease, Mental retardation (Autosomal dominant 5), Mental retardation (X-linked 106), Methylmalonic aciduria (cblB type), Microcephaly (short stature), Microcephaly 20 (Primary, autosomal recessive), Microcephaly 5 (Primary autosomal recessive), Microcephaly, Microcytic anemia, Mitochondrial DNA-depletion syndrome 3, Mitochondrial pyruvate carrier deficiency, Mucolipidosis III alpha/beta (Atypical), Mulibrey nanism syndrome, Multiple cafe-au-lait spots, Multiple congenital anomalies-hypotonia-seizures syndrome 1, Multiple myeloma, Muscle eye brain disease, Muscle weakness, Muscular diseases, Muscular dystrophies, Myelodysplastic syndrome, Myopathies, Myopathy (X-linked, with excessive autophagy) Myotonic dystrophy (Type 1), Myotonic dystrophy (Type 2), Neoplasm of the brain, Neoplasm of the breast, Neoplasm of the large intestine, Nephrocalcinosis, Nephrolithiasis, Nephronophthisis 1, Nephronophthisis, Nephropathic cystinosis, Neurofibromatosis (Peripheral), Neurofibromatosis (Type 1), Neurofibromatosis (Von Recklinghausen), Nonsyndromic hearing loss and deafness, Occipital horn syndrome, Ocular albinism (Type I), Oral-facial-digital syndrome, Orofaciodigital syndrome XVIII, Osteopetrosis (Autosomal recessive 8), Osteopetrosis (Autosomal recessive 1), Ovarian cancer, Pancreatic cancer 2, Paraganglioma and gastric stromal sarcoma, Paragangliomas 1, Parkinson's disease linked to Chromosome 17, Parkinson's disease, Partial albinism, Peutz-Jeghers syndrome, Phenylketonuria, Pheochromocytoma, Polymicrogyria with seizures, Polymicrogyria without seizures, Primary pulmonary hypertension, Progressive familial intrahepatic cholestasis 4, Progressive sclerosing poliodystrophy, Pseudo-Hurler polydystrophy, Pseudohypoaldosteronism type 1 (Autosomal dominant), PTEN hamartoma tumor syndrome, Pustular psoriasis (Generalized), Pyknodysostosis, Renal agenesis, Reticulate acropigmentation of Kitamura, Retinitis pigmentosa 26, Retinitis pigmentosa with skeletal anomalies, Retinitis pigmentosa without skeletal anomalies, Retinitis pigmentosa, Retinoblastoma, Rh-null (Regulator type), Rolandic epilepsy, Rubinstein-Taybi syndrome 2, Schizophrenia, Seizures, Sengers syndrome, Senior-Loken syndrome 7, Severe myoclonic epilepsy (Infancy), Severe X-linked myotubular myopathy, Short rib polydactyly syndrome 5, Short-rib thoracic dysplasia 14 with polydactyly, Short-rib thoracic dysplasia 15 with polydactyly, Short-rib thoracic dysplasia 3 with polydactyly, Short-rib thoracic dysplasia 3 without polydactyly, Sj√∂gren-Larsson syndrome, Snyder Robinson syndrome, Spastic paraplegia 11 (Autosomal recessive), Spastic paraplegia 4 (Autosomal dominant), Spherocytosis type 2, Spherocytosis type 3, Spondyloepiphyseal dysplasia tarda, Spondylometaphyseal dysplasia (Sedaghatian type), Stargardt disease 1, Tracheoesophageal fistula, Transient bullous dermolysis of the newborn, Transitional cell carcinoma of the bladder, Tuberous sclerosis, Turcot syndrome, Tyrosinase-negative oculocutaneous albinism, Tyrosinase-positive oculocutaneous albinism, Unverricht-Lundborg syndrome, Usher syndrome (Type 1), Usher syndrome (Type 1D), Wilms tumor 1, and Xeroderma pigmentosum (Group C), and wherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from: Autism, Blood group ERIK, Breast cancer, Ovarian cancer, Dementia, Epilepsy, Mental retardation, Muscular dystrophies, Myopathies, Neurofibromatosis 1, Parkinson's disease, or Schizophrenia, and wherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from: 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency, Amyotrophic lateral sclerosis, Ataxia-telangiectasia syndrome, Atypical cystic fibrosis, Autism, Autism spectrum disorders, Beckwith-Wiedemann syndrome, Beta thalassemia, Blood group ERIK, Breast cancer, Ovarian cancer, Carbonic anhydrase VA deficiency, Charcot-Marie-Tooth disease, CHARGE syndrome, Ciliary dyskinesia, Congenital hemolytic anemia, Deficiency of iodide peroxidase, Dementia, Dyskeratosis congenita, Epilepsy, Epileptic encephalopathy, Fabry disease, Familial dysautonomia, Familial isolated growth hormone deficiency type II, Frasier syndrome, Frontotemporal dementia, Huntington's disease, Lysosomal acid lipase deficiency, Marfan syndrome, Meier-Gorlin syndrome 3, Menkes Disease, Mental retardation, Mitochondrial DNA-depletion syndrome 3, Multiple congenital anomalies-hypotonia-seizures syndrome 1, Muscular dystrophies, Myopathies, Myotonic dystrophy type 1, Myotonic dystrophy type 2, Neurofibromatosis 1, Neurofibromatosis (Peripheral), Neurofibromatosis (Von Recklinghausen), Occipital horn syndrome, Osteopetrosis autosomal recessive 1, Parkinson's disease, Parkinson's linked to Chromosome 17, Progressive sclerosing poliodystrophy, Pustular psoriasis, Retinoblastoma, Schizophrenia, Spondylometaphyseal dysplasia, or Tuberous sclerosis, and wherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from: 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency, Amyotrophic lateral sclerosis, Ataxia-telangiectasia syndrome, Atypical cystic fibrosis, Autism spectrum disorders, Beckwith-Wiedemann syndrome, Beta thalassemia, Carbonic anhydrase VA deficiency, Charcot-Marie-Tooth disease, CHARGE syndrome, Ciliary dyskinesia, Congenital hemolytic anemia, Deficiency of iodide peroxidase, Dyskeratosis congenita, Epileptic encephalopathy, Fabry disease, Familial dysautonomia, Familial isolated growth hormone deficiency type II, Frasier syndrome, Frontotemporal dementia, Huntington's disease, Lysosomal acid lipase deficiency, Marfan syndrome, Meier-Gorlin syndrome 3, Menkes Disease, Mitochondrial DNA-depletion syndrome 3, Multiple congenital anomalies-hypotonia-seizures syndrome 1, Myotonic dystrophy type 1, Myotonic dystrophy type 2, Neurofibromatosis (Peripheral), Neurofibromatosis (Von Recklinghausen), Occipital horn syndrome, Osteopetrosis autosomal recessive 1, Parkinson's linked to Chromosome 17, Progressive sclerosing poliodystrophy, Pustular psoriasis, Retinoblastoma, Spondylometaphyseal dysplasia, or Tuberous sclerosis.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from Table 14 or 15.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from Table 14.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is other than a disease selected from Table 14.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is selected from Table 15.

Another aspect provided herein is a disease associated with or mediated by a mutation in a gene, wherein the disease is other than a disease selected from Table 15.

In Vitro and In Vivo Assays of RNA Transcripts

In one aspect, the cell(s) contacted or cultured with Compound (I) is from a cell line. In another aspect, the cell(s) contacted or cultured with Compound (I) is a cell line derived from a subject with a disease (e.g., a disease identified herein). In another aspect, the cell(s) contacted or cultured with Compound (I) is from a cell line known to have aberrant RNA transcript levels transcribed from a particular gene(s). In another aspect, the cell(s) contacted or cultured with Compound (I) is from a cell line derived from a subject with a disease known to have aberrant RNA transcript levels transcribed from a particular gene(s). In another aspect, the cell(s) contacted or cultured with Compound (I) is a cancer cell line. In another aspect, the cell(s) contacted or cultured with Compound (I) is from a cell line derived from a subject with a disease known to have an aberrant amount of an RNA isoform(s) transcribed from a particular gene(s), an aberrant amount of a protein isoform(s) produced from the particular gene(s), or both. Non-limiting examples of cell lines include 293, 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, H1B54, H1B55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NSO, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63, YAC-1, and YAR cells. In another aspect, the cells are fibroblasts differentiated from PSC (pluripotent stem cells). In another aspect, the cells are human fibroblasts. In another aspect, the cells are from a patient.

In another aspect, provided herein is a method for determining whether Compound (I) modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell or tissue sample with Compound (I); and (b) determining the amount of the RNA transcript produced by the tissue sample, wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that Compound (I) modulates the amount of the RNA transcript.

In another aspect, provided herein is a method for determining whether Compound (I) modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell or a first tissue sample with Compound (I), (b) contacting a second cell or a second tissue sample with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first cell or first tissue sample and the second cell or second tissue sample; and (d) comparing the amount of the RNA transcript produced by the first cell or first tissue sample to the amount of the RNA transcript produced by the second cell or second tissue sample, wherein an alteration in the amount of the RNA transcript produced by the first cell or first tissue sample relative to the amount of the RNA transcript produced by the second cell or second tissue sample indicates that Compound (I) modulates the amount of the RNA transcript. Any tissue sample containing cells may be used in the accordance with these methods. In another aspect, the tissue sample is a blood sample, a skin sample, a muscle sample, or a tumor sample. Techniques known to one skilled in the art may be used to obtain a tissue sample from a subject.

In another aspect, a dose-response assay is performed. In another aspect, the dose response assay comprises: (a) contacting a cell(s) with a concentration of Compound (I); (b) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that Compound (I) modulates the amount of the RNA transcript; (c) repeating steps (a) and (b), wherein the only experimental variable changed is the concentration of the compound; and (d) comparing the amount of the RNA transcript produced at the different concentrations of the compound. In another aspect, the dose response assay comprises: (a) culturing a cell(s) in the presence of Compound (I), (b) isolating the RNA transcript from the cell(s) after a certain period of time; (c) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that Compound (I) modulates the amount of the RNA transcript; (d) repeating steps (a), (b), and (c), wherein the only experimental variable changed is the concentration of the compound; and (e) comparing the amount of the RNA transcript produced at the different concentrations of the compound. In another aspect, the dose-response assay comprises: (a) contacting each well of a microtiter plate containing cells with a different concentration of Compound (I); (b) determining the amount of an RNA transcript produced by cells in each well; and (c) assessing the change of the amount of the RNA transcript at the different concentrations of the compound or form thereof.

In another aspect, the dose response assay comprises: (a) contacting cells with a concentration of Compound (I), wherein the cells are within the wells of a tissue culture container (e.g., a 96-well plate) at about the same density within each well, and wherein the cells are contacted with different concentrations of Compound (I) in different wells; (b) isolating the RNA from said cells in each well; (c) determining the amount of the RNA transcript produced by the cell(s) in each well; and (d) assessing change in the amount of the RNA transcript in the presence of one or more concentrations of compound relative to the amount of the RNA transcript in the presence of a different concentration of the compound or the absence of Compound (I) or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO).

In another aspect, contacting of the cell(s) with the compound occurs in cell culture. In another aspect, contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject.

In another aspect described herein, the cell(s) is contacted or cultured with Compound (I), or a tissue sample is contacted with Compound (I), or a negative control for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In another aspect described herein, the cell(s) is contacted or cultured with Compound (I), or a tissue sample is contacted with Compound (I), or a negative control for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.

In another aspect described herein, the cell(s) is contacted or cultured with a certain concentration of Compound (I), or a tissue sample is contacted with a certain concentration of Compound (I), wherein the certain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 60 μM, 75 μM, 100 μM, or 150 μM. In one aspect described herein, the cell(s) is contacted or cultured with certain concentration of Compound (I), or a tissue sample is contacted with a certain concentration of Compound (I), wherein the certain concentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In another aspect described herein, the cell(s) is contacted or cultured with certain concentration of Compound (I), or a tissue sample is contacted with a certain concentration of Compound (I), wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In another aspect described herein, the cell(s) is contacted or cultured with certain concentration of Compound (I), or a tissue sample is contacted with a certain concentration of Compound (I), wherein the certain concentration is between 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.

In another aspect, provided herein is a method for determining whether Compound (I) modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering Compound (I) to a subject (in another aspect, a non-human animal); and (b) determining the amount of the RNA transcript in a sample obtained from the subject, wherein an alteration in the amount of the RNA transcript measured in the sample from the subject administered the compound or form thereof relative to the amount of the RNA transcript in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that Compound (I) modulates the amount of the RNA transcript. In another aspect, provided herein is a method for determining whether Compound (I) modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering Compound (I) to a first subject (in another aspect, a non-human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in another aspect, a non-human animal) of the same species as the first subject; and (c) determining the amount of the RNA transcript in a first tissue sample from the first subject and the amount of the RNA transcript in the second tissue sample from the second subject; and (d) comparing the amount of the RNA transcript in the first tissue sample to the amount of the RNA transcript in the second tissue sample, wherein an alteration in the amount of the RNA transcript in the first tissue sample relative to the amount of the RNA transcript in the second tissue sample indicates that Compound (I) modulates the amount of the RNA transcript.

In another aspect, Compound (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In another aspect, a single dose of Compound (I) is administered to a subject in accordance with the methods described herein. In another aspect, 2, 3, 4, 5 or more doses of Compound (I) is administered to a subject in accordance with the methods described herein. In another aspect, Compound (I) is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.

In another aspect, provided herein is a method for determining whether Compound (I) modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering Compound (I) to a subject (in another aspect, a non-human animal); and (b) determining the amount of two or more RNA transcript splice variants in a sample obtained from the subject, wherein an alteration in the amount of the two or more RNA transcript splice variants measured in the sample from the subject administered the compound or form thereof relative to the amount of the two or more RNA transcript splice variants in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that Compound (I) modulates the splicing of the RNA transcript. In another aspect, provided herein is a method for determining whether Compound (I) modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering Compound (I) to a first subject (in another aspect, a non-human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in another aspect, a non-human animal) of the same species as the first subject; and (c) determining the amount of two or more RNA transcript splice variants in a first tissue sample from the first subject and the amount of two or more RNA transcript splice variants in the second tissue sample from the second subject; and (d) comparing the amount of the two or more RNA transcript splice variants in the first tissue sample to the amount of the two or more RNA transcript splice variants in the second tissue sample, wherein an alteration in the amount of the two or more RNA transcript splice variants in the first tissue sample relative to the amount of the two or more RNA transcript splice variants in the second tissue sample indicates that Compound (I) modulates the splicing of the RNA transcript. In another aspect, Compound (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In another aspect, a single dose of Compound (I) is administered to a subject in accordance with the methods described herein. In another aspect, 2, 3, 4, 5 or more doses of Compound (I) is administered to a subject in accordance with the methods described herein. In another aspect, Compound (I) is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent. In another aspect, Compound (I) that is contacted or cultured with a cell(s) or a tissue sample or administered to a subject is a compound described herein.

Techniques known to one skilled in the art may be used to determine the amount of an RNA transcript(s). In one aspect, the amount of one, two, three or more RNA transcripts is measured using deep sequencing, such as ILLUMIINA® RNASeq, ILLUMIINA® next generation sequencing (NGS), ION TORRENT™ RNA next generation sequencing, 454™ pyrosequencing, or Sequencing by Oligo Ligation Detection (SOLID™). In another aspect, the amount of RNA transcripts is measured using an exon array, such as the GENECHIP® human exon array. In another aspect, the amount of one, two, three or more RNA transcripts is determined by RT-PCR. In another aspect, the amount of one, two, three or more RNA transcripts is measured by RT-qPCR. Techniques for conducting these assays are known to one skilled in the art.

In another aspect, the stability of one or more RNA transcripts is determined by serial analysis of gene expression (SAGE), differential display analysis (DD), RNA arbitrarily primer (RAP)-PCR, restriction endonuclease-lytic analysis of differentially expressed sequences (READS), amplified restriction fragment-length polymorphism (ALFP), total gene expression analysis (TOGA), RT-PCR, RT-qPCR, high-density cDNA filter hybridization analysis (HDFCA), suppression subtractive hybridization (SSH), differential screening (DS), cDNA arrays, oligonucleotide chips, or tissue microarrays. In another aspect, the stability of one or more RNA transcripts is determined by Northern blots, RNase protection, or slot blots.

In another aspect, the transcription in a cell(s) or tissue sample is inhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) the cell or the tissue sample is contacted or cultured with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D. In another aspect, the transcription in a cell(s) or tissue sample is inhibited with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while the cell(s) or tissue sample is contacted or cultured with Compound (I).

In another aspect, the level of transcription of one or more RNA transcripts is determined by nuclear run-on assay or an in vitro transcription initiation and elongation assay. In another aspect, the detection of transcription is based on measuring radioactivity or fluorescence. In another aspect, a PCR-based amplification step is used.

In one aspect, the amount of alternatively spliced forms of the RNA transcripts of a particular gene are measured to see if there is an alteration in the amount of one, two or more alternatively spliced forms of the RNA transcripts of the gene. In another aspect, the amount of an isoform(s) encoded by a particular gene is measured to see if there is an alteration in the amount of the isoform(s). In another aspect, the levels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, or northern blotting. In another aspect, sequence-specific techniques may be used to detect the levels of an individual spliceoform. In another aspect, splicing is measured in vitro using nuclear extracts. In another aspect, detection is based on measuring radioactivity or fluorescence. Techniques known to one skilled in the art may be used to measure alterations in the amount of alternatively spliced forms of an RNA transcript of a gene and alterations in the amount of an isoform encoded by a gene.

Modulating Isoform Splicing

In some aspects, analysis is performed on data derived from the assay to measure the magnitude of splicing to determine the amount of exons spliced into an mRNA transcript that is produced in the presence of Compound (I) relative to the amount in the absence of Compound (I) or presence of a negative control. In a preferred aspect, the method utilized is calculation of change in Percent Spliced In (ΔPSI). The method utilizes read data from RNAseq (or any other method that can distinguish mRNA splice isoforms) to calculate the ratio (percentage) between reads that either demonstrate inclusion (junctions between the upstream exon and the exon of interest) or exclusion (junction between the upstream and downstream exons, excluding the exon of interest), to demonstrate whether the presence of Compound (I) affects the amount of exon inclusion relative to the amount of inclusion in the absence of Compound (I) or the presence of a negative control. The ΔPSI value is derived from the formula:

ΔPSI (%)=(C−U)×100

Where “U” represents the Percent Spliced In value for splicing to occur in the absence of Compound (I):

U=(a+b)/2/[(a+b)/2+c]

Where “C” represents the Percent Spliced In value for splicing to occur in the presence of Compound (I).

C=(a+b)/2/[(a+b)/2+c]

The values for “a” and “b” represent the number of reads supporting the probability for potential inclusion or exclusion of an exon in an RNA transcript. The “a” value is derived from the number of reads within an exon triplet covering, in 5′ to 3′ order: the last few bases (>1 nucleotide) of an upstream exon operably linked to the first few bases (>1 nucleotide) of a middle exon. The “b” value is derived from the number of reads within an exon triplet covering, in 5′ to 3′ order: the last few bases (>1 nucleotide) of the middle exon operably linked to the first few bases (>1 nucleotide) of a downstream exon. The number of reads will indicate whether the splice junction of a middle exon has been identified as potentially having a CNN Motif(s) by the CNN Model described herein, wherein the inclusion or exclusion of the middle exon may be modulated in the presence of Compound (I) to produce one or more mature RNA isoforms from the gene transcript. The value for “c” represents the number of reads supporting the exclusion of the middle exon.

Accordingly, an alteration in the CNN Motifs may affect the splicing toward one Class or another (inclusion or exclusion) of the middle exon in the presence of Compound (I), thus making the PSI value for “C” in the presence of Compound (I) different from the PSI value for “U” in the absence of Compound (I). The statistically significant value for the probability of inclusion or exclusion may be obtained according to statistical or probability analysis methods known to those of ordinary skill in the art.

In some aspects, a statistical analysis or other probability analysis is performed on data from the assay utilized to measure an RNA transcript. In certain aspects, for example, a Fisher's Exact Test statistical analysis is performed by comparing the total number of reads for the inclusion and exclusion of a middle exon based on data from one or more assays used to measure whether the amount of an RNA transcript is modulated in the presence of Compound (I) relative to the amount in the absence of Compound (I) or presence of a negative control. In specific aspects, the statistical analysis results in a confidence value for those modulated RNA transcripts of 10%, 5%, 4%, 3%, 2%, %, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%. In some specific aspects, the confidence value is a p value for those modulated RNA transcripts of 10%, 5%, 4%, 3%, 2%, 10%, 0.5%, 0.1%, 0.010%, 0.0010% or 0.00010%. In certain specific aspects, an exact test, student t-test or p value for those modulated RNA transcripts is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%, respectively.

[In certain aspects, a further analysis is performed to determine how Compound (I) is changing the amount of an RNA transcript(s). In specific aspects, a further analysis is performed to determine if modulation in the amount of an RNA transcript(s) in the presence of Compound (I) relative the amount of the RNA transcript(s) in the absence of Compound (I) or a form thereof, or the presence of a negative control is due to changes in transcription, splicing, and/or stability of the RNA transcript(s). Techniques known to one skilled in the art may be used to determine whether Compound (I) changes, e.g., the transcription, splicing and/or stability of an RNA transcript(s).

In certain aspects, the stability of one or more RNA transcripts is determined by serial analysis of gene expression (SAGE), differential display analysis (DD), RNA arbitrary primer (RAP)-PCR, restriction endonuclease-lytic analysis of differentially expressed sequences (READS), amplified restriction fragment-length polymorphism (ALFP), total gene expression analysis (TOGA), RT-PCR, RT-RPA (recombinase polymerase amplification), RT-qPCR, RNA-Seq, digital color-coded barcode technology, high-density cDNA filter hybridization analysis (HDFCA), suppression subtractive hybridization (SSH), differential screening (DS), cDNA arrays, oligonucleotide chips, or tissue microarrays. In other aspects, the stability of one or more RNA transcripts is determined by Northern blot, RNase protection, or slot blot.

In some aspects, the transcription in a cell(s) or tissue sample is inhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours) the cell or the tissue sample is contacted or cultured with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D. In other aspects, the transcription in a cell(s) or tissue sample is inhibited with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while the cell(s) or tissue sample is contacted or cultured with Compound (I).

In certain aspects, the level of transcription of one or more RNA transcripts is determined by nuclear run-on assay or an in vitro transcription initiation and elongation assay. In some aspects, the detection of transcription is based on measuring radioactivity or fluorescence. In some aspects, a PCR-based amplification step is used.

In specific aspects, the amount of alternatively spliced forms of the RNA transcripts of a particular gene are measured to see if there is modulation in the amount of one, two or more alternatively spliced forms of the RNA transcripts of the gene. In some aspects, the amount of an isoform(s) encoded by a particular gene is measured to see if there is modulation in the amount of the isoform(s). In certain aspects, the levels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, RNA-Seq, digital color-coded barcode technology, or Northern blot. In other aspects, sequence-specific techniques may be used to detect the levels of an individual spliceoform. In certain aspects, splicing is measured in vitro using nuclear extracts. In some aspects, detection is based on measuring radioactivity or fluorescence. Techniques known to one skilled in the art may be used to measure modulation in the amount of alternatively spliced forms of an RNA transcript of a gene and modulation in the amount of an isoform encoded by a gene.

Examples

To describe in more detail and assist in understanding the present description, the following non-limiting examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed. The examples below illustrate the usefulness of the CNN Model and the 39 CNN Motifs identified herein.

Identification of Genes Affected by Compound (I) Splicing Modulation Using a Convolutional Neural Network (CNN) Model

A specific deep learning convolutional neural network (CNN) was applied and optimized to discover nucleotide motifs likely to be responsive to splicing modulation by a small molecule splicing modulator Compound (I). As described herein, motifs likely to be responsive in 171 additional disease-associated genes using OMIM and ClinVar were identified. As further described herein, in vitro validation demonstrated that the CNN Model successfully predicted Compound (I) splice modulation in minigene assays and in patient-specific cell lines. This approach suggests that the integration of genomic datasets, clinical annotation of disease associated variants, and deep learning techniques have significant potential to predict therapeutic targeting for precision medicine.

The effect on splicing modulation and corresponding splice differences toward exon inclusion or exclusion was determined by counting the RNASeq reads covering two splice junctions of exon triplets (three consecutive exons: Exon U, Exon X, Exon D) and the corresponding intervening introns, then comparing the change in Percent Spliced In (ΔPSI or Δψ) of the middle exon (Exon X) after treatment (as shown in FIG. 2A)^52,53. 934 exon triplets were identified showing differential middle exon inclusion or exclusion in response to Compound (I) treatment. Of these, 254 were exon inclusion events (Δψ≥0.1 and FDR<0.1) and 680 were exon exclusion events (Δψ≤−0.1 and FDR<0.1) (as shown in FIG. 2B). Compound (I) exhibited selective splicing modulation activity for splicing changes in 0.58% of all expressed triplets (934 out of 161,097 expressed triplets). The effect of Compound (I) treatment on genes, as shown in FIG. 2C, demonstrated by reproducible PSI changes (Δψ) determined by RNA-seq, was confirmed. The splicing results were evaluated by RT-PCR in independent replicate experiments, confirming all the calculated Δψ values. These results suggest that Compound (I) targets a specific subset of exons for splicing modulation.

Pre-mRNA splicing is driven by sequence elements throughout exons and introns. These sequences govern interaction with the spliceosome and splicing factors and regulate the fate of exon recognition and inclusion^2,54. These sequence signatures within the exon triplets are the key determinate of small molecule splicing modulator compound responsiveness. To identify such sequences, a convolutional neural network (CNN) model was trained using the inclusion-response set (254 exon triplets), exclusion-response set (680 exon triplets) and the unchanged-response set (382 exon triplets, Δψ≤0.01) identified by RNASeq (see Table 16).

Gene Modulation Using Compound (I)

The effect of Compound (I) on transcriptome-wide splicing as measured by RNA sequence (RNASeq) analysis is provided in Table 16 (where Intron 1 is upstream of the affected Exon and Intron 2 is downstream; the Effect shown is Exc, Inc, or Unc representing Exclusion, Inclusion and Unchanged, respectively; C-PSI, T-PSI and ΔPSI are the average Percent Spliced In values for the initial PSI, Treated-PSI and ΔPSI, respectively and the associated p value), in which six different wildtype (WT) human fibroblast cell lines were treated with Compound (I) and vehicle (DMSO) for seven days.

TABLE 16

Gene
Intron1
Exon
Intron2
Effect
C-PSI
T-PSI
ΔPSI
p value

A1BG-AS1
58859211-
58864687-
58864841-
Exc
0.729
0.361
−0.368
5.73E−04

58864686
58864840
58865079

AAAS
53708226-
53708535-
53708634-
Exc
0.811
0.645
−0.166
9.73E−10

53708534
53708633
53708877

AAMDC
77532288-
77552065-
77552107-
Unc
0.465
0.460
−0.005
8.72E−01

77552064
77552106
77553524

ABCA1
107645439-
107646708-
107646850-
Exc
0.895
0.724
−0.172
4.32E−06

107646707
107646849
107651382

ABCA2
139917505-
139918290-
139918293-
Unc
0.900
0.902
0.003
9.85E−01

139918289
139918292
139918594

ABCA6
67085684-
67087284-
67087404-
Exc
0.991
0.852
−0.139
6.61E−06

67087283
67087403
67092380

ABCA9
66992156-
67003900-
67004014-
Exc
0.993
0.553
−0.439
6.55E−22

67003899
67004013
67004202

ABCB6
220079805-
220080719-
220080903-
Exc
0.979
0.874
−0.104
4.77E−04

220080718
220080902
220081085

ABCC3
48752838-
48752992-
48753137-
Exc
0.968
0.817
−0.150
1.13E−16

48752991
48753136
48753243

ABCC3
48736730-
48738284-
48738476-
Unc
0.856
0.850
−0.006
9.15E−01

48738283
48738475
48741041

ABCD4
74766379-
74766853-
74766972-
Unc
0.844
0.849
0.005
9.14E−01

74766852
74766971
74769577

ABHD14A-
52018175-
52019223-
52019288-
Exc
0.950
0.825
−0.125
1.20E−04

ACY1
52019222
52019287
52019376

ABHD16A
31668806-
31669851-
31669908-
Unc
0.820
0.826
0.006
9.16E−01

31669850
31669907
31670926

ABI1
27059275-
27060004-
27060019-
Inc
0.559
0.699
0.141
8.08E−08

27060003
27060018
27065993

ABI2
204267458-
204276008-
204276095-
Inc
0.475
0.634
0.158
8.84E−08

204276007
204276094
204281630

ABI3BP
100581230-
100581682-
100581754-
Exc
0.791
0.629
−0.162
7.19E−09

100581681
100581753
100582845

ABI3BP
100581230-
100582846-
100582921-
Exc
0.566
0.361
−0.205
3.25E−05

100582845
100582920
100583676

ABI3BP
100581230-
100581682-
100581754-
Exc
0.404
0.162
−0.241
2.59E−09

100581681
100581753
100583676

ABI3BP
100499054-
100506572-
100506647-
Unc
0.797
0.792
−0.005
1.77E−01

100506571
100506646
100508297

AC024560.3
197348740-
197349058-
197349202-
Exc
0.827
0.651
−0.176
5.59E−04

197349057
197349201
197350090

AC027612.6
91825060-
91842946-
91843024-
Inc
0.380
0.557
0.177
1.59E−05

91842945
91843023
91843393

AC037459.4
22447255-
22449064-
22449182-
Exc
0.864
0.542
−0.322
9.15E−124

22449063
22449181
22451245

ACAA1
38170880-
38173087-
38173130-
Exc
0.935
0.787
−0.148
1.21E−14

38173086
38173129
38173416

ACACA
35564715-
35567381-
35567405-
Exc
0.816
0.625
−0.191
3.02E−08

35567380
35567404
35578644

ACAD10
112147489-
112150302-
112150462-
Exc
0.960
0.786
−0.173
7.85E−04

112150301
112150461
112153624

ACAD10
112147489-
112148077-
112148170-
Unc
0.245
0.239
−0.006
8.44E−01

112148076
112148169
112150301

ACAP3
1230009-
1230098-
1230197-
Unc
0.867
0.859
−0.008
8.80E−01

1230097
1230196
1230826

ACBD4
43214144-
43214386-
43214507-
Exc
0.816
0.628
−0.187
3.62E−04

43214385
43214506
43214734

ACBD5
27508787-
27512136-
27512169-
Inc
0.127
0.253
0.126
5.61E−05

27512135
27512168
27512266

ACCS
44102871-
44103615-
44103743-
Unc
0.118
0.126
0.008
9.66E−01

44103614
44103742
44104718

ACIN1
23551046-
23559191-
23559311-
Inc
0.504
0.611
0.107
5.87E−05

23559190
23559310
23559730

ACLY
40049428-
40052873-
40052903-
Inc
0.610
0.792
0.181
1.68E−22

40052872
40052902
40054001

ACOT9
23751335-
23754036-
23754134-
Unc
0.891
0.887
−0.005
9.58E−01

23754035
23754133
23761241

ACOX1
73953648-
73956296-
73956457-
Inc
0.642
0.791
0.149
1.57E−04

73956295
73956456
73969705

ACSL3
223752607-
223765392-
223765499-
Inc
0.342
0.507
0.164
1.87E−10

223765391
223765498
223773450

ACSL4
108926896-
108939373-
108939426-
Exc
0.896
0.729
−0.167
5.02E−04

108939372
108939425
108976367

ACTN1
69349310-
69349590-
69349773-
Exc
0.978
0.863
−0.115
1.11E−92

69349589
69349772
69350884

ACTN1
69343958-
69345175-
69345241-
Unc
0.102
0.098
−0.003
1.48E−01

69345174
69345240
69345705

ACY1
52018175-
52019223-
52019288-
Exc
0.950
0.825
−0.125
1.20E−04

52019222
52019287
52019376

AD000671.6
36235323-
36235527-
36235640-
Exc
0.519
0.093
−0.426
1.77E−15

36235526
36235639
36236025

ADA
43249789-
43251229-
43251294-
Exc
0.943
0.813
−0.131
1.85E−05

43251228
43251293
43251469

ADAM15
155032820-
155033239-
155033309-
Unc
0.797
0.805
0.008
8.01E−01

155033238
155033308
155034720

ADAM33
3655341-
3655420-
3655497-
Exc
0.970
0.861
−0.108
6.77E−10

3655419
3655496
3655673

ADAMTSL4
150521976-
150522298-
150522372-
Exc
0.900
0.716
−0.183
3.37E−07

150522297
150522371
150524680

ADAMTSL4
150528843-
150529097-
150529270-
Exc
0.956
0.724
−0.231
2.64E−30

150529096
150529269
150529414

ADARB1
46603426-
46604389-
46604509-
Exc
0.761
0.649
−0.113
9.54E−05

46604388
46604508
46604837

ADK
76158338-
76285014-
76285185-
Exc
0.974
0.833
−0.141
7.08E−16

76285013
76285184
76349039

AFMID
76198833-
76200909-
76200982-
Inc
0.128
0.647
0.519
8.70E−13

76200908
76200981
76202026

AFTPH
64800203-
64806620-
64806681-
Unc
0.889
0.889
−0.001
9.61E−01

64806619
64806680
64812555

AFTPH
64800203-
64806620-
64808408-
Unc
0.838
0.832
−0.006
9.12E−01

64806619
64808407
64812555

AHI1
135813430-
135816952-
135817037-
Inc
0.370
0.584
0.214
7.37E−04

135816951
135817036
135818325

AK4
65613349-
65613961-
65614236-
Unc
0.694
0.703
0.010
8.91E−01

65613960
65614235
65656392

AKAP11
42869879-
42871184-
42871319-
Exc
0.944
0.786
−0.158
2.49E−07

42871183
42871318
42872668

AKAP13
86199019-
86201768-
86201822-
Inc
0.740
0.874
0.134
3.44E−04

86201767
86201821
86207793

AKIP1
8933219-
8934000-
8934081-
Exc
0.528
0.339
−0.189
1.79E−06

8933999
8934080
8936372

AKIP1
8936478-
8938834-
8938915-
Exc
0.983
0.769
−0.214
1.28E−34

8938833
8938914
8940883

AKR1A1
46033850-
46034157-
46034357-
Exc
0.941
0.687
−0.254
3.92E−47

46034156
46034356
46034598

AL163636.6
21152918-
21161706-
21161810-
Inc
0.172
0.283
0.112
1.19E−06

21161705
21161809
21167513

ALDH3B1
67782930-
67785997-
67786107-
Exc
0.932
0.792
−0.140
1.96E−08

67785996
67786106
67786241

ALDH4A1
19212123-
19212958-
19213006-
Exc
0.958
0.792
−0.166
4.30E−04

19212957
19213005
19215855

ALKBH1
78146314-
78161081-
78161244-
Exc
0.967
0.828
−0.139
3.85E−04

78161080
78161243
78170711

ALKBH3
43911379-
43923066-
43923276-
Exc
0.950
0.802
−0.148
2.58E−06

43923065
43923275
43940587

ALKBH3
43911379-
43913591-
43913680-
Exc
0.858
0.549
−0.309
8.23E−17

43913590
43913679
43923065

AMBRA1
46529921-
46534277-
46534364-
Unc
0.637
0.640
0.003
6.56E−01

46534276
46534363
46563494

AMDHD2
2571125-
2577562-
2577617-
Unc
0.810
0.813
0.003
9.67E−01

2577561
2577616
2577773

AMIGO2
47472849-
47472925-
47473032-
Unc
0.540
0.534
−0.006
8.12E−01

47472924
47473031
47473244

AMMECR1L
128631847-
128641777-
128641887-
Exc
0.970
0.829
−0.142
1.23E−05

128641776
128641886
128643383

AMOTL1
94501727-
94528177-
94528327-
Unc
0.757
0.757
−0.001
9.49E−01

94528176
94528326
94532555

AMPD2
110162901-
110167925-
110168056-
Exc
0.844
0.690
−0.154
3.82E−04

110167924
110168055
110168283

AMZ2P1
62969046-
62969360-
62969636-
Unc
0.832
0.836
0.004
8.86E−01

62969359
62969635
62970672

ANAPC11
79849710-
79851428-
79851491-
Unc
0.705
0.708
0.003
9.31E−01

79851427
79851490
79852342

ANK2
114290962-
114293689-
114293782-
Exc
0.671
0.422
−0.249
4.15E−06

114293688
114293781
114294245

ANKRD10
111545611-
111552877-
111553009-
Exc
0.380
0.100
−0.280
4.11E−21

111552876
111553008
111558379

ANKRD10
1115456Il-
111552877-
111553042-
Exc
0.390
0.088
−0.302
4.37E−24

li 1552876
111553041
111558379

ANKRD11
89357592-
89358089-
89358186-
Inc
0.347
0.523
0.176
3.41E−09

89358088
89358185
89371613

ANKRD17
74000980-
74005248-
74006001-
Unc
0.859
0.862
0.003
9.24E−01

74005247
74006000
74007457

ANKRD36
97875447-
97875537-
97875610-
Exc
0.301
0.066
−0.235
1.47E−04

97875536
97875609
97877282

ANO6
45610175-
45695797-
45695877-
Exc
0.882
0.765
−0.117
1.59E−10

45695796
45695876
45725077

ANO6
45610175-
45664245-
45664308-
Unc
0.124
0.133
0.009
6.17E−01

45664244
45664307
45695796

ANXA2
60678286-
60689457-
60689538-
Inc
0.054
0.154
0.100
0.00E+00

60689456
60689537
60690141

AOX1
201474138-
201476107-
201476217-
Unc
0.904
0.896
−0.008
4.94E−01

201476106
201476216
201477331

AP1G1
71799488-
71801780-
71801789-
Inc
0.251
0.489
0.238
4.95E−16

71801779
71801788
71803525

AP2M1
183898040-
183898433-
183898530-
Exc
0.423
0.261
−0.162
1.38E−70

183898432
183898529
183898636

AP2M1
183898040-
183898433-
183898439-
Exc
0.605
0.423
−0.182
3.32E−109

183898432
183898438
183898636

APBB2
41035322-
41067593-
41067691-
Exc
0.698
0.538
−0.161
9.66E−05

41067592
41067690
41102655

APOL1
36651046-
36653129-
36653183-
Exc
0.862
0.753
−0.109
1.35E−06

36653128
36653182
36653364

APP
27354791-
27369675-
27369732-
Exc
0.739
0.590
−0.149
8.80E−131

27369674
27369731
27372329

ARHGAP12
32120729-
32128565-
32128640-
Inc
0.554
0.896
0.342
4.84E−20

32128564
32128639
32132388

ARHGAP12
32141526-
32142994-
32143135-
Inc
0.788
0.929
0.140
1.26E−10

32142993
32143134
32150322

ARHGAP23
36654069-
36654656-
36654753-
Exc
0.821
0.687
−0.134
6.60E−20

36654655
36654752
36656838

ARHGEF10
1824901-
1828214-
1828331-
Inc
0.536
0.725
0.190
4.24E−10

1828213
1828330
1830800

ARHGEF10
1772280-
1791519-
1791603-
Unc
0.859
0.860
0.002
9.61E−01

1791518
1791602
1806125

ARHGEF10L
17958962-
17961043-
17961058-
Exc
0.874
0.744
−0.130
1.03E−03

17961042
17961057
17961329

ARHGEF12
120300227-
120300421-
120300541-
Exc
0.810
0.709
−0.102
2.31E−06

120300420
120300540
120302479

ARHGEF25
58008801-
58009020-
58009098-
Exc
0.959
0.856
−0.103
8.02E−06

58009019
58009097
58009294

ARID4B
235359431-
235377084-
235377342-
Exc
0.662
0.512
−0.150
2.83E−04

235377083
235377341
235383107

ARID5A
97213255-
97215058-
97215197-
Unc
0.520
0.523
0.004
7.80E−01

97215057
97215196
97215489

ARIH2
48960245-
48962151-
48962405-
Exc
0.530
0.371
−0.159
1.77E−04

48962150
48962404
48964894

ARIH2
48960245-
48962151-
48962273-
Exc
0.646
0.470
−0.175
3.49E−06

48962150
48962272
48964894

ARIH2
48960245-
48982569-
48982615-
Unc
0.897
0.906
0.009
9.17E−01

48982568
48982614
48999044

ARIH2
48965247-
48982569-
48982615-
Unc
0.289
0.292
0.002
9.70E−01

48982568
48982614
48999044

ARMC10
102727212-
102732924-
102733101-
Unc
0.780
0.781
0.002
9.84E−01

102732923
102733100
102737723

ARSJ
114824832-
114827821-
114827902-
Unc
0.103
0.103
0.000
9.59E−01

114827820
114827901
114899592

ARSK
94903754-
94916596-
94916647-
Inc
0.039
0.219
0.180
1.16E−06

94916595
94916646
94918619

ASAP2
9528676-
9531191-
9531326-
Inc
0.700
0.900
0.200
4.73E−06

9531190
9531325
9533610

ASCC2
30221247-
30221611-
30221770-
Exc
0.863
0.730
−0.133
4.24E−05

30221610
30221769
30228233

ASCC2
30228332-
30230478-
30230540-
Unc
0.605
0.615
0.009
9.35E−01

30230477
30230539
30234166

ASL
65551650-
65551731-
65551809-
Exc
0.850
0.744
−0.106
3.00E−04

65551730
65551808
65552320

ASPH
62555993-
62556504-
62556561-
Exc
0.839
0.726
−0.113
8.37E−70

62556503
62556560
62557158

ASPH
62557192-
62559309-
62559438-
Inc
0.786
0.955
0.169
1.59E−243

62559308
62559437
62563608

ASUN
27067062-
27067341-
27067512-
Exc
0.834
0.705
−0.128
1.87E−04

27067340
27067511
27068934

ASXL1
31017235-
31017704-
31017857-
Exc
0.851
0.696
−0.155
9.56E−04

31017703
31017856
31019123

ATG10
81474407-
81548381-
81548479-
Inc
0.811
0.970
0.159
1.16E−03

81548380
81548478
81571963

ATG12
115173462-
115176194-
115176310-
Unc
0.624
0.633
0.009
8.94E−01

115176193
115176309
115176514

ATG13
46639926-
46651595-
46651651-
Unc
0.845
0.854
0.010
7.41E−01

46651594
46651650
46665828

ATG13
46639441-
46639875-
46639926-
Unc
0.224
0.228
0.003
9.18E−01

46639874
46639925
46651594

ATG16L1
234181699-
234182367-
234182424-
Exc
0.763
0.487
−0.277
9.35E−10

234182366
234182423
234183321

ATG4B
242590751-
242592722-
242592785-
Unc
0.109
0.110
0.001
9.93E−01

242592721
242592784
242592926

ATG7
11340330-
11340836-
11340891-
Exc
0.993
0.892
−0.101
4.09E−07

11340835
11340890
11348416

ATG9A
220079805-
220080719-
220080903-
Exc
0.979
0.874
−0.104
4.77E−04

220080718
220080902
220081085

ATP2C1
130613182-
130613575-
130613620-
Inc
0.666
0.818
0.152
3.71E−07

130613574
130613619
130649259

ATP2C1
130613182-
130613552-
130613620-
Inc
0.677
0.824
0.146
4.82E−07

130613551
130613619
130649259

ATP2C1
130613182-
130613434-
130613620-
Inc
0.684
0.826
0.142
7.77E−07

130613433
130613619
130649259

ATP5C1
7844818-
7848937-
7848974-
Unc
0.215
0.207
−0.007
7.79E−01

7848936
7848973
7849621

ATP5SL
41939579-
41942297-
41942378-
Inc
0.850
0.964
0.114
2.08E−09

41942296
41942377
41944122

ATP6C
2571125-
2577562-
2577617-
Unc
0.810
0.813
0.003
9.67E−01

2577561
2577616
2577773

ATPAF1
47118301-
47119489-
47119540-
Exc
0.964
0.745
−0.219
3.04E−29

47119488
47119539
47123798

ATXN1
16658133-
16753464-
16753579-
Exc
0.820
0.688
−0.132
3.78E−04

16753463
16753578
16761528

ATXN3
92559663-
92560090-
92560176-
Exc
0.950
0.785
−0.165
1.73E−07

92560089
92560175
92562436

ATXN3
92559663-
92560090-
92560195-
Exc
0.908
0.636
−0.271
5.26E−07

92560089
92560194
92562436

AUP1
74755617-
74755878-
74756063-
Exc
0.928
0.813
−0.114
4.48E−17

74755877
74756062
74756258

AUTS2
70236631-
70239014-
70239086-
Exc
0.901
0.758
−0.143
1.11E−03

70239013
70239085
70240342

AVL9
32615685-
32619831-
32619885-
Exc
0.972
0.592
−0.379
4.43E−19

32619830
32619884
32620413

B3GALNT1
160804577-
160818927-
160819022-
Inc
0.700
0.864
0.164
6.43E−04

160818926
160819021
160821214

B3GALNT1
160804577-
160807732-
160807851-
Unc
0.150
0.156
0.007
8.87E−01

160807731
160807850
160818926

BAG6
31607004-
31607277-
31607424-
Exc
0.597
0.458
−0.139
2.29E−11

31607276
31607423
31607975

BANP
88017866-
88037901-
88038018-
Inc
0.825
0.985
0.160
5.85E−04

88037900
88038017
88039695

BAX
49458220-
49458805-
49458857-
Exc
0.937
0.832
−0.105
1.22E−06

49458804
49458856
49459454

BAZ1A
35255208-
35255332-
35255428-
Exc
0.877
0.692
−0.185
9.82E−04

35255331
35255427
35261980

BAZ2A
57011317-
57024560-
57024650-
Unc
0.551
0.549
−0.002
9.42E−01

57024559
57024649
57029965

BBS4
73004649-
73007632-
73007744-
Exc
0.982
0.750
−0.232
1.36E−11

73007631
73007743
73009118

BBS5
170349520-
170350251-
170350347-
Exc
1.000
0.824
−0.176
7.16E−07

170350250
170350346
170355995

BBX
107497367-
107508634-
107508724-
Inc
0.640
0.757
0.117
5.10E−05

107508633
107508723
107510086

BCAR1
75269885-
75271081-
75271243-
Exc
0.908
0.761
−0.147
5.95E−05

75271080
75271242
75276367

BCAR1
75269885-
75270780-
75270897-
Exc
0.982
0.797
−0.185
3.94E−21

75270779
75270896
75271080

BCAR1
75269885-
75270726-
75270897-
Exc
0.959
0.642
−0.317
2.84E−18

75270725
75270896
75271080

BCL2L2
23777409-
23778025-
23778142-
Unc
0.905
0.898
−0.007
9.53E−01

23778024
23778141
23780181

BCOR
39930413-
39930890-
39930944-
Exc
0.661
0.452
−0.209
8.56E−04

39930889
39930943
39931601

BEND6
56857354-
56879260-
56879324-
Unc
0.101
0.100
0.000
9.69E−01

56879259
56879323
56879930

BIN1
127808489-
127808730-
127808820-
Exc
0.878
0.726
−0.152
1.40E−04

127808729
127808819
127815048

BIN1
127808489-
127808730-
127808820-
Exc
0.884
0.712
−0.172
6.43E−05

127808729
127808819
127816586

BIRC6
32658873-
32660564-
32660654-
Exc
0.787
0.552
−0.235
3.99E−06

32660563
32660653
32661120

BIRC6
32800434-
32815873-
32816046-
Unc
0.108
0.108
0.000
8.86E−01

32815872
32816045
32818981

BLOC1S6
45879724-
45884333-
45884475-
Exc
0.724
0.597
−0.127
5.48E−04

45884332
45884474
45897625

BLOC1S6
45879724-
45884333-
45884475-
Exc
0.779
0.516
−0.263
3.98E−23

45884332
45884474
45895297

BLOC1S6
45879724-
45895298-
45895386-
Unc
0.834
0.841
0.007
7.47E−01

45895297
45895385
45897625

BMP2K
79800046-
79808328-
79808439-
Exc
0.554
0.274
−0.281
2.14E−11

79808327
79808438
79831763

BOK
242501892-
242509540-
242509704-
Exc
0.874
0.748
−0.126
4.30E−04

242509539
242509703
242511711

BPTF
65955992-
65959449-
65959623-
Exc
0.585
0.199
−0.386
5.43E−23

65959448
65959622
65960327

BPTF
65871861-
65882244-
65882433-
Inc
0.665
0.832
0.167
2.66E−04

65882243
65882432
65887959

BRD8
137492957-
137495244-
137495289-
Exc
0.610
0.401
−0.208
1.57E−11

137495243
137495288
137495757

BRD8
137503768-
137504159-
137504378-
Unc
0.735
0.739
0.004
9.45E−01

137504158
137504377
137504910

BRD8
137501798-
137502207-
137502417-
Unc
0.729
0.722
−0.007
8.43E−01

137502206
137502416
137503622

BROX
222886285-
222889026-
222889143-
Inc
0.863
0.968
0.105
5.17E−07

222889025
222889142
222892266

BTBD19
45274579-
45275885-
45276099-
Exc
0.992
0.721
−0.270
1.50E−07

45275884
45276098
45276225

BTBD19
45274579-
45275885-
45275922-
Exc
0.988
0.668
−0.320
3.77E−06

45275884
45275921
45276225

BTBD3
11871603-
11898426-
11898660-
Unc
0.230
0.232
0.001
9.69E−01

11898425
11898659
11898981

BTF3L4
52522052-
52525507-
52525574-
Unc
0.893
0.902
0.008
5.65E−01

52525506
52525573
52530496

C10orf118
115923089-
115932900-
115933025-
Unc
0.238
0.228
−0.010
9.66E−01

115932899
115933024
115933773

C11orf30
76169403-
76170980-
76171130-
Inc
0.629
0.903
0.274
3.48E−04

76170979
76171129
76174864

C11orf30
76169403-
76170977-
76171130-
Inc
0.729
0.936
0.207
7.07E−05

76170976
76171129
76174864

C11orf30
76248995-
76250643-
76250685-
Unc
0.754
0.753
−0.001
8.84E−01

76250642
76250684
76253259

C11orf57
111945083-
111945611-
111945641-
Unc
0.395
0.390
−0.005
9.74E−01

111945610
111945640
111946290

C11orf70
101929687-
101937216-
101937383-
Exc
0.973
0.843
−0.130
1.77E−04

101937215
101937382
101946603

C12orf29
88429516-
88433925-
88434043-
Inc
0.745
0.897
0.152
1.32E−05

88433924
88434042
88436601

C14orf159
91580628-
91611565-
91611658-
Unc
0.121
0.124
0.003
9.48E−01

91611564
91611657
91623982

C16orf13
684798-
685518-
685775-
Exc
0.760
0.447
−0.313
4.99E−04

685517
685774
686093

C1orf85
156264357-
156264550-
156264808-
Exc
0.844
0.698
−0.147
4.56E−15

156264549
156264807
156265316

C1RL
7254684-
7260847-
7261076-
Exc
0.865
0.689
−0.176
6.02E−11

7260846
7261075
7261705

C2CD5
22610096-
22612426-
22612477-
Inc
0.523
0.770
0.247
3.77E−06

22612425
22612476
22622642

C2CD5
22610096-
22611418-
22611490-
Inc
0.854
1.000
0.146
1.04E−06

22611417
22611489
22612425

C2CD5
22610096-
22611418-
22611520-
Inc
0.881
1.000
0.119
3.44E−07

22611417
22611519
22612425

C2orf76
120075080-
120078730-
120078781-
Unc
0.865
0.858
−0.008
9.03E−01

120078729
120078780
120097402

C3orf18
50599179-
50602897-
50603293-
Inc
0.427
0.627
0.200
5.28E−04

50602896
50603292
50604893

C5orf42
37162669-
37164375-
37164430-
Exc
0.973
0.869
−0.103
7.10E−04

37164374
37164429
37165640

C5orf45
179275067-
179280197-
179280277-
Inc
0.132
0.390
0.258
3.00E−06

179280196
179280276
179280377

C8orf59
86129732-
86131552-
86131593-
Inc
0.127
0.317
0.191
1.66E−25

86131551
86131592
86132534

C8orf59
86129732-
86131465-
86131593-
Inc
0.105
0.225
0.119
9.55E−14

86131464
86131592
86132534

C9orf156
100672899-
100675155-
100675258-
Inc
0.130
0.274
0.145
1.03E−03

100675154
100675257
100675682

C9orf156
100675841-
100678446-
100678621-
Unc
0.758
0.762
0.004
8.93E−01

100678445
100678620
100684699

C9orf85
74562029-
74586421-
74586535-
Exc
0.609
0.362
−0.247
1.04E−04

74586420
74586534
74597572

CA5BP1
15706982-
15711086-
15711182-
Inc
0.727
0.908
0.181
1.00E−03

15711085
15711181
15720904

CACNA1C
2721180-
2742795-
2742879-
Unc
0.201
0.192
−0.009
9.98E−01

2742794
2742878
2743462

CALU
128388859-
128394316-
128394510-
Inc
0.625
0.807
0.182
2.09E−164

128394315
128394509
128394582

CAMK2D
114375672-
114376882-
114376978-
Exc
0.251
0.079
−0.173
8.44E−18

114376881
114376977
114378490

CAMK2G
75583843-
75585037-
75585106-
Unc
0.881
0.890
0.009
9.67E−01

75585036
75585105
75597225

CAMSAP1
138742308-
138754313-
138754455-
Unc
0.817
0.816
−0.001
9.89E−01

138754312
138754454
138758301

CAMTA1
6845636-
6880241-
6880311-
Inc
0.732
0.895
0.163
4.82E−15

6880240
6880310
6885151

CAPN10
241535939-
241536098-
241536360-
Unc
0.895
0.887
−0.008
9.33E−01

241536097
241536359
241537304

CAPN7
15283761-
15287033-
15287179-
Exc
0.963
0.863
−0.101
2.98E−08

15287032
15287178
15288238

CAPN7
15288965-
15292482-
15292531-
Exc
0.969
0.852
−0.117
1.75E−06

15292481
15292530
15292622

CAPRIN2
30869611-
30872013-
30873850-
Exc
0.835
0.625
−0.210
9.09E−11

30872012
30873849
30876192

CAPRIN2
30869611-
30872013-
30872160-
Exc
0.768
0.538
−0.230
2.34E−08

30872012
30872159
30876192

CAPRIN2
30869611-
30873745-
30873850-
Exc
0.722
0.471
−0.251
4.48E−09

30873744
30873849
30876192

CAPRIN2
30884445-
30886563-
30886646-
Exc
0.473
0.150
−0.323
6.22E−16

30886562
30886645
30887901

CARD8
48737801-
48741640-
48741790-
Exc
0.667
0.426
−0.242
6.35E−05

48741639
48741789
48744218

CARD8
48737801-
48741640-
48741784-
Exc
0.477
0.185
−0.293
7.65E−05

48741639
48741783
48744218

CARF
203782767-
203806583-
203806704-
Unc
0.801
0.806
0.005
9.25E−01

203806582
203806703
203817281

CARKD
111276627-
111277537-
111277626-
Exc
0.962
0.771
−0.191
4.83E−12

111277536
111277625
111279785

CASP3
185559623-
185569619-
185569786-
Inc
0.330
0.471
0.141
7.63E−05

185569618
185569785
185570548

CAST
96058403-
96062458-
96062564-
Exc
0.278
0.161
−0.117
4.69E−21

96062457
96062563
96063192

CAST
96058403-
96062498-
96062564-
Exc
0.425
0.268
−0.156
1.16E−32

96062497
96062563
96063192

CCBL2
89435151-
89453935-
89454035-
Inc
0.399
0.517
0.119
3.36E−04

89453934
89454034
89458267

CCDC126
23637671-
23643705-
23643899-
Unc
0.337
0.340
0.003
9.87E−01

23643704
23643898
23650789

CCDC136
128445956-
128446291-
128446450-
Unc
0.872
0.871
−0.001
9.71E−01

128446290
128446449
128446741

CCDC25
27605797-
27606012-
27606116-
Exc
0.871
0.699
−0.171
2.16E−10

27606011
27606115
27610028

CCDC25
27610105-
27614236-
27614288-
Unc
0.813
0.813
0.000
9.07E−01

27614235
27614287
27619935

CCDC90B
82985784-
82989769-
82989873-
Exc
0.857
0.745
−0.113
1.89E−11

82989768
82989872
82991183

CCNDBP1
43477806-
43478018-
43478078-
Exc
0.923
0.767
−0.156
9.47E−08

43478017
43478077
43481396

CCNL1
156868171-
156869518-
156869720-
Exc
0.326
0.204
−0.123
2.22E−04

156869517
156869719
156869965

CCNL2
1326246-
1326677-
1326956-
Unc
0.890
0.889
−0.001
9.31E−01

1326676
1326955
1328058

CCNT1
49089613-
49089782-
49089946-
Unc
0.876
0.872
−0.005
9.13E−01

49089781
49089945
49091920

CCNYL1
208591601-
208598671-
208598772-
Unc
0.795
0.792
−0.002
4.41E−01

208598670
208598771
208602134

CD27-AS1
6557904-
6560036-
6560147-
Unc
0.432
0.429
−0.003
9.65E−01

6560035
6560146
6560634

CD27-AS1
6557904-
6559507-
6560147-
Unc
0.533
0.525
−0.008
8.65E−01

6559506
6560146
6560634

CD44
35211520-
35232793-
35232997-
Inc
0.595
0.873
0.277
5.56E−09

35232792
35232996
35236398

CD46
207940541-
207941124-
207941169-
Exc
0.653
0.522
−0.131
9.35E−20

207941123
207941168
207943665

CD46
207959028-
207963598-
207963691-
Inc
0.527
0.748
0.221
6.66E−57

207963597
207963690
207966863

CD55
207512763-
207513736-
207513854-
Exc
0.278
0.162
−0.116
4.30E−09

207513735
207513853
207532890

CD99P1
2541495-
2544638-
2544684-
Exc
0.966
0.694
−0.272
3.51E−05

2544637
2544683
2556014

CD99P1
2537539-
2540731-
2540776-
Exc
0.599
0.141
−0.458
3.02E−12

2540730
2540775
2541425

CDC14B
99272072-
99277931-
99278075-
Exc
0.458
0.228
−0.230
1.57E−09

99277930
99278074
99284787

CDC14B
99266072-
99271955-
99272072-
Inc
0.547
0.795
0.248
1.82E−08

99271954
99272071
99277930

CDC16
115000608-
115002120-
115002175-
Exc
0.870
0.559
−0.311
2.24E−37

115002119
115002174
115002273

CDC42BPA
227300124-
227300372-
227300615-
Unc
0.779
0.775
−0.004
9.88E−01

227300371
227300614
227307504

CDCA7L
21948126-
21951235-
21951370-
Unc
0.738
0.747
0.009
8.31E−01

21951234
21951369
21956371

CDK16
47078064-
47081672-
47081742-
Inc
0.286
0.566
0.280
8.90E−04

47081671
47081741
47082950

CDK16
47078505-
47081660-
47081742-
Inc
0.094
0.246
0.152
2.82E−06

47081659
47081741
47082950

CDK16
47078505-
47081660-
47081780-
Inc
0.056
0.169
0.113
3.41E−05

47081659
47081779
47082950

CDK5RAP2
123220901-
123222850-
123223026-
Unc
0.858
0.858
0.000
9.52E−01

123222849
123223025
123230137

CEP164
117252585-
117253512-
117253659-
Unc
0.235
0.229
−0.006
9.69E−01

117253511
117253658
117257918

CEP290
88447524-
88448117-
88448191-
Inc
0.761
0.941
0.180
1.02E−07

88448116
88448190
88449352

CHD3
7810807-
7810919-
7811021-
Exc
0.533
0.342
−0.191
6.58E−16

7810918
7811020
7811211

CHEK2
29095926-
29099493-
29099555-
Exc
0.613
0.260
−0.353
6.09E−08

29099492
29099554
29105993

CHKB
51018232-
51018486-
51018512-
Exc
0.958
0.848
−0.110
5.70E−05

51018485
51018511
51018618

CIRBP
1272051-
1273600-
1273715-
Unc
0.128
0.129
0.001
9.31E−01

1273599
1273714
1274305

CIRBP
1272051-
1273493-
1273715-
Unc
0.152
0.144
−0.007
8.95E−01

1273492
1273714
1274305

CKLF
66586697-
66592093-
66592252-
Exc
0.541
0.438
−0.103
5.18E−04

66592092
66592251
66597024

CLASP1
122165292-
122166600-
122166624-
Inc
0.165
0.429
0.264
5.96E−14

122166599
122166623
122168441

CLASP2
33592888-
33600617-
33600668-
Unc
0.637
0.628
−0.009
9.35E−01

33600616
33600667
33600798

CLCN6
11888277-
11888515-
11888682-
Exc
0.604
0.333
−0.271
5.43E−06

11888514
11888681
11889252

CLK1
201724470-
201724848-
201724939-
Inc
0.451
0.655
0.204
2.02E−11

201724847
201724938
201725960

CMC1
28283304-
28304782-
28304872-
Inc
0.748
0.878
0.130
1.98E−04

28304781
28304871
28357823

CNOT10
32804356-
32805947-
32805983-
Exc
1.000
0.899
−0.101
2.05E−05

32805946
32805982
32806173

COL12A1
75875496-
75884754-
75885027-
Inc
0.758
0.876
0.118
0.00E+00

75884753
75885026
75887378

COL16A1
32145287-
32145405-
32145453-
Exc
0.543
0.400
−0.143
1.15E−23

32145404
32145452
32145642

COL16A1
32134457-
32136157-
32136248-
Exc
0.349
0.163
−0.186
5.75E−27

32136156
32136247
32137215

COL16A1
32134457-
32136203-
32136248-
Exc
0.508
0.277
−0.231
2.46E−41

32136202
32136247
32137215

COL6A3
238296828-
238303230-
238303848-
Exc
0.394
0.175
−0.219
9.35E−95

238303229
238303847
238305369

COL6A3
238290143-
238296225-
238296828-
Inc
0.310
0.501
0.191
2.58E−146

238296224
238296827
238305369

COPB2
139102278-
139103846-
139104043-
Inc
0.457
0.696
0.239
4.28E−04

139103845
139104042
139108310

COPS7A
6833985-
6837092-
6837168-
Exc
0.870
0.743
−0.127
1.13E−17

6837091
6837167
6837388

COPS8
237994686-
237995375-
237995440-
Inc
0.080
0.311
0.230
1.16E−37

237995374
237995439
237995769

COQ6
74425928-
74426118-
74426226-
Exc
0.943
0.796
−0.147
1.71E−06

74426117
74426225
74427875

COX20
244999059-
245005246-
245005361-
Exc
0.649
0.446
−0.203
1.39E−13

245005245
245005360
245005496

CPEB2
15034836-
15042088-
15042112-
Exc
0.257
0.132
−0.125
8.15E−04

15042087
15042111
15054037

CPNE1
34220846-
34246852-
34246937-
Unc
0.361
0.358
−0.003
9.59E−01

34246851
34246936
34252681

CPSF7
61188046-
61188664-
61188730-
Inc
0.065
0.211
0.146
3.45E−14

61188663
61188729
61188861

CPT1C
50194598-
50195078-
50195211-
Exc
0.503
0.145
−0.358
3.72E−05

50195077
50195210
50195495

CPT1C
50194598-
50195078-
50195147-
Exc
0.651
0.285
−0.366
5.73E−06

50195077
50195146
50195495

CRAT
131870357-
131871458-
131871557-
Exc
0.574
0.424
−0.150
5.12E−05

131871457
131871556
131872761

CREBBP
3824695-
3827614-
3827659-
Inc
0.836
0.969
0.133
2.33E−10

3827613
3827658
3828011

CRLS1
5990559-
5996007-
5996137-
Exc
0.992
0.889
−0.103
1.14E−06

5996006
5996136
6012657

CRNDE
54953122-
54954210-
54954251-
Exc
0.973
0.867
−0.106
2.55E−09

54954209
54954250
54957496

CRYZ
75190519-
75196066-
75196105-
Exc
0.196
0.091
−0.105
1.56E−04

75196065
75196104
75198639

CRYZ
75172679-
75172787-
75172889-
Exc
0.838
0.322
−0.516
1.73E−58

75172786
75172888
75175781

CSAD
53554629-
53554911-
53554976-
Exc
0.398
0.224
−0.174
6.03E−04

53554910
53554975
53555056

CSDE1
115279477-
115280092-
115280185-
Unc
0.104
0.096
−0.008
2.11E−01

115280091
115280184
115280583

CSNK1A1
148892773-
148897357-
148897441-
Unc
0.113
0.116
0.003
7.55E−01

148897356
148897440
148899852

CTDSPL
37988703-
37998602-
37998635-
Exc
0.596
0.336
−0.261
1.76E−10

37998601
37998634
38006061

CTIF
46065684-
46066129-
46066203-
Unc
0.235
0.241
0.006
9.23E−01

46066128
46066202
46145908

CTSB
11710989-
11721885-
11721973-
Unc
0.220
0.219
−0.001
9.29E−01

11721884
11721972
11725509

CUTC
101507148-
101510126-
101510154-
Exc
0.509
0.240
−0.269
5.92E−10

101510125
101510153
101514285

CWC25
36966019-
36966529-
36966654-
Exc
0.181
0.024
−0.157
6.59E−08

36966528
36966653
36966720

CYB561D2
50388992-
50389440-
50389478-
Exc
0.959
0.823
−0.136
2.79E−05

50389439
50389477
50390671

CYLD
50776753-
50778641-
50778778-
Inc
0.441
0.856
0.415
6.01E−15

50778640
50778777
50783486

CYP20A1
204131405-
204143296-
204143412-
Exc
0.974
0.830
−0.145
1.01E−04

204143295
204143411
204144781

CYP20A1
204103858-
204110569-
204110619-
Exc
0.700
0.410
−0.290
2.73E−05

204110568
204110618
204116689

DAB2
39394524-
39417291-
39417387-
Inc
0.138
0.334
0.196
1.02E−04

39417290
39417386
39418282

DBT
100671858-
100672001-
100672193-
Exc
0.982
0.880
−0.103
2.36E−04

100672000
100672192
100676249

DCAF10
37819399-
37842086-
37842284-
Exc
0.661
0.533
−0.128
5.29E−04

37842085
37842283
37854776

DCAF11
24586603-
24586877-
24586942-
Exc
0.982
0.828
−0.154
1.63E−15

24586876
24586941
24587263

DCAF17
172325541-
172330376-
172330486-
Exc
0.962
0.826
−0.135
1.29E−03

172330375
172330485
172333369

DCAF8
160213825-
160231075-
160231149-
Inc
0.762
0.864
0.102
2.04E−04

160231074
160231148
160231906

DCAF8
160210161-
160213750-
160213825-
Unc
0.907
0.899
−0.009
5.77E−01

160213749
160213824
160231074

DCP1A
53326858-
53338207-
53338321-
Inc
0.890
0.990
0.100
3.80E−04

53338206
53338320
53346270

DCTD
183836729-
183837572-
183837693-
Unc
0.232
0.235
0.003
9.85E−01

183837571
183837692
183838463

DCTD
183836729-
183837572-
183837693-
Unc
0.126
0.122
−0.004
9.67E−01

183837571
183837692
183838440

DCUN1D5
102937297-
102953477-
102953569-
Inc
0.856
0.993
0.137
8.56E−23

102953476
102953568
102953984

DDB2
47256224-
47256308-
47256486-
Exc
0.923
0.772
−0.151
9.72E−09

47256307
47256485
47256820

DGKA
56331837-
56332295-
56332345-
Exc
0.999
0.873
−0.126
8.04E−15

56332294
56332344
56332698

DGUOK
74154180-
74166037-
74166150-
Unc
0.285
0.287
0.002
9.97E−01

74166036
74166149
74173845

DHRSX
2209645-
2310395-
2310516-
Exc
0.127
0.024
−0.103
2.86E−11

2310394
2310515
2326785

DIMT1
61686810-
61687998-
61688062-
Exc
0.991
0.851
−0.140
4.42E−19

61687997
61688061
61688752

DIS3
73355142-
73355427-
73355495-
Exc
0.338
0.170
−0.168
3.13E−04

73355426
73355494
73355742

DIS3
73352519-
73354984-
73355142-
Inc
0.537
0.720
0.183
8.07E−05

73354983
73355141
73355426

DLG1
196876668-
196888511-
196888610-
Exc
0.613
0.500
−0.113
3.68E−05

196888510
196888609
196921295

DLGAP1-AS1
3594483-
3596577-
3596674-
Unc
0.832
0.834
0.002
8.24E−01

3596576
3596673
3597173

DMD
31191722-
31196049-
31196088-
Exc
0.495
0.086
−0.409
9.35E−12

31196048
31196087
31196785

DMKN
35990932-
35991280-
35991322-
Unc
0.224
0.230
0.006
7.69E−01

35991279
35991321
35991434

DMTF1
86781872-
86783706-
86783845-
Exc
0.219
0.076
−0.144
3.88E−04

86783705
86783844
86792810

DMTF1
86781872-
86792555-
86792649-
Exc
0.254
0.098
−0.157
5.81E−05

86792554
86792648
86792810

DMTF1
86823419-
86824000-
86824145-
Exc
0.944
0.779
−0.165
1.51E−14

86823999
86824144
86824346

DMWD
46287549-
46287899-
46287974-
Unc
0.648
0.642
−0.006
9.50E−01

46287898
46287973
46288851

DNAAF2
50092767-
50094730-
50094874-
Unc
0.680
0.673
−0.007
9.48E−01

50094729
50094873
50100004

DNAJC14
56222499-
56223273-
56223421-
Unc
0.764
0.767
0.003
9.33E−01

56223272
56223420
56224479

DNAJC19
180703785-
180704786-
180704811-
Inc
0.676
0.811
0.135
1.53E−05

180704785
180704810
180705810

DNAJC19
180703785-
180704731-
180704811-
Inc
0.808
0.910
0.102
1.73E−08

180704730
180704810
180705810

DNAJC2
102967132-
102967779-
102967826-
Exc
0.152
0.051
−0.102
1.95E−05

102967778
102967825
102968102

DNAJC24
31392407-
31436358-
31436497-
Unc
0.904
0.896
−0.008
9.12E−01

31436357
31436496
31447833

DNM1L
32890096-
32891198-
32891231-
Exc
0.271
0.050
−0.221
4.56E−18

32891197
32891230
32892997

DNM1L
32890877-
32891198-
32891231-
Exc
0.547
0.180
−0.366
2.76E−09

32891197
32891230
32892997

DNM1L
32890096-
32890799-
32890877-
Inc
0.545
0.788
0.243
2.25E−04

32890798
32890876
32891197

DNMT1
10288044-
10290863-
10290911-
Exc
0.279
0.138
−0.141
3.31E−04

10290862
10290910
10291025

DOCK5
25240295-
25246325-
25246458-
Inc
0.085
0.336
0.251
2.26E−12

25246324
25246457
25246606

DOCK7
62943497-
62953069-
62953084-
Exc
0.912
0.691
−0.221
1.17E−04

62953068
62953083
62954604

DPH3
16302337-
16305662-
16305737-
Inc
0.511
0.757
0.247
1.39E−21

16305661
16305736
16306275

DPH7
140470855-
140471922-
140472056-
Unc
0.854
0.850
−0.004
9.52E−01

140471921
140472055
140473076

DPH7
140470620-
140471922-
140472056-
Unc
0.724
0.718
−0.006
8.33E−01

140471921
140472055
140473076

DPM1
49552800-
49557402-
49557493-
Unc
0.894
0.893
−0.001
9.37E−01

49557401
49557492
49558567

DPY19L4
95732243-
95738559-
95738670-
Exc
0.975
0.874
−0.101
4.43E−04

95738558
95738669
95750596

DRAM2
111663316-
111667364-
111667504-
Exc
0.924
0.755
−0.169
2. ISE−17

111667363
111667503
111668848

DRAM2
111680209-
1116822lO-
111682334-
Inc
0.466
0.668
0.202
5.23E−07

111682209
ll 1682333
111682659

DSCR3
38604753-
38605663-
38605744-
Exc
0.922
0.634
−0.288
9.92E−45

38605662
38605743
38610760

DTNBP1
15638036-
15651544-
15651595-
Exc
0.963
0.855
−0.108
2.61E−04

15651543
15651594
15652317

DTNBP1
15638036-
15651544-
15651640-
Exc
0.927
0.751
−0.176
9.68E−04

15651543
15651639
15652317

DUS2
68057255-
68059318-
68059398-
Unc
0.869
0.860
−0.009
9.16E−01

68059317
68059397
68071908

DUSP11
73994031-
73994288-
73994335-
Exc
0.981
0.659
−0.322
9.71E−32

73994287
73994334
73996391

DUSP22
311963-
335114-
335164-
Exc
0.729
0.479
−0.250
9.80E−08

335113
335163
345853

DYNC2H1
103027500-
103029406-
103029539-
Exc
0.988
0.828
−0.160
3.48E−06

103029405
103029538
103029638

EBPL
50237332-
50243913-
50243983-
Exc
0.861
0.680
−0.181
4.60E−04

50243912
50243982
50265389

EBPL
50235345-
50243913-
50243983-
Exc
0.743
0.441
−0.302
1.74E−04

50243912
50243982
50265389

ECHDC2
53370506-
53370706-
53370763-
Unc
0.889
0.882
−0.007
9.98E−01

53370705
53370762
53373539

EDC3
74967484-
74979432-
74979521-
Exc
0.181
0.069
−0.112
6.98E−05

74979431
74979520
74988220

EDEM2
33719587-
33721908-
33721959-
Inc
0.134
0.409
0.276
6.98E−09

33721907
33721958
33722540

EDRF1
127414408-
127417572-
127417674-
Exc
0.713
0.348
−0.365
4.46E−06

127417571
127417673
127417926

EFEMP1
56149583-
56150034-
56150075-
Inc
0.322
0.447
0.125
4.08E−106

56150033
56150074
56150845

EHBP1
63206471-
63215066-
63215174-
Exc
0.236
0.133
−0.103
3.49E−13

63215065
63215173
63217850

EHBP1L1
65349437-
65351063-
65351237-
Unc
0.844
0.841
−0.004
8.14E−01

65351062
65351236
65351711

EHMT2
31856525-
31856746-
31856848-
Exc
0.894
0.761
−0.133
1.07E−04

31856745
31856847
31857004

EIF4A2
186502486-
186502751-
186502891-
Exc
0.760
0.622
−0.138
4.02E−43

186502750
186502890
186503671

EIF4E2
233421241-
233422594-
233422729-
Exc
0.969
0.858
−0.111
1.51E−25

233422593
233422728
233428956

EIF4G2
10822635-
10823208-
10823322-
Unc
0.881
0.889
0.009
7.64E−02

10823207
10823321
10823595

EIF4H
73604249-
73604577-
73604637-
Inc
0.082
0.194
0.113
1.21E−34

73604576
73604636
73609070

ELK1
47500875-
47509320-
47509426-
Exc
0.470
0.261
−0.209
2.18E−09

47509319
47509425
47509821

ELMOD3
85598333-
85598563-
85598686-
Unc
0.688
0.679
−0.009
9.08E−01

85598562
85598685
85604466

ELMOD3
85582294-
85582678-
85582840-
Unc
0.747
0.738
−0.010
9.67E−01

85582677
85582839
85584089

ELN
73471044-
73471970-
73472027-
Exc
0.682
0.531
−0.151
2.07E−13

73471969
73472026
73474215

ELN
73474378-
73474470-
73474515-
Exc
0.989
0.821
−0.167
4.96E−48

73474469
73474514
73474705

ELOVL1
43830680-
43830857-
43831048-
Exc
0.954
0.841
−0.113
6.36E−25

43830856
43831047
43831234

EMC4
34520048-
34520630-
34520791-
Unc
0.808
0.806
−0.001
9.68E−01

34520629
34520790
34521953

EMC4
34520048-
34520638-
34520791-
Unc
0.656
0.655
−0.002
9.81E−01

34520637
34520790
34521953

ENC1
73932324-
73933390-
73933527-
Inc
0.108
0.356
0.248
7.14E−06

73933389
73933526
73936131

ENC1
73932324-
73933319-
73933444-
Unc
0.133
0.128
−0.006
7.41E−01

73933318
73933443
73936131

ENOSF1
677873-
678696-
678738-
Exc
0.942
0.804
−0.138
2.00E−05

678695
678737
683245

EP400
132446500-
132448077-
132448188-
Unc
0.220
0.214
−0.006
9.02E−01

132448076
132448187
132464241

EPB41L1
34806885-
34807683-
34807767-
Exc
0.939
0.839
−0.101
6.57E−07

34807682
34807766
34809785

EPB41L1
34802363-
34807683-
34807767-
Exc
0.878
0.759
−0.119
4.31E−04

34807682
34807766
34809785

EPB41L2
131191267-
131191468-
131191522-
Inc
0.302
0.713
0.411
1.34E−16

131191467
131191521
131197813

EPS15L1
16472796-
16487933-
16488066-
Unc
0.858
0.852
−0.006
9.33E−01

16487932
16488065
16495939

ERBB2IP
65350780-
65370852-
65371059-
Exc
0.434
0.245
−0.190
2.48E−22

65370851
65371058
65372143

ERLEC1
54028980-
54035436-
54035598-
Exc
0.858
0.745
−0.112
5.82E−15

54035435
54035597
54036350

ERMAP
43304593-
43305704-
43305725-
Exc
0.981
0.830
−0.151
1.04E−08

43305703
43305724
43305822

ERMARD
170151760-
170153383-
170153469-
Unc
0.103
0.108
0.005
8.37E−01

170153382
170153468
170153959

ERMARD
170151760-
170153413-
170153469-
Unc
0.103
0.108
0.005
8.37E−01

170153412
170153468
170153959

ETHE1
44015719-
44030667-
44030812-
Exc
0.990
0.882
−0.108
1.26E−06

44030666
44030811
44031248

ETHE1
44015719-
44030353-
44030502-
Exc
0.853
0.637
−0.216
4.42E−20

44030352
44030501
44030666

EVA1A
75749614-
75753238-
75753326-
Unc
0.538
0.533
−0.005
4.61E−01

75753237
75753325
75787805

EVC
5815890-
5819938-
5819982-
Exc
0.872
0.376
−0.496
1.54E−60

5819937
5819981
5825343

EVI5L
7920955-
7921978-
7922011-
Exc
0.676
0.479
−0.197
1.73E−05

7921977
7922010
7923076

FAM104A
71205908-
71208817-
71208880-
Exc
0.310
0.197
−0.113
1.25E−03

71208816
71208879
71223303

FAM111A
58910778-
58910970-
58913330-
Exc
0.900
0.699
−0.201
4.46E−04

58910969
58913329
58916308

FAM114A1
38870168-
38879692-
38880048-
Unc
0.898
0.906
0.008
6.74E−01

38879691
38880047
38893363

FAM134C
40738910-
40739852-
40739883-
Exc
0.979
0.878
−0.101
1.32E−06

40739851
40739882
40744073

FAM13B
137354204-
137354644-
137354836-
Unc
0.861
0.861
0.001
1.00E+00

137354643
137354835
137356719

FAM13B
137281687-
137281917-
137282001-
Unc
0.874
0.874
0.000
9.76E−01

137281916
137282000
137284643

FAM149B1
74994699-
74994951-
74995077-
Exc
0.927
0.795
−0.133
2.48E−04

74994950
74995076
74999069

FAM160B2
21946810-
21947272-
21947366-
Unc
0.101
0.108
0.007
8.30E−01

21947271
21947365
21951950

FAM172A
93300229-
93386436-
93386537-
Exc
0.824
0.677
−0.147
1.92E−05

93386435
93386536
93388830

FAM172A
93388933-
93410351-
93410475-
Inc
0.644
0.790
0.146
5.58E−05

93410350
93410474
93447215

FAM173A
771942-
772084-
772135-
Unc
0.795
0.796
0.002
7.41E−01

772083
772134
772308

FAM175A
84390305-
84391356-
84391550-
Unc
0.888
0.892
0.005
8.51E−01

84391355
84391549
84397795

FAM175A
84403398-
84405145-
84405320-
Unc
0.119
0.113
−0.005
8.75E−01

84405144
84405319
84406138

FAM204A
120095936-
120101239-
120101440-
Exc
0.583
0.449
−0.134
1.38E−05

120101238
120101439
120101781

FAM208B
5773167-
5777267-
5777510-
Unc
0.816
0.807
−0.009
7.29E−01

5777266
5777509
5781580

FAM211A-
16342729-
16342974-
16343018-
Exc
0.279
0.155
−0.124
3.11E−100

AS1
16342973
16343017
16343498

FAM211A-
16342729-
16342895-
16343018-
Exc
0.313
0.180
−0.133
1.77E−110

AS1
16342894
16343017
16343498

FAM211A-
16342729-
16342842-
16343018-
Exc
0.328
0.179
−0.149
2.05E−136

AS1
16342841
16343017
16343498

FAM21C
46268807-
46272721-
46272874-
Inc
0.421
0.663
0.243
1.76E−04

46272720
46272873
46274400

FAM35A
88930732-
88935646-
88935853-
Unc
0.737
0.743
0.006
9.25E−01

88935645
88935852
88939831

FAM45A
120863710-
120864276-
120864535-
Unc
0.655
0.664
0.009
8.17E−01

120864275
120864534
120864822

FAP
163054251-
163054689-
163054809-
Exc
0.561
0.303
−0.258
4.88E−06

163054688
163054808
163055266

FBXL12
9922394-
9923907-
9923951-
Exc
0.170
0.025
−0.145
5.57E−07

9923906
9923950
9929220

FBXL3
77592858-
77595792-
77595997-
Inc
0.757
0.926
0.169
4.58E−04

77595791
77595996
77600961

FBXO25
381445-
382886-
382936-
Exc
0.840
0.715
−0.125
8.60E−05

382885
382935
385614

FBXW11
171337802-
171341347-
171341410-
Exc
0.474
0.318
−0.156
4.86E−05

171341346
171341409
171433461

FBXW11
171337802-
171341347-
171341410-
Exc
0.775
0.569
−0.206
2.10E−04

171341346
171341409
171423893

FDPS
155278757-
155279544-
155279757-
Unc
0.113
0.122
0.008
9.95E−01

155279543
155279756
155279833

FGF5
81188334-
81196063-
81196167-
Exc
0.766
0.541
−0.225
8.66E−07

81196062
81196166
81207478

FGFR1
38286909-
38287200-
38287467-
Unc
0.906
0.899
−0.007
8.46E−01

38287199
38287466
38314873

FGFR1OP
167424382-
167426996-
167427056-
Inc
0.506
0.802
0.295
3.12E−10

167426995
167427055
167435896

FHL2
106002998-
106013104-
106013155-
Exc
0.550
0.449
−0.101
1.22E−10

106013103
106013154
106015298

FHOD3
33935609-
33952643-
33952708-
Unc
0.902
0.893
−0.009
9.47E−01

33952642
33952707
34081894

FIP1L1
54244091-
54245240-
54245285-
Exc
0.467
0.329
−0.138
4.26E−06

54245239
54245284
54245391

FIP1L1
54294351-
54306749-
54306776-
Exc
0.450
0.228
−0.223
2.87E−18

54306748
54306775
54308819

FIP1L1
54257307-
54257597-
54257666-
Inc
0.426
0.529
0.104
5.19E−05

54257596
54257665
54265896

FLAD1
154961326-
154962036-
154962184-
Exc
0.922
0.744
−0.177
7.38E−05

154962035
154962183
154962634

FLNA
153583441-
153585619-
153585643-
Exc
0.631
0.481
−0.150
1.98E−91

153585618
153585642
153585801

FLNB
58124257-
58127585-
58127657-
Unc
0.788
0.791
0.003
9.83E−01

58127584
58127656
58128376

FLNB
58124257-
58127585-
58127624-
Unc
0.710
0.709
−0.001
9.04E−01

58127584
58127623
58128376

FN1
216244041-
216245534-
216245804-
Exc
0.330
0.226
−0.104
0.00E+00

216245533
216245803
216246934

FNBP1
132671279-
132678245-
132678260-
Unc
0.306
0.316
0.009
7.86E−01

132678244
132678259
132686122

FNBP4
47746331-
47747289-
47747389-
Inc
0.151
0.431
0.280
8.28E−14

47747288
47747388
47752925

FNIP2
159754781-
159754953-
159755043-
Exc
0.722
0.580
−0.142
4.97E−06

159754952
159755042
159756556

FOSL1
65660768-
65661485-
65661593-
Unc
0.889
0.887
−0.001
9.75E−01

65661484
65661592
65664279

FOXN3
89647151-
89656731-
89656794-
Exc
0.301
0.077
−0.224
8.32E−15

89656730
89656793
89747293

FOXN3
89647151-
89656728-
89656794-
Exc
0.347
0.097
−0.250
1.19E−16

89656727
89656793
89747293

FOXRED2
36897455-
36900145-
36900415-
Unc
0.857
0.865
0.008
9.89E−01

36900144
36900414
36900561

FRS2
69925837-
69931696-
69931764-
Unc
0.100
0.095
−0.006
9.70E−01

69931695
69931763
69955959

FRYL
48503751-
48504845-
48504863-
Inc
0.035
0.222
0.187
4.68E−08

48504844
48504862
48507563

FUT8
66083092-
66083808-
66083910-
Inc
0.006
0.234
0.228
4.47E−59

66083807
66083909
66096209

FXR2
7495244-
7495389-
7495476-
Inc
0.020
0.152
0.132
1.28E−12

7495388
7495475
7495571

FYN
112101839-
112167792-
112167833-
Exc
0.877
0.741
−0.136
3.57E−07

112167791
112167832
112194170

GAB1
144361536-
144378833-
144378923-
Exc
0.400
0.213
−0.187
2.06E−04

144378832
144378922
144380537

GABPB2
151070479-
151076038-
151076152-
Exc
0.702
0.490
−0.213
2.46E−04

151076037
151076151
151079512

GABRE
151128449-
151129755-
151129838-
Exc
0.122
0.006
−0.116
4.60E−05

151129754
151129837
151130894

GALNS
88902676-
88904030-
88904174-
Exc
0.989
0.869
−0.120
2.92E−09

88904029
88904173
88907399

GALNS
88908380-
88909114-
88909238-
Exc
0.935
0.666
−0.269
2.89E−11

88909113
88909237
88923165

GAS7
9862573-
9872994-
9873080-
Unc
0.871
0.876
0.005
4.60E−01

9872993
9873079
9885120

GBP3
89481098-
89485809-
89485895-
Unc
0.358
0.367
0.009
5.52E−01

89485808
89485894
89486214

GBP3
89481098-
89485813-
89485895-
Unc
0.234
0.225
−0.009
7.69E−01

89485812
89485894
89486214

GEMIN8
14039631-
14044171-
14044341-
Unc
0.696
0.687
−0.009
9.24E−01

14044170
14044340
14047895

GFPT2
179728609-
179729423-
179729585-
Exc
0.912
0.756
−0.156
9.65E−06

179729422
179729584
179731771

GGCT
30538555-
30540152-
30540298-
Inc
0.755
0.964
0.209
2.33E−17

30540151
30540297
30544184

GIT2
110383155-
110385061-
110385310-
Exc
0.977
0.876
−0.101
4.89E−06

110385060
110385309
110388971

GIT2
110385310-
110388972-
110389122-
Inc
0.822
0.946
0.124
1.00E−08

110388971
110389121
110390896

GK
30714801-
30715849-
30715867-
Exc
0.606
0.246
−0.360
1.00E−04

30715848
30715866
30718530

GLIS3
4125942-
4286038-
4286524-
Unc
0.807
0.808
0.001
8.26E−01

4286037
4286523
4299420

GLIS3
4118882-
4125734-
4125942-
Unc
0.614
0.605
−0.008
9.77E−01

4125733
4125941
4286037

GLRB
158065112-
158073870-
158074163-
Unc
0.754
0.752
−0.002
6.97E−01

158073869
158074162
158091583

GLS
191778091-
191784941-
191784975-
Exc
0.710
0.295
−0.414
1.11E−16

191784940
191784974
191785749

GLS
191775048-
191777919-
191778091-
Inc
0.699
0.876
0.177
1.35E−06

191777918
191778090
191784940

GLT8D1
52734513-
52738740-
52738969-
Unc
0.449
0.441
−0.009
5.89E−01

52738739
52738968
52739462

GNAS
57470740-
57473996-
57474041-
Unc
0.314
0.316
0.003
7.51E−01

57473995
57474040
57478582

GNAS
57470740-
57473996-
57474041-
Unc
0.602
0.595
−0.006
4.76E−01

57473995
57474040
57478585

GOLGA4
37396679-
37402734-
37402797-
Exc
0.445
0.313
−0.132
4.72E−06

37402733
37402796
37407570

GOLGB1
121437349-
121438493-
121438616-
Exc
0.523
0.340
−0.183
4.28E−05

121438492
121438615
121441108

GOLGB1
121437349-
121438493-
121438601-
Exc
0.519
0.326
−0.193
1.78E−05

121438492
121438600
121441108

GOLT1B
21654883-
21661317-
21661496-
Exc
0.977
0.875
−0.101
1.30E−06

21661316
21661495
21665228

GPATCH8
42513914-
42516039-
42516084-
Unc
0.137
0.136
−0.002
9.47E−01

42516038
42516083
42541839

GPBP1
56531860-
56532940-
56533000-
Unc
0.223
0.231
0.008
6.31E−01

56532939
56532999
56542126

GPR133
131621560-
131622189-
131622775-
Exc
0.972
0.837
−0.136
1.65E−07

131622188
131622774
131623712

GPR180
95264645-
95271404-
95271585-
Exc
0.676
0.385
−0.291
1.84E−08

95271403
95271584
95271721

GRB10
50771606-
50778572-
50778688-
Unc
0.239
0.231
−0.007
9.10E−01

50778571
50778687
50823583

GRTPAP1
48853770-
48854566-
48854593-
Exc
0.992
0.878
−0.114
2.78E−07

48854565
48854592
48855649

GTF2I
74157860-
74158478-
74158590-
Inc
0.407
0.799
0.392
8.75E−13

74158477
74158589
74159096

GTF2I
74131271-
74133198-
74133261-
Inc
0.309
0.435
0.126
5.68E−11

74133197
74133260
74143123

GTF3A
28004759-
28006868-
28006942-
Exc
0.818
0.713
−0.105
5.18E−10

28006867
28006941
28008275

GUF1
44696531-
44697632-
44697752-
Exc
0.965
0.859
−0.107
1.21E−04

44697631
44697751
44699424

GUSB
65439692-
65439906-
65440059-
Exc
0.567
0.435
−0.132
1.21E−04

65439905
65440058
65441001

HACL1
15624497-
15626755-
15626850-
Exc
0.868
0.550
−0.318
7.12E−06

15626754
15626849
15628031

HAUS7
152719967-
152720335-
152720512-
Exc
0.465
0.347
−0.119
9.05E−04

152720334
152720511
152720999

HCFC1R1
3073363-
3073475-
3073532-
Exc
0.922
0.794
−0.128
8.08E−07

3073474
3073531
3073847

HDAC10
50685396-
50686121-
50686206-
Exc
0.741
0.534
−0.207
7.53E−05

50686120
50686205
50686318

HDAC7
48189551-
48189689-
48189800-
Exc
0.465
0.218
−0.247
1.91E−13

48189688
48189799
48189989

HDAC9
18633653-
18668973-
18669105-
Unc
0.509
0.518
0.009
9.69E−01

18668972
18669104
18674249

HECTD3
45475356-
45475658-
45475794-
Exc
0.929
0.801
−0.128
8.69E−06

45475657
45475793
45475872

HER3
89591404-
89597369-
89597393-
Exc
0.804
0.430
−0.374
8.53E−19

89597368
89597392
89597484

HIPK3
33369560-
33369712-
33369775-
Exc
0.190
0.084
−0.105
3.69E−06

33369711
33369774
33370067

HMCN1
186143775-
186147548-
186147899-
Unc
0.589
0.585
−0.003
8.17E−01

186147547
186147898
186151299

HMGXB4
35659868-
35659975-
35660090-
Exc
0.335
0.200
−0.135
4.79E−04

35659974
35660089
35660640

HNRNPA2B1
26230081-
26230613-
26230749-
Inc
0.761
0.874
0.113
3.95E−08

26230612
26230748
26232114

HNRNPD
83276555-
83277690-
83277837-
Exc
0.452
0.346
−0.106
7.97E−15

83277689
83277836
83277948

HNRNPDL
83346037-
83346716-
83346821-
Inc
0.187
0.302
0.115
2.19E−16

83346715
83346820
83347189

HNRNPK
86588315-
86588817-
86588889-
Unc
0.894
0.893
−0.001
8.03E−01

86588816
86588888
86589431

HPS1
100193849-
100195029-
100195172-
Exc
0.900
0.795
−0.105
1.72E−08

100195028
100195171
100195391

HSCB
29139967-
29140603-
29140698-
Unc
0.869
0.864
−0.006
9.85E−01

29140602
29140697
29147228

HSD17B4
118792064-
118807331-
118807396-
Inc
0.022
0.619
0.597
5.07E−105

118807330
118807395
118809602

HSF2
122744832-
122749048-
122749102-
Inc
0.256
0.583
0.328
1.59E−12

122749047
122749101
122752574

HUWE1
53652220-
53652747-
53652990-
Exc
0.384
0.270
−0.114
3.10E−05

53652746
53652989
53654360

IFT88
21157159-
21163950-
21164007-
Exc
0.845
0.579
−0.266
4.98E−06

21163949
21164006
21165105

IGF2BP2
185376198-
185390329-
185390458-
Exc
0.643
0.384
−0.258
1.12E−16

185390328
185390457
185393083

IL15RA
6002531-
6005706-
6005802-
Inc
0.493
0.782
0.289
1.07E−03

6005705
6005801
6008107

1L15RA
6002531-
6005706-
6005805-
Inc
0.571
0.825
0.254
7.29E−04

6005705
6005804
6008107

IL17RA
17586493-
17586743-
17586845-
Unc
0.834
0.841
0.008
7.57E−01

17586742
17586844
17588616

IL17RC
9974388-
9974504-
9974543-
Unc
0.575
0.582
0.007
9.92E−01

9974503
9974542
9974636

IL6
22766901-
22767132-
22767254-
Unc
0.899
0.895
−0.003
6.25E−01

22767131
22767253
22768311

INF2
105181194-
105181621-
105181678-
Inc
0.599
0.732
0.133
3.41E−05

105181620
105181677
105185131

ING4
6760552-
6761437-
6761476-
Exc
0.993
0.866
−0.128
1.40E−09

6761436
6761475
6761827

INO80E
30012362-
30012786-
30012852-
Inc
0.539
0.828
0.289
8.16E−06

30012785
30012851
30016541

INO80E
30012362-
30012533-
30015979-
Inc
0.562
0.819
0.258
1.08E−04

30012532
30015978
30016541

INO80E
30012362-
30012533-
30012852-
Inc
0.702
0.902
0.201
4.35E−06

30012532
30012851
30016541

INO80E
30012362-
30012735-
30012852-
Inc
0.794
0.942
0.148
2.03E−07

30012734
30012851
30016541

INPP1
191208688-
191224372-
191224425-
Inc
0.091
0.224
0.133
5.46E−04

191224371
191224424
191224764

INTS9
28695294-
28704264-
28704327-
Unc
0.832
0.830
−0.002
9.06E−01

28704263
28704326
28707729

IP6K2
48731674-
48731892-
48731959-
Inc
0.134
0.552
0.419
6.60E−13

48731891
48731958
48732522

IP6K2
48731674-
48732127-
48732258-
Unc
0.290
0.296
0.006
8.95E−01

48732126
48732257
48732522

IPOS
30833573-
30834593-
30834752-
Exc
0.993
0.892
−0.101
9.08E−09

30834592
30834751
30837234

IQCB1
121545028-
121547317-
121547480-
Inc
0.705
0.868
0.163
7.90E−04

121547316
121547479
121547707

IRAK4
44162076-
44165023-
44165169-
Exc
0.554
0.239
−0.315
4.03E−08

44165022
44165168
44165982

ISOC2
55966698-
55967003-
55967213-
Exc
0.875
0.761
−0.115
1.01E−06

55967002
55967212
55967715

IST1
71956584-
71957191-
71957284-
Exc
0.951
0.805
−0.146
5.81E−27

71957190
71957283
71958671

ITGB1BP1
9558862-
9560119-
9560230-
Inc
0.310
0.522
0.212
3.37E−10

9560118
9560229
9562607

KANSL3
97285282-
97285409-
97285500-
Unc
0.889
0.892
0.003
9.79E−01

97285408
97285499
97297048

KAT6A
41906821-
41907138-
41907226-
Unc
0.182
0.186
0.005
9.37E−01

41907137
41907225
41909418

KATNBL1
34455892-
34470022-
34470201-
Inc
0.077
0.219
0.142
3.89E−05

34470021
34470200
34502151

KCTD20
36438035-
36442566-
36442840-
Unc
0.899
0.893
−0.006
6.98E−01

36442565
36442839
36446897

KDM4C
7103871-
7105402-
7105501-
Exc
0.174
0.022
−0.152
7.90E−05

7105401
7105500
7128065

KDM5A
394829-
395292-
395374-
Inc
0.301
0.443
0.143
3.33E−04

395291
395373
401924

KIAA0100
26960770-
26960913-
26961105-
Exc
0.975
0.850
−0.125
1.28E−22

26960912
26961104
26961534

KIAA0232
6873410-
6878387-
6878485-
Unc
0.894
0.885
−0.009
6.15E−01

6878386
6878484
6882513

KIAA0368
114213836-
114235177-
114235281-
Unc
0.809
0.813
0.003
8.91E−01

114235176
114235280
114246264

KIAA0753
6526892-
6528075-
6528182-
Unc
0.857
0.858
0.001
8.05E−01

6528074
6528181
6531436

KIAA1551
32113806-
32123123-
32123291-
Unc
0.893
0.898
0.005
9.29E−01

32123122
32123290
32133811

KIAA1586
56912195-
56915572-
56915653-
Unc
0.866
0.863
−0.003
9.48E−01

56915571
56915652
56917483

KIAA1731
93454579-
93455120-
93455217-
Unc
0.833
0.838
0.005
9.89E−01

93455119
93455216
93456206

KIF3A
132039312-
132042143-
132042152-
Exc
0.525
0.260
−0.265
3.02E−06

132042142
132042151
132046650

KIFC3
57806201-
57819376-
57819579-
Unc
0.168
0.165
−0.003
9.58E−01

57819375
57819578
57828910

KIFC3
57806201-
57824842-
57824979-
Unc
0.109
0.104
−0.005
9.03E−01

57824841
57824978
57828910

KITLG
88900915-
88909311-
88909395-
Exc
0.985
0.884
−0.101
2.32E−16

88909310
88909394
88910110

KLC1
104145883-
104151323-
104151374-
Exc
0.286
0.176
−0.110
1.43E−06

104151322
104151373
104153417

KLC1
104153549-
104158696-
104158763-
Inc
0.330
0.755
0.425
1.93E−42

104158695
104158762
104166991

KLHL12
202861788-
202862367-
202862554-
Unc
0.855
0.860
0.005
9.23E−01

202862366
202862553
202863311

KTN1
56128331-
56130673-
56130760-
Inc
0.268
0.525
0.257
7.38E−64

56130672
56130759
56133958

KTN1
56139731-
56139890-
56139974-
Inc
0.387
0.495
0.108
4.17E−12

56139889
56139973
56142552

KTN1
56047073-
56068475-
56068599-
Unc
0.410
0.406
−0.004
9.19E−01

56068474
56068598
56078736

L3HYPDH
59939809-
59941157-
59941245-
Inc
0.197
0.344
0.147
4.42E−06

59941156
59941244
59942586

LACC1
44463119-
44464250-
44464411-
Exc
0.925
0.789
−0.136
1.91E−05

44464249
44464410
44465584

LAMTOR3
100813192-
100815112-
100815158-
Exc
0.890
0.750
−0.140
9.62E−12

100815111
100815157
100815491

LAS1L
64744143-
64744444-
64744495-
Exc
0.214
0.004
−0.210
4.86E−12

64744443
64744494
64744844

LBR
225594535-
225597993-
225598119-
Unc
0.885
0.885
0.000
9.73E−01

225597992
225598118
225599038

LDB2
16504497-
16507463-
16507606-
Unc
0.623
0.618
−0.006
8.46E−01

16507462
16507605
16510157

LENG8
54963932-
54964725-
54964836-
Exc
0.899
0.779
−0.120
1.85E−19

54964724
54964835
54965608

LETMD1
51442969-
51445875-
51445991-
Exc
0.439
0.207
−0.232
2.76E−10

51445874
51445990
51450132

LETMD1
51442969-
51449927-
51450029-
Exc
0.516
0.214
−0.302
1.21E−17

51449926
51450028
51450132

LETMD1
51442969-
51445875-
51445991-
Exc
0.872
0.524
−0.348
4.96E−10

51445874
51445990
51449617

LETMD1
51442969-
51447561-
51447644-
Exc
0.904
0.512
−0.392
1.12E−15

51447560
51447643
51449617

LETMD1
51442969-
51447595-
51447644-
Exc
0.909
0.511
−0.398
1.35E−16

51447594
51447643
51449617

LGALS8
236706088-
236706215-
236706341-
Inc
0.243
0.408
0.165
7.61E−08

236706214
236706340
236706859

LINC00963
132251579-
132255695-
132255875-
Exc
0.837
0.709
−0.128
8.09E−04

132255694
132255874
132265601

LMAN2L
97377763-
97399256-
97399339-
Exc
0.956
0.849
−0.108
1.64E−05

97399255
97399338
97400145

LMAN2L
97400264-
97402874-
97402955-
Inc
0.049
0.228
0.179
2.48E−06

97402873
97402954
97403685

LMO7
76210863-
76287318-
76287389-
Exc
0.761
0.597
−0.164
5.14E−38

76287317
76287388
76301164

LONRF1
12594650-
12594781-
12594870-
Inc
0.005
0.243
0.239
7.33E−11

12594780
12594869
12595503

LOXL3
74763599-
74763836-
74764056-
Exc
0.907
0.751
−0.156
1.95E−05

74763835
74764055
74776495

LPHN2
82451040-
82452973-
82453026-
Exc
0.469
0.362
−0.107
4.04E−04

82452972
82453025
82456074

LPHN2
82451040-
82452944-
82453026-
Exc
0.413
0.261
−0.152
2.47E−06

82452943
82453025
82456074

LPHN2
82417827-
82418671-
82418710-
Inc
0.193
0.455
0.263
1.56E−19

82418670
82418709
82421560

LPIN1
11913872-
11916212-
11916320-
Inc
0.118
0.532
0.414
4.79E−35

11916211
11916319
11919644

LRCH3
197581317-
197585705-
197585777-
Inc
0.352
0.633
0.281
1.38E−12

197585704
197585776
197592293

LRP12
105521303-
105544135-
105544192-
Unc
0.738
0.739
0.002
9.98E−01

105544134
105544191
105601046

LRRC28
99796331-
99816781-
99816822-
Exc
0.764
0.347
−0.417
1.41E−23

99816780
99816821
99827461

LRRC32
76369079-
76370627-
76372553-
Exc
0.939
0.838
−0.101
2.33E−04

76370626
76372552
76376914

LSM1
38021359-
38027320-
38027436-
Inc
0.827
0.957
0.130
2.13E−27

38027319
38027435
38029482

LTA4H
96396843-
96397616-
96397760-
Exc
0.864
0.762
−0.103
6.37E−05

96397615
96397759
96400091

LTBP1
33540337-
33567905-
33568031-
Exc
0.947
0.834
−0.114
1.40E−16

33567904
33568030
33572433

LTBP3
65307353-
65307484-
65307625-
Exc
0.663
0.325
−0.338
3.24E−05

65307483
65307624
65307715

LTBP4
41128573-
41128855-
41128927-
Exc
0.869
0.723
−0.147
5.23E−04

41128854
41128926
41129508

LUC7L
258188-
258600-
258664-
Exc
0.196
0.001
−0.195
5.16E−33

258599
258663
270647

LUC7L
277336-
278332-
278402-
Exc
0.388
0.003
−0.385
4.67E−27

278331
278401
279277

LYPLAL1
219352589-
219366424-
219366594-
Exc
0.949
0.848
−0.101
5.35E−04

219366423
219366593
219383873

LYRM7
130517993-
130522721-
130522803-
Exc
0.934
0.750
−0.184
5.86E−05

130522720
130522802
130535223

LZTFL1
45877277-
45879419-
45879544-
Exc
0.856
0.727
−0.129
1.28E−03

45879418
45879543
45883480

MACF1
39929359-
39930767-
39930785-
Exc
0.611
0.503
−0.108
1.71E−07

39930766
39930784
39934286

MACF1
39715776-
39717518-
39717614-
Inc
0.005
0.126
0.121
3.68E−08

39717517
39717613
39719969

MADD
47291302-
47295378-
47295528-
Exc
0.989
0.788
−0.201
1.89E−04

47295377
47295527
47296113

MADD
47346129-
47348289-
47348359-
Unc
0.883
0.887
0.005
9.39E−01

47348288
47348358
47350208

MAGOHB
10763280-
10765239-
10765578-
Inc
0.098
0.210
0.111
6.40E−04

10765238
10765577
10766037

MAGOHB
10760536-
10761697-
10761983-
Inc
0.140
0.249
0.109
4.64E−06

10761696
10761982
10762429

MAN2C1
75654795-
75654983-
75655090-
Exc
0.899
0.652
−0.247
3.24E−12

75654982
75655089
75656828

MAP2K5
67995747-
68020254-
68020284-
Unc
0.835
0.842
0.007
7.64E−01

68020253
68020283
68040568

MAP3K3
61769223-
61769602-
61769780-
Exc
0.933
0.803
−0.130
2.79E−11

61769601
61769779
61770908

MAP4K4
102486878-
102487956-
102488148-
Exc
0.453
0.327
−0.126
1.29E−18

102487955
102488147
102490108

MAP7D1
36639080-
36640499-
36640610-
Unc
0.666
0.668
0.002
9.54E−01

36640498
36640609
36641799

MAPK11
50705912-
50705998-
50706057-
Exc
0.972
0.797
−0.175
6.33E−04

50705997
50706056
50706248

MAPK12
50685396-
50686121-
50686206-
Exc
0.741
0.534
−0.207
7.53E−05

50686120
50686205
50686318

MAPK9
179707609-
179713975-
179714068-
Unc
0.198
0.200
0.001
9.40E−01

179713974
179714067
179718847

MAPKAP1
128246863-
128268589-
128268697-
Inc
0.571
0.683
0.112
9.36E−08

128268588
128268696
128305337

MARK3
103964866-
103966493-
103966538-
Inc
0.538
0.737
0.199
3.24E−16

103966492
103966537
103969218

MARK3
103958372-
103966493-
103966538-
Inc
0.758
0.880
0.122
1.67E−04

103966492
103966537
103969218

MAZ
29820063-
29820861-
29821086-
Unc
0.160
0.165
0.005
8.90E−01

29820860
29821085
29821397

MBD1
47799326-
47799704-
47799842-
Unc
0.848
0.858
0.010
7.89E−01

47799703
47799841
47799933

MBD5
148779254-
148811960-
148812019-
Exc
0.267
0.017
−0.250
2.05E−06

148811959
148812018
148936268

MBNL1
152165563-
152173331-
152173367-
Inc
0.612
0.771
0.159
6.22E−15

152173330
152173366
152174055

MBOAT2
9000895-
9002720-
9002853-
Exc
0.993
0.819
−0.174
3.07E−22

9002719
9002852
9004299

MBOAT2
9000895-
9002401-
9002453-
Exc
0.949
0.296
−0.653
6.20E−17

9002400
9002452
9004299

MCCC2
70900296-
70922467-
70922581-
Unc
0.850
0.845
−0.005
9.93E−01

70922466
70922580
70927947

ME3
86161441-
86168408-
86168802-
Inc
0.222
0.453
0.231
1.78E−04

86168407
86168801
86176132

MECR
29543198-
29547350-
29547434-
Unc
0.195
0.195
0.000
9.67E−01

29547349
29547433
29557242

MED13
60032929-
60033041-
60033200-
Exc
0.975
0.819
−0.156
1.34E−14

60033040
60033199
60033699

MED15
20922919-
20929400-
20929520-
Exc
0.596
0.429
−0.167
7.19E−05

20929399
20929519
20936897

MED23
131931387-
131936464-
131936482-
Unc
0.210
0.217
0.007
9.45E−01

131936463
131936481
131937046

MEG3
101297872-
101298849-
101298979-
Exc
0.273
0.138
−0.135
1.15E−09

101298848
101298978
101302503

MEG3
101296087-
101298849-
101298979-
Exc
0.654
0.482
−0.172
6.45E−05

101298848
101298978
101302503

MEG3
101297872-
101302076-
101302217-
Exc
0.660
0.431
−0.229
5.34E−23

101302075
101302216
101302503

MEG3
101297872-
101302073-
101302217-
Exc
0.659
0.428
−0.232
2.36E−23

101302072
101302216
101302503

MEG3
101296087-
101297758-
101297872-
Inc
0.606
0.798
0.192
3.43E−14

101297757
101297871
101298848

MEGF6
3415391-
3415702-
3415831-
Exc
0.752
0.480
−0.271
1.38E−06

3415701
3415830
3416151

MEGF6
3413348-
3413552-
3413684-
Exc
0.622
0.264
−0.358
3.37E−12

3413551
3413683
3413796

MEGF6
3407524-
3409203-
3409332-
Unc
0.852
0.860
0.008
3.46E−01

3409202
3409331
3410334

MEIS1
66795889-
66796182-
66796278-
Unc
0.654
0.655
0.002
3.87E−01

66796181
66796277
66798377

METAP1
99917019-
99926920-
99927018-
Inc
0.022
0.202
0.179
7.38E−14

99926919
99927017
99950017

METAP1
99917019-
99926920-
99927022-
Inc
0.011
0.126
0.114
4.21E−09

99926919
99927021
99950017

METTL10
126449073-
126450869-
126451128-
Unc
0.492
0.482
−0.010
8.27E−01

126450868
126451127
126453960

METTL14
119625207-
119626766-
119626977-
Exc
0.896
0.795
−0.102
8.30E−04

119626765
119626976
119631152

METTL21A
208478168-
208485365-
208485419-
Unc
0.142
0.135
−0.007
8.61E−01

208485364
208485418
208486529

MFF
228205097-
228207461-
228207536-
Exc
0.326
0.185
−0.141
1.63E−11

228207460
228207535
228211941

MFF
228190144-
228195342-
228195563-
Exc
0.902
0.752
−0.150
4.68E−17

228195341
228195562
228197134

MFF
228205097-
228211942-
228212101-
Exc
0.851
0.689
−0.162
1.35E−17

228211941
228212100
228217229

MFF
228190144-
228193394-
228195563-
Exc
0.914
0.743
−0.171
3.75E−23

228193393
228195562
228197134

MFF
228205097-
228207461-
228207536-
Exc
0.378
0.171
−0.206
1.50E−12

228207460
228207535
228220392

MFF
228190144-
228193394-
228193506-
Exc
0.836
0.448
−0.387
1.16E−33

228193393
228193505
228195341

MFF
228193506-
228194322-
228194500-
Inc
0.091
0.196
0.104
3.48E−05

228194321
228194499
228195341

MFSD12
3546167-
3546253-
3546424-
Exc
0.952
0.836
−0.117
1.26E−06

3546252
3546423
3547269

MGEA5
103552701-
103553670-
103553756-
Exc
0.921
0.814
−0.107
2.90E−10

103553669
103553755
103557736

MGLL
127414034-
127429419-
127429509-
Unc
0.893
0.892
−0.002
8.74E−01

127429418
127429508
127439895

MGST2
140587232-
140599697-
140599797-
Exc
0.942
0.729
−0.213
1.98E−06

140599696
140599796
140616350

MICU3
16921747-
16927197-
16927229-
Unc
0.814
0.806
−0.008
8.50E−01

16927196
16927228
16935291

MINK1
4795530-
4795697-
4795808-
Exc
0.424
0.289
−0.134
7.35E−05

4795696
4795807
4795950

MIR22HG
1617309-
1617665-
1617748-
Exc
0.817
0.649
−0.168
3.76E−05

1617664
1617747
1619423

MKNK2
2037829-
2039630-
2039856-
Unc
0.552
0.545
−0.007
4.92E−01

2039629
2039855
2040132

MKS1
56291749-
56292102-
56292200-
Exc
0.973
0.797
−0.176
4.57E−04

56292101
56292199
56293448

MLF1
158289181-
158310223-
158310371-
Exc
1.000
0.824
−0.176
2.77E−04

158310222
158310370
158314650

MLH1
37053591-
37055923-
37056036-
Exc
1.000
0.890
−0.110
1.29E−10

37055922
37056035
37058996

MLH1
37053591-
37055923-
37056036-
Exc
0.982
0.802
−0.179
1.88E−07

37055922
37056035
37061800

MLLT10
21827842-
21846550-
21846754-
Unc
0.212
0.204
−0.008
9.92E−01

21846549
21846753
21875222

MLLT6
36877001-
36878131-
36878481-
Exc
0.838
0.636
−0.202
3.61E−04

36878130
36878480
36878930

MLST8
2257347-
2258211-
2258336-
Exc
0.881
0.640
−0.241
1.01E−18

2258210
2258335
2258450

MMP19
56234667-
56234890-
56235021-
Exc
0.952
0.743
−0.209
2.66E−07

56234889
56235020
56236136

MMP19
56234667-
56234890-
56234992-
Exc
0.920
0.626
−0.293
2.11E−06

56234889
56234991
56236136

MORF4L2
102933529-
102939609-
102939658-
Exc
0.154
0.053
−0.101
8.00E−52

102939608
102939657
102940098

MORF4L2
102933580-
102939609-
102939658-
Exc
0.385
0.203
−0.183
8.78E−18

102939608
102939657
102940098

MORF4L2
102933549-
102939609-
102939658-
Exc
0.597
0.281
−0.316
1.77E−28

102939608
102939657
102940098

MOSPD1
134031065-
134033120-
134033196-
Exc
0.971
0.832
−0.139
1.45E−09

134033119
134033195
134033309

MOSPD1
134023223-
134025509-
134025671-
Inc
0.625
0.832
0.207
1.93E−09

134025508
134025670
134030846

MPDZ
13183585-
13186269-
13186386-
Exc
0.894
0.770
−0.124
4.45E−07

13186268
13186385
13188782

MPI
75188667-
75189352-
75189561-
Exc
0.908
0.800
−0.107
1.24E−04

75189351
75189560
75189852

MPPE1
11897356-
11897525-
11897620-
Unc
0.416
0.424
0.008
9.19E−01

11897524
11897619
11906201

MPV17
27535640-
27535861-
27536022-
Exc
0.916
0.811
−0.106
2.99E−07

27535860
27536021
27545314

MRI1
13875924-
13876768-
13876944-
Unc
0.692
0.700
0.008
9.25E−01

13876767
13876943
13879172

MRI1
13875924-
13876768-
13876880-
Unc
0.604
0.611
0.007
9.69E−01

13876767
13876879
13879172

MRPL33
27995560-
27997291-
27997398-
Exc
0.447
0.291
−0.156
3.59E−28

27997290
27997397
28002299

MRPL55
228296020-
228296138-
228296176-
Unc
0.278
0.270
−0.008
9.35E−01

228296137
228296175
228296655

MRPL55
228296020-
228296138-
228296210-
Unc
0.243
0.235
−0.008
9.55E−01

228296137
228296209
228296655

MSRB3
65672646-
65702309-
65702436-
Exc
0.521
0.420
−0.101
1.46E−04

65702308
65702435
65720605

MSRB3
65672646-
65700643-
65700807-
Inc
0.140
0.290
0.149
1.45E−04

65700642
65700806
65702308

MTCH2
47656287-
47657097-
47657124-
Exc
0.915
0.813
−0.102
2.02E−16

47657096
47657123
47660250

MTIF2
55491002-
55493517-
55493655-
Unc
0.163
0.155
−0.008
6.61E−01

55493516
55493654
55494704

MTMR2
95598841-
95620776-
95620849-
Exc
0.262
0.122
−0.141
3.54E−05

95620775
95620848
95621319

MTMR2
95621426-
95647406-
95647477-
Inc
0.506
0.679
0.173
8.49E−04

95647405
95647476
95657038

MTMR3
30416874-
30418018-
30418129-
Exc
0.810
0.641
−0.169
6.23E−06

30418017
30418128
30418597

MTMR3
30418687-
30419446-
30419473-
Exc
0.384
0.214
−0.169
3.78E−06

30419445
30419472
30421618

MTMR6
25823631-
25825787-
25825914-
Exc
0.934
0.675
−0.259
7.28E−27

25825786
25825913
25825990

MTRR
7871037-
7873486-
7873640-
Exc
0.770
0.468
−0.302
2.38E−12

7873485
7873639
7875370

MTRR
7871037-
7873486-
7873626-
Exc
0.625
0.288
−0.336
1.13E−09

7873485
7873625
7875370

MTSS1L
70712313-
70713218-
70713227-
Exc
0.308
0.193
−0.115
6.64E−12

70713217
70713226
70713532

MXI1
111988080-
112004586-
112004632-
Unc
0.892
0.898
0.006
9.46E−01

112004585
112004631
112038937

MXRA7
74676962-
74679929-
74680010-
Unc
0.158
0.165
0.007
3.84E−01

74679928
74680009
74681153

MYBL1
67477061-
67478299-
67478479-
Exc
0.243
0.053
−0.190
9.27E−05

67478298
67478478
67478918

MYCBP2
77699604-
77700453-
77700678-
Exc
0.898
0.773
−0.125
4.67E−06

77700452
77700677
77713330

MYCBP2
77673149-
77692475-
77692655-
Unc
0.215
0.207
−0.007
8.24E−01

77692474
77692654
77695507

MYEF2
48441569-
48443297-
48443369-
Inc
0.369
0.722
0.353
1.36E−04

48443296
48443368
48443669

MYLK
123444926-
123451743-
123451950-
Exc
0.802
0.611
−0.191
4.65E−34

123451742
123451949
123452533

MYLK
123550518-
123554715-
123554783-
Inc
0.244
0.589
0.345
1.49E−21

123554714
123554782
123595405

MYLK
123550518-
123595406-
123595465-
Inc
0.739
0.897
0.158
1.79E−05

123595405
123595464
123603052

MYNN
169500432-
169501265-
169501349-
Exc
0.805
0.625
−0.181
2.38E−05

169501264
169501348
169502409

MYNN
169491251-
169491819-
169491886-
Inc
0.186
0.328
0.142
7.51E−05

169491818
169491885
169492052

MYO18A
27442859-
27443462-
27443474-
Inc
0.106
0.359
0.253
2.29E−07

27443461
27443473
27445062

MYO18A
27449272-
27464034-
27464103-
Unc
0.324
0.330
0.005
7.92E−01

27464033
27464102
27467357

MYO19
34870392-
34870956-
34871026-
Exc
0.980
0.870
−0.109
9.03E−04

34870955
34871025
34871700

MYO1B
192265195-
192267358-
192267445-
Inc
0.293
0.483
0.190
3.03E−41

192267357
192267444
192272840

MYO1B
192265195-
192265475-
192265562-
Inc
0.169
0.296
0.128
2.28E−11

192265474
192265561
192267357

MYO5A
52628754-
52630007-
52630082-
Exc
0.180
0.063
−0.118
5.42E−05

52630006
52630081
52632392

MYO5A
52638659-
52641015-
52641024-
Inc
0.823
0.953
0.130
1.78E−04

52641014
52641023
52643450

MYO5A
52632592-
52635314-
52635395-
Unc
0.610
0.617
0.007
9.78E−01

52635313
52635394
52638557

N6AMT2
21306261-
21311862-
21311945-
Unc
0.745
0.755
0.010
9.61E−01

21311861
21311944
21331593

NABP1
192546744-
192547218-
192547322-
Inc
0.531
0.729
0.198
2.10E−25

192547217
192547321
192548454

NADK2
36207368-
36208727-
36208793-
Exc
0.107
0.005
−0.102
2.64E−11

36208726
36208792
36211945

NAE1
66860487-
66860580-
66860684-
Exc
0.974
0.859
−0.115
2.65E−09

66860579
66860683
66864749

NAE1
66860487-
66860571-
66860684-
Exc
0.912
0.596
−0.315
1.31E−08

66860570
66860683
66864749

NBN
90993752-
90994181-
90994231-
Exc
0.173
0.017
−0.156
9.26E−10

90994180
90994230
90994949

NCK2
106471746-
106497784-
106498506-
Unc
0.595
0.586
−0.008
9.98E−01

106497783
106498505
106509437

NCOR2
124810917-
124811955-
124812180-
Unc
0.657
0.657
0.000
9.08E−01

124811954
124812179
124815390

NCOR2
124810917-
124812093-
124812180-
Unc
0.682
0.681
−0.001
9.02E−01

124812092
124812179
124815390

NEDD1
97301403-
97301480-
97301635-
Unc
0.870
0.878
0.008
9.75E−01

97301479
97301634
97303529

NEDD1
97301079-
97301382-
97301635-
Unc
0.829
0.826
−0.003
9.29E−01

97301381
97301634
97303529

NEK1
170506701-
170508710-
170508765-
Exc
0.982
0.830
−0.152
4.60E−07

170508709
170508764
170509799

NEO1
73566347-
73567033-
73567066-
Inc
0.029
0.149
0.120
6.18E−09

73567032
73567065
73570471

NEXN
78383959-
78390873-
78390915-
Exc
0.792
0.654
−0.138
1.27E−08

78390872
78390914
78392098

NF2
30077591-
30079009-
30079069-
Inc
0.564
0.807
0.244
4.92E−09

30079008
30079068
30090740

NF2
30077591-
30079009-
30079054-
Inc
0.733
0.900
0.167
1.66E−10

30079008
30079053
30090740

NFE2L1
46133961-
46134394-
46134484-
Exc
0.483
0.327
−0.156
1.37E−34

46134393
46134483
46134705

NIN
51230683-
51233025-
51233115-
Unc
0.888
0.896
0.008
8.80E−01

51233024
51233114
51233497

NIPA2
23021430-
23033278-
23033414-
Exc
0.771
0.608
−0.163
9.71E−04

23033277
23033413
23033893

NIPA2
23021430-
23027801-
23027923-
Exc
0.511
0.326
−0.185
1.06E−05

23027800
23027922
23033277

NLRC5
57108596-
57110731-
57110815-
Exc
0.979
0.857
−0.122
1.51E−05

57110730
57110814
57111207

NLRX1
119042183-
119043065-
119043135-
Exc
0.885
0.742
−0.143
1.09E−03

119043064
119043134
119043609

NPEPPS
45646861-
45654447-
45654527-
Inc
0.036
0.172
0.135
4.25E−07

45654446
45654526
45656755

NPR2
35802605-
35802729-
35802801-
Exc
0.979
0.878
−0.101
2.79E−11

35802728
35802800
35805507

NPRL3
162775-
167300-
167375-
Exc
0.852
0.697
−0.155
1.74E−05

167299
167374
169124

NPRL3
169255-
174936-
175073-
Unc
0.201
0.206
0.006
9.15E−01

174935
175072
180520

NPRL3
162775-
180521-
180591-
Unc
0.856
0.858
0.003
9.12E−01

180520
180590
188148

NRG1
32617925-
32620736-
32620878-
Inc
0.328
0.510
0.182
1.86E−07

32620735
32620877
32621265

NSFL1C
1435778-
1436359-
1436516-
Exc
0.337
0.214
−0.123
3.38E−07

1436358
1436515
1438844

NSFL1C
1435778-
1436359-
1436365-
Exc
0.498
0.345
−0.153
1.50E−10

1436358
1436364
1438844

NSMCE2
126163520-
126168242-
126168341-
Inc
0.029
0.162
0.133
3.75E−10

126168241
126168340
126194344

NSUN4
46810817-
46812593-
46812748-
Exc
0.941
0.817
−0.124
8.10E−04

46812592
46812747
46818539

NT5C2
104865559-
104871502-
104871563-
Exc
0.657
0.351
−0.306
4.94E−05

104871501
104871562
104899162

NTMT1
132388575-
132394929-
132395081-
Unc
0.837
0.828
−0.009
8.12E−01

132394928
132395080
132396332

NTPCR
233086491-
233091303-
233091466-
Unc
0.776
0.785
0.009
8.51E−01

233091302
233091465
233092092

NUB1
151042553-
151046159-
151046327-
Exc
0.984
0.858
−0.126
3.03E−19

151046158
151046326
151048509

NUBP2
1836657-
1836758-
1836957-
Unc
0.569
0.575
0.006
7.28E−01

1836757
1836956
1837677

NUMB
73822475-
73833605-
73833690-
Unc
0.700
0.697
−0.003
8.55E−01

73833604
73833689
73876644

NUP43
150057759-
150059779-
150059915-
Exc
0.983
0.865
−0.118
7.07E−08

150059778
150059914
150063525

NUP62
50413142-
50430951-
50431106-
Inc
0.662
0.787
0.124
1.01E−03

50430950
50431105
50432582

NUP98
3704672-
3707294-
3707425-
Unc
0.872
0.862
−0.009
8.71E−01

3707293
3707424
3712576

NUPL2
23226766-
23235458-
23235535-
Exc
0.846
0.602
−0.244
4.56E−09

23235457
23235534
23236298

NUTF2
67880889-
67881181-
67881360-
Unc
0.107
0.104
−0.003
9.22E−01

67881180
67881359
67899004

NUTM2A-AS1
89048253-
89067714-
89067818-
Exc
0.220
0.100
−0.120
1.51E−07

89067713
89067817
89086386

OARD1
41035177-
41036580-
41036693-
Exc
0.830
0.563
−0.267
6.53E−07

41036579
41036692
41037814

OCRL
128710530-
128718321-
128718345-
Inc
0.104
0.364
0.260
1.97E−18

128718320
128718344
128720978

ODF2
131223290-
131231462-
131231633-
Exc
0.974
0.872
−0.102
3.16E−04

131231461
131231632
131233586

ODF2L
86820543-
86822127-
86822286-
Exc
0.786
0.514
−0.272
2.12E−07

86822126
86822285
86824469

OFD1
13780564-
13781864-
13781975-
Inc
0.850
0.981
0.131
7.32E−06

13781863
13781974
13785245

OPN3
241761300-
241767722-
241767882-
Unc
0.441
0.437
−0.004
9.18E−01

241767721
241767881
241803183

OPTN
13150290-
13150962-
13151016-
Exc
0.341
0.121
−0.220
4.83E−19

13150961
13151015
13151111

OPTN
13142303-
13150138-
13150290-
Inc
0.210
0.387
0.176
8.72E−24

13150137
13150289
13151111

ORMDL1
190647329-
190647740-
190647850-
Exc
0.702
0.407
−0.295
6.70E−15

190647739
190647849
190648994

OS9
58112966-
58113882-
58114047-
Exc
0.525
0.344
−0.181
3.42E−70

58113881
58114046
58114188

OSBPL8
76844760-
76853639-
76853676-
Inc
0.096
0.296
0.200
5.73E−12

76853638
76853675
76881289

OSBPL8
76844769-
76853639-
76853676-
Inc
0.078
0.269
0.191
2.58E−22

76853638
76853675
76881289

OSER1-AS1
42843644-
42846007-
42846323-
Unc
0.153
0.153
0.000
8.79E−01

42846006
42846322
42853460

P4HA2
131554338-
131562390-
131562915-
Unc
0.162
0.155
−0.007
7.05E−01

131562389
131562914
131563482

P4HA2
131554338-
131562625-
131562915-
Unc
0.167
0.160
−0.007
7.10E−01

131562624
131562914
131563482

PACRGL
20715163-
20726431-
20726512-
Exc
0.216
0.095
−0.120
7.77E−05

20726430
20726511
20728907

PACRGL
20706438-
20709426-
20709494-
Exc
0.845
0.666
−0.179
1.22E−04

20709425
20709493
20714410

PACRGL
20709494-
20711306-
20711397-
Exc
0.805
0.563
−0.242
1.38E−05

20711305
20711396
20714410

PACRGL
20706438-
20711306-
20711397-
Exc
0.767
0.462
−0.305
8.76E−06

20711305
20711396
20714410

PAM
102296934-
102309820-
102310141-
Exc
0.601
0.478
−0.123
4.07E−33

102309819
102310140
102325975

PARD3
34690846-
34739245-
34739377-
Exc
0.749
0.584
−0.165
4.33E−06

34739244
34739376
34759012

PARD3
34620273-
34625127-
34625172-
Unc
0.809
0.805
−0.003
8.88E−01

34625126
34625171
34626205

PARL
183551378-
183551512-
183551614-
Exc
0.937
0.819
−0.118
1.42E−10

183551511
183551613
183558357

PARP11
3935400-
3938076-
3938197-
Exc
0.495
0.250
−0.245
8.16E−04

3938075
3938196
3939055

PARP6
72542434-
72543186-
72543299-
Inc
0.705
0.870
0.164
2.78E−06

72543185
72543298
72543547

PARP6
72542434-
72543186-
72543296-
Inc
0.754
0.902
0.148
1.76E−07

72543185
72543295
72543547

PATL1
59423214-
59423429-
59423519-
Exc
0.878
0.710
−0.168
2.80E−12

59423428
59423518
59423971

PCBP2
53861078-
53861589-
53861628-
Exc
0.649
0.431
−0.218
2.54E−160

53861588
53861627
53862560

PCID2
113839875-
113845186-
113845290-
Exc
0.973
0.757
−0.217
1.52E−31

113845185
113845289
113849384

PCM1
17830197-
17838100-
17838265-
Exc
0.579
0.444
−0.135
4.45E−05

17838099
17838264
17842955

PCNXL2
233344436-
233353645-
233353678-
Exc
1.000
0.899
−0.101
1.52E−05

233353644
233353677
233353776

PCNXL2
233152901-
233160892-
233161146-
Unc
0.882
0.891
0.009
9.04E−01

233160891
233161145
233190013

PCNXL4
60559138-
60574304-
60575046-
Exc
0.648
0.498
−0.151
3.73E−06

60574303
60575045
60581417

PCYT2
79863031-
79863258-
79863324-
Exc
0.954
0.804
−0.150
4.38E−10

79863257
79863323
79863545

PDE4DIP
144857729-
144859759-
144859999-
Inc
0.682
0.821
0.140
6.83E−07

144859758
144859998
144863317

PDGFC
157771569-
157782581-
157782642-
Unc
0.135
0.141
0.006
9.73E−01

157782580
157782641
157891937

PDLIM2
22447255-
22449064-
22449182-
Exc
0.864
0.542
−0.322
9. ISE−124

22449063
22449181
22451245

PDP1
94929308-
94930139-
94930174-
Unc
0.185
0.184
−0.002
8.92E−01

94930138
94930173
94934243

PDPR
70148344-
70148773-
70148834-
Unc
0.272
0.268
−0.005
9.18E−01

70148772
70148833
70154363

PDXDC2P
70010636-
70010714-
70011907-
Unc
0.250
0.246
−0.004
9.01E−01

70010713
70011906
70011979

PDZD11
69509205-
69509372-
69509444-
Inc
0.160
0.417
0.257
8.46E−39

69509371
69509443
69509709

PEAK1
77544869-
77576225-
77576373-
Exc
0.371
0.201
−0.170
7.16E−08

77576224
77576372
77577299

PEAK1
77578847-
77657505-
77657568-
Unc
0.807
0.806
−0.001
9.36E−01

77657504
77657567
77712347

PEX1
92136441-
92138643-
92138726-
Exc
0.785
0.444
−0.341
1.47E−05

92138642
92138725
92140257

PEX11A
90227180-
90229662-
90229778-
Exc
0.719
0.316
−0.403
1.16E−07

90229661
90229777
90233807

PEX5
7354438-
7354837-
7354948-
Exc
0.442
0.279
−0.163
9.51E−06

7354836
7354947
7355207

PFDN1
139661119-
139680001-
139680168-
Exc
0.784
0.458
−0.326
1.30E−56

139680000
139680167
139682625

PFDN5
53689424-
53690214-
53690336-
Unc
0.167
0.175
0.008
9.25E−01

53690213
53690335
53691633

PFDN5
53689424-
53690238-
53690336-
Unc
0.173
0.180
0.007
9.26E−01

53690237
53690335
53691633

PFDN6
33258022-
33258103-
33258228-
Exc
0.964
0.847
−0.117
1.39E−14

33258102
33258227
33258492

PFKM
48528822-
48529074-
48529167-
Exc
0.683
0.563
−0.120
1.32E−05

48529073
48529166
48531503

PHC3
169840533-
169846128-
169846176-
Inc
0.225
0.373
0.148
6.06E−04

169846127
169846175
169846471

PHKG2
30764879-
30767503-
30767594-
Exc
0.976
0.799
−0.177
1.74E−07

30767502
30767593
30767687

PHLDB1
118478415-
118484009-
118484166-
Inc
0.095
0.239
0.143
5.84E−04

118484008
118484165
118484530

PHLPP2
71715809-
71718379-
71718505-
Unc
0.866
0.867
0.001
9.68E−01

71718378
71718504
71724421

PI4KB
151280278-
151282687-
151282732-
Exc
0.296
0.168
−0.129
2.68E−07

151282686
151282731
151288048

PI4KB
151288986-
151298648-
151298850-
Exc
0.509
0.314
−0.195
1.63E−06

151298647
151298849
151299746

PIGF
46808731-
46815214-
46815319-
Unc
0.142
0.139
−0.004
9.38E−01

46815213
46815318
46819613

PIGG
521020-
524225-
524535-
Exc
0.946
0.784
−0.162
3.14E−07

524224
524534
527606

PIGN
59829563-
59830764-
59830890-
Inc
0.622
0.945
0.323
5.16E−07

59830763
59830889
59854076

PIGP
38441925-
38444445-
38444611-
Unc
0.161
0.163
0.001
9.58E−01

38444444
38444610
38444733

PIGQ
630973-
632248-
632310-
Unc
0.785
0.790
0.005
6.73E−01

632247
632309
632882

PIGT
44044984-
44045157-
44045295-
Exc
0.917
0.752
−0.165
6.18E−17

44045156
44045294
44047934

PIGT
44044984-
44045157-
44045335-
Exc
0.918
0.751
−0.167
3.18E−17

44045156
44045334
44047934

PIK3C2A
17167490-
17169064-
17169176-
Exc
0.982
0.871
−0.111
1.27E−08

17169063
17169175
17170213

PIKFYVE
209138458-
209138742-
209138778-
Exc
0.499
0.309
−0.190
6.54E−04

209138741
209138777
209141435

PILRB
99950747-
99950833-
99950894-
Exc
0.952
0.688
−0.264
9.36E−10

99950832
99950893
99952765

PIN1
9946079-
9947499-
9947552-
Inc
0.025
0.131
0.107
4.07E−07

9947498
9947551
9949111

PINX1
10623427-
10677703-
10677780-
Unc
0.726
0.736
0.010
8.30E−01

10677702
10677779
10683661

PKIG
43160620-
43211226-
43211373-
Exc
0.569
0.417
−0.152
1.06E−06

43211225
43211372
43218437

PLA2G12A
110638870-
110639839-
110639916-
Exc
0.977
0.669
−0.308
3.05E−28

110639838
110639915
110650757

PLA2G12A
110638870-
110639845-
110639916-
Exc
0.940
0.460
−0.480
4.91E−21

110639844
110639915
110650757

PLA2R1
160832737-
160833196-
160833232-
Exc
0.953
0.831
−0.122
2.11E−08

160833195
160833231
160833794

PLAGL1
144290116-
144306272-
144306312-
Exc
0.234
0.047
−0.187
2.90E−06

144306271
144306311
144329226

PLAGL1
144285956-
144287295-
144287336-
Exc
0.939
0.713
−0.225
1.52E−10

144287294
144287335
144290043

PLAGL1
144285956-
144287295-
144287350-
Exc
0.918
0.657
−0.261
1.80E−09

144287294
144287349
144290043

PLAGL1
144285956-
144287295-
144287368-
Exc
0.909
0.637
−0.272
3.25E−09

144287294
144287367
144290043

PLBD2
113822071-
113822656-
113822752-
Exc
0.988
0.840
−0.148
1.86E−68

113822655
113822751
113823016

PLD3
40854632-
40871460-
40871838-
Unc
0.890
0.883
−0.007
5.77E−01

40871459
40871837
40872325

PLD3
40854676-
40871625-
40871838-
Unc
0.798
0.790
−0.008
9.05E−01

40871624
40871837
40872290

PLSCR4
145941565-
145968344-
145968425-
Unc
0.700
0.691
−0.009
6.67E−01

145968343
145968424
145968746

PMS2P3
75140437-
75141633-
75141746-
Exc
0.932
0.700
−0.232
2.63E−04

75141632
75141745
75141912

PNPLA8
108156019-
108161920-
108161966-
Inc
0.701
0.871
0.170
9.72E−05

108161919
108161965
108166472

PODNL1
14044807-
14046793-
14046858-
Exc
0.645
0.491
−0.154
2.46E−06

14046792
14046857
14047179

POLR3GL
145457605-
145457935-
145458004-
Exc
0.976
0.858
−0.118
1.04E−12

145457934
145458003
145459651

PPAP2A
54763978-
54786788-
54786943-
Exc
0.736
0.379
−0.356
4.31E−08

54786787
54786942
54830399

PPFIBP1
27826761-
27827125-
27827155-
Exc
0.858
0.757
−0.100
3.19E−05

27827124
27827154
27829360

PPIL3
201746212-
201747065-
201747159-
Exc
0.868
0.767
−0.101
4.82E−04

201747064
201747158
201750420

PPIL3
201746212-
201747065-
201747106-
Exc
0.800
0.666
−0.134
8.74E−04

201747064
201747105
201750420

PPIP5K2
102515890-
102518935-
102519109-
Exc
0.381
0.132
−0.249
5.73E−16

102518934
102519108
102520372

PPM1M
52280829-
52280990-
52281245-
Exc
0.844
0.454
−0.390
1.59E−21

52280989
52281244
52281697

PPP1R12A
80199549-
80199946-
80200114-
Exc
0.738
0.616
−0.122
1.02E−06

80199945
80200113
80201005

PPP1R12A
80199549-
80199946-
80200078-
Exc
0.642
0.515
−0.128
2.82E−05

80199945
80200077
80201005

PPP1R18
30647167-
30652185-
30653824-
Unc
0.868
0.877
0.009
7.54E−01

30652184
30653823
30654890

PPP1R21
48725875-
48732703-
48732736-
Exc
0.918
0.799
−0.119
9.11E−04

48732702
48732735
48734407

PPP2R3C
35568591-
35576510-
35576581-
Exc
0.987
0.858
−0.129
4.10E−13

35576509
35576580
35577344

PPP3CB
75198179-
75199630-
75199660-
Inc
0.238
0.638
0.401
6.54E−47

75199629
75199659
75204482

PPP3CC
22390532-
22396982-
22397012-
Inc
0.100
0.299
0.199
1.62E−08

22396981
22397011
22398127

PPP4C
30087797-
30092580-
30092632-
Exc
0.957
0.851
−0.105
2.62E−16

30092579
30092631
30093804

PPP4C
30087797-
30092521-
30092632-
Exc
0.926
0.767
−0.159
4.27E−15

30092520
30092631
30093804

PPP6R2
50874882-
50875417-
50875498-
Exc
0.490
0.339
−0.151
9.91E−07

50875416
50875497
50875934

PPP6R3
68228296-
68272613-
68272740-
Unc
0.419
0.422
0.003
9.79E−01

68272612
68272739
68286968

PPP6R3
68228296-
68272613-
68272718-
Unc
0.248
0.240
−0.008
9.10E−01

68272612
68272717
68286968

PPRC1
103897796-
103898376-
103898523-
Exc
0.976
0.852
−0.124
8.23E−06

103898375
103898522
103898635

PRDM5
121737730-
121737987-
121738080-
Unc
0.855
0.846
−0.010
8.96E−01

121737986
121738079
121739507

PREB
27354377-
27354542-
27354700-
Exc
0.971
0.867
−0.104
2.68E−05

27354541
27354699
27354877

PREPL
44573530-
44586636-
44587178-
Inc
0.142
0.262
0.119
1.92E−04

44586635
44587177
44588518

PREPL
44573530-
44586636-
44586890-
Inc
0.140
0.248
0.108
6.19E−04

44586635
44586889
44588518

PRKAG1
49399327-
49399526-
49399636-
Exc
0.940
0.814
−0.126
2.16E−17

49399525
49399635
49406844

PRKAG1
49399327-
49399526-
49399665-
Exc
0.899
0.703
−0.196
5.74E−17

49399525
49399664
49406844

PRKAG1
49397706-
49398290-
49398417-
Exc
0.977
0.763
−0.214
3.87E−53

49398289
49398416
49398746

PRKAG1
49397074-
49397341-
49397379-
Exc
0.985
0.741
−0.244
7.28E−73

49397340
49397378
49397539

PRMT2
48069652-
48081712-
48081849-
Exc
0.981
0.783
−0.199
1.98E−09

48081711
48081848
48083294

PRPF39
45565432-
45565627-
45565962-
Inc
0.472
0.663
0.190
7.61E−04

45565626
45565961
45566089

PRPF40B
50026664-
50026797-
50026908-
Exc
0.888
0.566
−0.322
1.00E−05

50026796
50026907
50027209

PRR16
119952888-
119954137-
119954261-
Exc
0.759
0.541
−0.218
2.87E−04

119954136
119954260
120021648

PRR4
11126321-
11187381-
11187485-
Exc
0.455
0.165
−0.290
5.30E−09

11187380
11187484
11199618

PRRC2B
134349112-
134349841-
134351923-
Unc
0.770
0.776
0.006
8.86E−01

134349840
134351922
134353130

PRRX1
170695543-
170699418-
170699490-
Inc
0.538
0.681
0.143
8.34E−20

170699417
170699489
170705188

PRUNE
150990381-
150991033-
150991146-
Inc
0.727
0.932
0.205
2.28E−05

150991032
150991145
150997086

PRUNE
150990381-
150990943-
150991146-
Inc
0.774
0.944
0.171
4.97E−05

150990942
150991145
150997086

PRUNE
150999804-
151001262-
151001421-
Unc
0.759
0.768
0.009
9.56E−01

151001261
151001420
151006281

PSME4
54164678-
54167093-
54167138-
Exc
0.991
0.868
−0.123
6.57E−10

54167092
54167137
54175557

PTAR1
72333601-
72338242-
72338547-
Unc
0.873
0.866
−0.006
9.96E−01

72338241
72338546
72347054

PTAR1
72356775-
72365697-
72365867-
Unc
0.903
0.896
−0.008
9.79E−01

72365696
72365866
72374768

PTPN13
87672278-
87674162-
87674219-
Exc
0.423
0.293
−0.131
2.96E−05

87674161
87674218
87679412

PTPN21
88962837-
88963547-
88963635-
Exc
0.997
0.889
−0.108
2.48E−10

88963546
88963634
88967126

PTPN23
47437708-
47446142-
47446270-
Exc
0.846
0.653
−0.193
1.09E−07

47446141
47446269
47446494

PTPN4
120635119-
120639362-
120639407-
Exc
0.945
0.633
−0.312
7.64E−08

120639361
120639406
120639672

PTPRA
2903932-
2928628-
2928671-
Exc
0.733
0.548
−0.185
8.06E−12

2928627
2928670
2944917

PTPRG
62204658-
62216899-
62216986-
Unc
0.176
0.180
0.004
8.55E−01

62216898
62216985
62229480

PTPRS
5218544-
5218798-
5218810-
Unc
0.810
0.816
0.006
8.40E−01

5218797
5218809
5219320

PUF60
144900705-
144902836-
144902887-
Unc
0.702
0.706
0.004
8.39E−01

144902835
144902886
144903766

PUM2
20518407-
20526022-
20526147-
Unc
0.127
0.122
−0.005
9.57E−01

20526021
20526146
20527070

PVR
45161179-
45162010-
45162169-
Exc
0.822
0.704
−0.118
1.90E−08

45162009
45162168
45164558

PVR
45161179-
45162010-
45162034-
Exc
0.765
0.627
−0.138
3.54E−08

45162009
45162033
45164558

PXDN
1687924-
1691404-
1691476-
Exc
0.818
0.560
−0.258
9.68E−121

1691403
1691475
1695699

QTRTD1
113775712-
113775846-
113775954-
Inc
0.328
0.715
0.387
9.51E−07

113775845
113775953
113784083

R3HCC1L
99923155-
99946224-
99946321-
Inc
0.181
0.373
0.191
9.16E−04

99946223
99946320
99967857

R3HDM1
136362587-
136374238-
136374328-
Unc
0.194
0.189
−0.004
9.92E−01

136374237
136374327
136379063

R3HDM4
900953-
901420-
901547-
Exc
0.959
0.838
−0.121
5.37E−07

901419
901546
901975

RAB11FIP2
119774622-
119793493-
119793553-
Exc
0.147
0.036
−0.110
2.48E−14

119793492
119793552
119798482

RABEPK
127970001-
127982818-
127982980-
Exc
0.824
0.631
−0.192
1.69E−06

127982817
127982979
127990188

RAD1
34911918-
34913575-
34913684-
Exc
0.630
0.518
−0.112
4.26E−06

34913574
34913683
34914799

RAD51D
33433501-
33434385-
33434467-
Unc
0.181
0.182
0.001
9.34E−01

33434384
33434466
33446129

RAF1
12645789-
12647700-
12647799-
Unc
0.877
0.872
−0.005
7.91E−01

12647699
12647798
12650264

RALGPS2
178858832-
178861365-
178861443-
Exc
0.299
0.071
−0.228
7.32E−14

178861364
178861442
178863053

RALY
32661442-
32661625-
32661673-
Inc
0.721
0.832
0.111
9.14E−12

32661624
32661672
32663679

RAPH1
204326649-
204334962-
204335037-
Unc
0.185
0.191
0.005
6.97E−01

204334961
204335036
204354306

RBBP9
18474708-
18476482-
18476525-
Inc
0.845
0.961
0.116
3.55E−05

18476481
18476524
18477712

RBCK1
400376-
401515-
401651-
Exc
0.986
0.770
−0.216
8.18E−04

401514
401650
402770

RBM10
47028898-
47030427-
47030658-
Unc
0.773
0.764
−0.009
9.45E−01

47030426
47030657
47032526

RBM27
145616996-
145631274-
145631439-
Unc
0.697
0.699
0.003
9.86E−01

145631273
145631438
145634505

RBM4
66407595-
66410921-
66411612-
Unc
0.792
0.800
0.009
7.93E−01

66410920
66411611
66413497

RBM41
106332070-
106356627-
106356699-
Inc
0.206
0.467
0.262
1.16E−06

106356626
106356698
106358581

RBM5
50137485-
50137965-
50138039-
Unc
0.901
0.892
−0.009
7.37E−01

50137964
50138038
50140515

RCC1
28856452-
28857035-
28857128-
Unc
0.211
0.215
0.004
9.95E−01

28857034
28857127
28858314

RCOR3
211477483-
211485697-
211485830-
Exc
0.148
0.048
−0.101
3.06E−05

211485696
211485829
211486061

REPS1
139242262-
139247538-
139247619-
Exc
0.328
0.187
−0.141
5.65E−04

139247537
139247618
139251113

REV3L
111737676-
111793216-
111793344-
Inc
0.508
0.738
0.230
1.57E−08

111793215
111793343
111803952

RFC2
73657577-
73660992-
73661094-
Unc
0.898
0.892
−0.006
8.01E−01

73660991
73661093
73663341

RFWD2
176104223-
176105624-
176105684-
Inc
0.782
0.934
0.152
7.36E−10

176105623
176105683
176118141

RGL1
183605637-
183666538-
183666648-
Unc
0.290
0.297
0.008
9.66E−01

183666537
183666647
183711260

RGL2
33264893-
33266232-
33266429-
Exc
0.872
0.647
−0.225
2.35E−04

33266231
33266428
33266646

RGN
46944000-
46951077-
46951209-
Exc
0.924
0.580
−0.345
2.79E−05

46951076
46951208
46951459

RHBDD2
75508579-
75510683-
75510805-
Exc
0.388
0.279
−0.110
2.25E−04

75510682
75510804
75511146

RHOBTB1
62631410-
62631801-
62632049-
Exc
0.969
0.828
−0.141
1.82E−05

62631800
62632048
62634711

RHOT1
30535329-
30538135-
30538258-
Exc
0.379
0.258
−0.121
1.89E−04

30538134
30538257
30551634

RHOT1
30535329-
30536369-
30536465-
Exc
0.205
0.065
−0.140
2.04E−07

30536368
30536464
30551634

RHOT1
30535329-
30536369-
30536465-
Exc
0.284
0.096
−0.188
4.46E−05

30536368
30536464
30538134

RIF1
152276894-
152279464-
152279557-
Exc
0.995
0.814
−0.182
7.06E−08

152279463
152279556
152285297

RIF1
152324661-
152324988-
152325066-
Unc
0.593
0.600
0.006
8.92E−01

152324987
152325065
152325154

RILP
1549914-
1550200-
1550284-
Unc
0.641
0.641
0.000
5.97E−01

1550199
1550283
1551128

RILPL2
123907705-
123915055-
123915207-
Unc
0.850
0.850
0.001
9.24E−01

123915054
123915206
123920628

RIPK2
90770462-
90775057-
90775211-
Exc
0.705
0.527
−0.178
1.29E−03

90775056
90775210
90777568

RNASE4
21152918-
21161706-
21161810-
Inc
0.172
0.283
0.112
1.19E−06

21161705
21161809
21167513

RNF14
141353308-
141354369-
141354521-
Unc
0.819
0.812
−0.007
8.30E−01

141354368
141354520
141357867

RNF146
127601486-
127607195-
127607323-
Exc
0.726
0.487
−0.239
2.13E−14

127607194
127607322
127607760

RNF170
42716999-
42720559-
42720633-
Exc
0.801
0.683
−0.118
6.72E−05

42720558
42720632
42725146

RNF214
117153253-
117153462-
117153567-
Exc
0.986
0.818
−0.167
1.57E−08

117153461
117153566
117153830

RNF34
121838022-
121840545-
121840611-
Inc
0.031
0.154
0.123
9.16E−04

121840544
121840610
121853961

RNF8
373448JO-
37348926-
37349131-
Unc
0.898
0.893
−0.005
9.04E−01

37348925
37349130
37358517

RNFT1
58035806-
58039901-
58039978-
Exc
0.621
0.199
−0.422
2.53E−06

58039900
58039977
58040187

RNGTT
89479594-
89511283-
89511352-
Unc
0.908
0.900
−0.008
9.70E−01

89511282
89511351
89554075

ROBO1
78695341-
78696779-
78696806-
Exc
0.288
0.177
−0.110
9.96E−04

78696778
78696805
78700881

RP11-
79412708-
79413764-
79413857-
Exc
0.430
0.173
−0.257
5.68E−04

1055B8.7
79413763
79413856
79414061

RP11-14N7.2
148932921-
148933291-
148933369-
Inc
0.244
0.470
0.226
9.63E−19

148933290
148933368
148951244

RP11-
128214846-
128218018-
128218088-
Inc
0.564
0.975
0.411
1.21E−10

274B21.1
128218017
128218087
128218943

RP11-33B1.1
120415679-
120418966-
120419059-
Exc
0.958
0.767
−0.190
1.45E−05

120418965
120419058
120420715

RP11-
72875284-
72885773-
72885895-
Exc
0.366
0.205
−0.162
2.32E−04

383H13.1
72885772
72885894
72964773

RP11-
72875284-
72877644-
72877770-
Exc
0.714
0.322
−0.392
8.26E−31

383H13.1
72877643
72877769
72964773

RP11-
9808576-
9809164-
9809294-
Unc
0.108
0.115
0.007
9.25E−01

705C15.2
9809163
9809293
9809516

RP11-
9808576-
9809164-
9809246-
Unc
0.131
0.137
0.007
9.76E−01

705C15.2
9809163
9809245
9809516

RP11-
81565879-
81568515-
81568589-
Exc
0.886
0.668
−0.218
3.45E−15

773D16.1
81568514
81568588
81574368

RP11-
81565879-
81568519-
81568720-
Exc
0.504
0.147
−0.357
5.56E−10

773D16.1
81568518
81568719
81574368

RP1-178F15.4
153604717-
153605512-
153605634-
Unc
0.221
0.228
0.008
5.93E−01

153605511
153605633
153606433

RP13-
19212123-
19212958-
19213006-
Exc
0.958
0.792
−0.166
4.30E−04

279N23.2
19212957
19213005
19215855

RPAIN
5326150-
5329556-
5329620-
Exc
0.369
0.208
−0.160
5.41E−05

5329555
5329619
5335861

RPAIN
5329403-
5329556-
5329620-
Exc
0.889
0.597
−0.293
2.20E−13

5329555
5329619
5335861

RPAIN
5329403-
5331391-
5331532-
Exc
0.808
0.420
−0.388
3.96E−11

5331390
5331531
5335861

RPAIN
5326150-
5329291-
5329403-
Inc
0.773
0.916
0.143
3.51E−08

5329290
5329402
5329555

RPAIN
5326150-
5329291-
5329620-
Unc
0.544
0.540
−0.004
9.53E−01

5329290
5329619
5335861

RPAIN
5329620-
5331391-
5331532-
Unc
0.686
0.678
−0.008
9.72E−01

5331390
5331531
5335861

RPL7L1
42847690-
42848599-
42848705-
Exc
0.836
0.697
−0.139
3.61E−12

42848598
42848704
42851188

RPL7L1
42847690-
42848599-
42848821-
Exc
0.724
0.545
−0.179
7.34E−10

42848598
42848820
42851188

RPP14
58292145-
58296017-
58296134-
Exc
0.532
0.269
−0.263
4.78E−05

58296016
58296133
58296233

RPP14
58292145-
58296036-
58296134-
Exc
0.638
0.346
−0.291
8.98E−07

58296035
58296133
58296233

RPP38
15139409-
15144217-
15144336-
Unc
0.547
0.545
−0.001
9.89E−01

15144216
15144335
15145303

RPS24
79797063-
79799962-
79799984-
Unc
0.887
0.887
0.000
8.72E−01

79799961
79799983
79800372

RPS24
79797063-
79799959-
79799984-
Unc
0.788
0.787
−0.001
8.72E−01

79799958
79799983
79800372

RPS6KB2
67196095-
67196453-
67196494-
Exc
0.977
0.869
−0.108
3.73E−04

67196452
67196493
67196590

RPS6KB2
67196095-
67196384-
67196494-
Exc
0.965
0.797
−0.167
3.88E−04

67196383
67196493
67196590

RPUSD1
836929-
837068-
837180-
Unc
0.884
0.885
0.001
9.88E−01

837067
837179
837353

RRBP1
17641174-
17660644-
17660721-
Inc
0.417
0.538
0.121
8.20E−09

17660643
17660720
17662672

RRNAD1
156703313-
156703801-
156703845-
Unc
0.517
0.523
0.006
9.83E−01

156703800
156703844
156705516

RSU1
16824084-
16858972-
16859084-
Exc
0.911
0.802
−0.109
6.95E−22

16858971
16859083
16859313

RTEL1
62325842-
62326094-
62326328-
Exc
0.969
0.771
−0.197
2.00E−04

62326093
62326327
62326418

RTEL1-
62325842-
62326094-
62326328-
Exc
0.969
0.771
−0.197
2.00E−04

TNFRSF6B
62326093
62326327
62326418

RTN2
45992812-
45996418-
45996637-
Unc
0.584
0.577
−0.008
9.89E−01

45996417
45996636
45997423

RUFY2
70154209-
70156537-
70156639-
Exc
0.884
0.699
−0.185
1.17E−07

70156536
70156638
70161376

RUNX1
36171760-
36206707-
36206899-
Unc
0.804
0.812
0.008
7.25E−01

36206706
36206898
36231770

RWDD1
116892819-
116895221-
116895335-
Inc
0.291
0.554
0.263
7.98E−40

116895220
116895334
116901457

RWDD2B
30380445-
30380561-
30380629-
Exc
0.853
0.706
−0.147
1.60E−06

30380560
30380628
30380715

RWDD4
184572285-
184572371-
184572481-
Exc
0.976
0.815
−0.162
1.52E−17

184572370
184572480
184577033

RWDD4
184572285-
184572371-
184572477-
Exc
0.963
0.742
−0.221
1.04E−15

184572370
184572476
184577033

SBF1
50895103-
50895463-
50895541-
Exc
0.669
0.512
−0.156
5.40E−05

50895462
50895540
50897683

SCMH1
41617357-
41625397-
41625606-
Exc
0.591
0.412
−0.180
7.57E−04

41625396
41625605
41626546

SCRN3
175260546-
175262064-
175262133-
Unc
0.107
0.112
0.005
9.46E−01

175262063
175262132
175263002

SDCCAG8
243456522-
243456701-
243456797-
Inc
0.154
0.388
0.234
1.02E−09

243456700
243456796
243468014

SEC13
10359779-
10360823-
10360857-
Unc
0.268
0.273
0.005
7.94E−01

10360822
10360856
10362192

SEC31A
83778918-
83783687-
83783726-
Unc
0.738
0.735
−0.003
8.76E−01

83783686
83783725
83784470

SEC31A
83803094-
83819142-
83819216-
Unc
0.873
0.868
−0.004
8.31E−01

83819141
83819215
83821229

SEC31B
102249519-
102249765-
102250080-
Exc
0.783
0.464
−0.319
1.99E−05

102249764
102250079
102250462

SECISBP2L
49309826-
49311615-
49311750-
Exc
0.734
0.533
−0.201
1.87E−10

49311614
49311749
49319561

SEMA4F
74884752-
74884980-
74885079-
Exc
0.302
0.016
−0.286
8.40E−07

74884979
74885078
74889858

SENP1
48459464-
48460710-
48460749-
Exc
0.959
0.742
−0.218
4.11E−09

48460709
48460748
48465449

SENP6
76331342-
76332467-
76332575-
Exc
0.227
0.126
−0.101
1.01E−04

76332466
76332574
76333615

SENP6
76344528-
76350403-
76350421-
Exc
0.717
0.594
−0.123
1.33E−04

76350402
76350420
76357446

SENP6
76344528-
76350400-
76350421-
Exc
0.708
0.568
−0.140
1.63E−05

76350399
76350420
76357446

SERAC1
158571622-
158576347-
158576384-
Exc
0.783
0.575
−0.208
7.72E−05

158576346
158576383
158579304

SETD2
47108609-
47122406-
47122574-
Unc
0.111
0.109
−0.002
9.11E−01

47122405
47122573
47125209

SETD5
9476170-
9476274-
9476315-
Exc
0.328
0.138
−0.190
2.82E−11

9476273
9476314
9476507

SETX
135140373-
135144790-
135144877-
Inc
0.316
0.466
0.150
3.99E−06

135144789
135144876
135145001

SEZ6L2
29883848-
29884026-
29884065-
Unc
0.572
0.582
0.010
7.00E−01

29884025
29884064
29884560

SFXN4
120920482-
120920567-
120920594-
Exc
1.000
0.812
−0.188
2.01E−06

120920566
120920593
120921851

SGSM2
2268636-
2270565-
2270700-
Unc
0.311
0.317
0.005
9.14E−01

2270564
2270699
2274555

SGSM3
40796818-
40797597-
40797680-
Exc
0.784
0.494
−0.290
3.39E−19

40797596
40797679
40798142

SH3D19
152065203-
152065372-
152065441-
Inc
0.477
0.620
0.143
5.12E−10

152065371
152065440
152069073

SHMT2
57624784-
57625264-
57625344-
Exc
0.892
0.754
−0.138
3.03E−40

57625263
57625343
57625495

SIKE1
115321906-
115322731-
115322837-
Unc
0.896
0.891
−0.005
9.28E−01

115322730
115322836
115323069

SIPA1L1
71787899-
71867511-
71867636-
Exc
0.241
0.000
−0.241
8.40E−12

71867510
71867635
71979459

SIPA1L1
71867636-
71880665-
71880732-
Inc
0.609
0.986
0.377
2.94E−08

71880664
71880731
71979459

SLAIN2
48385802-
48396593-
48396671-
Unc
0.726
0.717
−0.009
7.85E−01

48396592
48396670
48422141

SLC15A4
129294019-
129294488-
129294599-
Inc
0.869
0.982
0.113
5.60E−08

129294487
129294598
129299319

SLC22A17
23816422-
23816723-
23816941-
Exc
0.855
0.684
−0.171
3.27E−04

23816722
23816940
23817369

SLC25A17
41175130-
41188529-
41188681-
Exc
0.969
0.772
−0.197
1.14E−05

41188528
41188680
41195026

SLC25A17
41175130-
41190518-
41190585-
Exc
0.966
0.769
−0.197
4.59E−05

41190517
41190584
41195026

SLC25A32
104415553-
104417004-
104417090-
Exc
0.935
0.801
−0.134
4.51E−09

104417003
104417089
104419861

SLC25A36
140682070-
140685842-
140685879-
Exc
0.273
0.073
−0.201
3.17E−11

140685841
140685878
140689768

SLC25A36
140682070-
140685776-
140685879-
Exc
0.326
0.096
−0.230
7.87E−13

140685775
140685878
140689768

SLC30A6
32419053-
32422413-
32422462-
Unc
0.781
0.790
0.009
9.62E−01

32422412
32422461
32422775

SLC35A1
88182738-
88187080-
88187258-
Exc
0.954
0.760
−0.194
7.27E−08

88187079
88187257
88210875

SLC35A3
100435719-
100440527-
100440626-
Inc
0.377
0.613
0.237
4.81E−04

100440526
100440625
100459092

SLC35D2
99083624-
99084280-
99084363-
Exc
0.977
0.841
−0.136
4.48E−07

99084279
99084362
99086372

SLC37A3
140037150-
140045669-
140045771-
Exc
0.790
0.548
−0.241
8.26E−05

140045668
140045770
140048425

SLC38A2
46761124-
46764295-
46764411-
Exc
0.902
0.748
−0.154
4.38E−139

46764294
46764410
46764558

SLC38A6
61509931-
61510168-
61510222-
Exc
0.865
0.653
−0.212
4.01E−06

61510167
61510221
61512063

SLC38A6
61512886-
61517230-
61517355-
Exc
0.988
0.717
−0.271
2.20E−16

61517229
61517354
61518504

SLC38A6
61512886-
61514869-
61515016-
Inc
0.033
0.190
0.157
1.74E−04

61514868
61515015
61517229

SLC38A9
54993821-
54998567-
54998723-
Unc
0.125
0.116
−0.009
9.71E−01

54998566
54998722
55007279

SLC39A9
69890920-
69908786-
69908984-
Unc
0.879
0.883
0.004
8.49E−01

69908785
69908983
69919957

SLC4A7
27446455-
27450847-
27451022-
Exc
0.804
0.378
−0.426
1.96E−29

27450846
27451021
27453132

SLC5A6
27428962-
27429351-
27429403-
Exc
0.938
0.763
−0.174
5.73E−04

27429350
27429402
27429744

SLC7A6
68300625-
68307725-
68307808-
Exc
0.429
0.224
−0.205
6.86E−07

68307724
68307807
68308593

SLC7A6
68300625-
68307721-
68307808-
Exc
0.542
0.312
−0.230
6.22E−09

68307720
68307807
68308593

SLC9B2
103947749-
103949904-
103950041-
Exc
0.875
0.553
−0.322
5.93E−13

103949903
103950040
103952856

SLFN11
33690846-
33693966-
33694083-
Unc
0.843
0.836
−0.006
9.73E−01

33693965
33694082
33700492

SLFN11
33690846-
33693966-
33694063-
Unc
0.843
0.836
−0.007
9.49E−01

33693965
33694062
33700492

SLIT2
20547723-
20550111-
20550183-
Exc
0.912
0.748
−0.163
2.81E−17

20550110
20550182
20550679

SLMAP
57850444-
57857363-
57857426-
Exc
0.606
0.339
−0.267
2.38E−05

57857362
57857425
57875767

SLMAP
57882660-
57893611-
57893734-
Unc
0.899
0.899
0.000
9.81E−01

57893610
57893733
57894802

SLMO1
12421629-
12427040-
12427111-
Exc
0.984
0.854
−0.130
5.35E−06

12427039
12427110
12427219

SLTM
59193487-
59204762-
59204810-
Inc
0.825
0.928
0.104
9.23E−05

59204761
59204809
59209133

SLTM
59191052-
59191668-
59192083-
Unc
0.730
0.731
0.001
9.55E−01

59191667
59192082
59193458

SLTM
59191052-
59191668-
59192137-
Unc
0.770
0.763
−0.007
7.30E−01

59191667
59192136
59193458

SMAD5
135468652-
135483521-
135483596-
Exc
0.787
0.590
−0.197
6.32E−07

135483520
135483595
135489280

SMARCA1
128626071-
128627017-
128627053-
Inc
0.618
0.870
0.253
3.54E−33

128627016
128627052
128630726

SMARCD1
50480662-
50481146-
50481269-
Exc
0.800
0.548
−0.252
3.33E−18

50481145
50481268
50482303

SMC5
72879362-
72882839-
72882892-
Exc
0.979
0.854
−0.125
5.98E−08

72882838
72882891
72892225

SMEK2
55795500-
55800755-
55800914-
Exc
0.955
0.819
−0.136
1.39E−13

55800754
55800913
55804450

SMEK2
55804493-
55805383-
55805479-
Unc
0.450
0.445
−0.005
9.40E−01

55805382
55805478
55806814

SMG7
183441785-
183471388-
183471527-
Unc
0.206
0.200
−0.006
9.36E−01

183471387
183471526
183481971

SMPDL3A
123110604-
123116822-
123117036-
Exc
0.855
0.702
−0.152
1.92E−04

123116821
123117035
123117968

SMURF2
62594609-
62602720-
62602759-
Exc
0.892
0.742
−0.150
9.59E−05

62602719
62602758
62657946

SMURF2
62589692-
62590109-
62590223-
Unc
0.111
0.111
−0.001
8.17E−01

62590108
62590222
62594499

SNAPC5
66786891-
66787668-
66787758-
Exc
0.779
0.646
−0.133
1.46E−04

66787667
66787757
66789979

SNED1
241992744-
242002208-
242002322-
Exc
0.880
0.660
−0.220
9.72E−05

242002207
242002321
242003003

SNHG14
25357042-
25360446-
25360804-
Exc
0.979
0.860
−0.119
1.90E−05

25360445
25360803
25362556

SNHG14
25328675-
25330337-
25330470-
Unc
0.851
0.852
0.001
9.66E−01

25330336
25330469
25332613

SNHG15
45023646-
45023956-
45024026-
Exc
0.960
0.832
−0.127
1.03E−05

45023955
45024025
45025619

SNRNP70
49604729-
49605371-
49606845-
Inc
0.210
0.325
0.114
5.34E−16

49605370
49606844
49607890

SNRNP70
49604729-
49605371-
49605431-
Inc
0.201
0.302
0.102
2.96E−13

49605370
49605430
49607890

SNRNP70
49604729-
49605371-
49605443-
Inc
0.199
0.299
0.100
6.96E−13

49605370
49605442
49607890

SNRPA1
101826007-
101826419-
101826499-
Exc
0.708
0.499
−0.209
1.53E−11

101826418
101826498
101827112

SNRPG
70515325-
70516482-
70516505-
Exc
0.856
0.696
−0.160
1.18E−28

70516481
70516504
70520749

SNX14
86246643-
86248556-
86248583-
Exc
0.829
0.668
−0.160
6.31E−15

86248555
86248582
86251702

SNX21
44463756-
44468961-
44469098-
Exc
0.314
0.167
−0.148
2.05E−04

44468960
44469097
44469277

SNX21
44463756-
44469087-
44469098-
Exc
0.423
0.263
−0.160
6.59E−05

44469086
44469097
44469277

SPATA20
48626548-
48626647-
48626849-
Exc
0.979
0.856
−0.123
9.61E−18

48626646
48626848
48627345

SPATA20
48624647-
48625026-
48625129-
Exc
0.948
0.815
−0.133
1.65E−08

48625025
48625128
48625643

SPATA20
48624647-
48625081-
48625129-
Exc
0.943
0.792
−0.151
1.04E−08

48625080
48625128
48625643

SPATA20
48624647-
48625026-
48625316-
Exc
0.790
0.531
−0.259
8.43E−05

48625025
48625315
48625643

SPATA20
48624647-
48625081-
48625316-
Exc
0.647
0.347
−0.300
9.22E−04

48625080
48625315
48625643

SPATA7
88857800-
88859737-
88859833-
Inc
0.670
0.925
0.255
4.37E−05

88859736
88859832
88862499

SPDL1
169015580-
169017757-
169017834-
Inc
0.107
0.355
0.248
7.98E−13

169017756
169017833
169018051

SPDL1
169015580-
169017760-
169017834-
Inc
0.104
0.345
0.241
1.54E−12

169017759
169017833
169018051

SPEN
16199632-
16202697-
16203174-
Unc
0.859
0.861
0.002
9.99E−01

16202696
16203173
16235815

SPIDR
48206620-
48320423-
48320524-
Unc
0.885
0.878
−0.007
9.47E−01

48320422
48320523
48352884

SPPL2A
51017521-
51018270-
51018324-
Inc
0.176
0.554
0.378
4.89E−81

51018269
51018323
51018517

SPTAN1
131353905-
131355262-
131355322-
Exc
0.289
0.040
−0.249
1.83E−69

131355261
131355321
131356453

SRSF2
74731241-
74731854-
74731958-
Unc
0.112
0.113
0.001
9.79E−01

74731853
74731957
74732235

ST6GALNAC6
130658612-
130660235-
130660290-
Inc
0.529
0.659
0.130
3.79E−04

130660234
130660289
130661781

ST7
116849992-
116859138-
116859231-
Exc
0.994
0.857
−0.137
3.24E−05

116859137
116859230
116869815

ST7
116849992-
116861977-
116862117-
Exc
0.989
0.771
−0.218
7.60E−05

116861976
116862116
116869815

STAG1
136261038-
136287607-
136287704-
Unc
0.878
0.885
0.007
7.91E−01

136287606
136287703
136323150

STAG2
123094717-
123155217-
123155282-
Unc
0.278
0.279
0.002
9.96E−01

123155216
123155281
123156380

STARD3
37814776-
37814962-
37815074-
Unc
0.862
0.871
0.009
8.06E−01

37814961
37815073
37815303

STARD3NL
38218023-
38218692-
38218748-
Inc
0.087
0.195
0.108
1.74E−04

38218691
38218747
38247047

STARD4
110836815-
110837660-
110837787-
Unc
0.769
0.760
−0.008
9.68E−01

110837659
110837786
110842027

STARD5
81614882-
81615240-
81615290-
Exc
0.949
0.780
−0.169
1.97E−04

81615239
81615289
81616142

STAT6
57501098-
57501442-
57501527-
Exc
0.856
0.732
−0.124
1.48E−08

57501441
57501526
57501945

STK16
220111599-
220111835-
220111969-
Exc
0.919
0.703
−0.216
4.52E−20

220111834
220111968
220112136

STK19
31946776-
31947191-
31947331-
Exc
0.943
0.773
−0.171
2.51E−11

31947190
31947330
31948227

STK38L
27455122-
27461272-
27461395-
Unc
0.907
0.898
−0.008
9.94E−01

27461271
27461394
27462046

STK40
36826942-
36833453-
36833686-
Inc
0.242
0.551
0.309
7.98E−08

36833452
36833685
36851323

STK40
36826942-
36833449-
36833686-
Inc
0.137
0.358
0.221
1.21E−04

36833448
36833685
36851323

STOML1
74281144-
74281371-
74281599-
Unc
0.817
0.818
0.001
8.95E−01

74281370
74281598
74282691

STOML1
74281144-
74281449-
74281599-
Unc
0.901
0.898
−0.004
8.91E−01

74281448
74281598
74282691

STRA13
79977258-
79977386-
79977571-
Exc
0.368
0.142
−0.226
1.53E−08

79977385
79977570
79977733

STRA13
79977258-
79977517-
79977571-
Exc
0.510
0.249
−0.261
8.77E−11

79977516
79977570
79977733

STRADA
61784100-
61784607-
61784779-
Exc
0.961
0.833
−0.129
8.80E−06

61784606
61784778
61787850

STRN3
31382864-
31388172-
31388313-
Inc
0.077
0.187
0.110
1.98E−05

31388171
31388312
31404368

STX16
57243184-
57244347-
57244510-
Exc
0.822
0.495
−0.327
9.78E−39

57244346
57244509
57245567

STX16
57243184-
57244358-
57244510-
Exc
0.715
0.335
−0.380
1.01E−32

57244357
57244509
57245567

STX16-
57243184-
57244347-
57244510-
Exc
0.822
0.495
−0.327
9.78E−39

NPEPL1
57244346
57244509
57245567

STX3
59562956-
59564756-
59564870-
Exc
0.868
0.629
−0.239
1.40E−09

59564755
59564869
59568327

STXBP3
109319046-
109321908-
109322033-
Exc
0.990
0.862
−0.128
6.63E−12

109321907
109322032
109325043

STXBP5
147660375-
147660473-
147660521-
Unc
0.829
0.827
−0.002
9.55E−01

147660472
147660520
147674458

STYXL1
75634723-
75643060-
75643206-
Exc
0.749
0.572
−0.177
1.03E−06

75643059
75643205
75651168

SUCO
172520767-
172522400-
172522511-
Inc
0.605
0.967
0.362
2.47E−27

172522399
172522510
172525008

SUGP2
19101959-
19104457-
19104550-
Inc
0.791
0.902
0.111
1.27E−03

19104456
19104549
19105174

SUGP2
19101959-
19104447-
19104550-
Inc
0.802
0.908
0.106
9.46E−04

19104446
19104549
19105174

SUGT1
53233385-
53235610-
53235706-
Exc
0.411
0.285
−0.126
1.95E−07

53235609
53235705
53236783

SULF1
70379186-
70408000-
70408162-
Exc
0.652
0.446
−0.206
1.38E−87

70407999
70408161
70414108

SULF1
70541915-
70550737-
70550880-
Exc
0.911
0.702
−0.209
0.00E+00

70550736
70550879
70550969

SUN2
39148671-
39150647-
39150712-
Exc
0.353
0.221
−0.132
1.12E−03

39150646
39150711
39151767

SUOX
56391124-
56391399-
56391508-
Unc
0.631
0.626
−0.005
9.30E−01

56391398
56391507
56395995

SUPT20H
37622074-
37622701-
37622737-
Exc
0.766
0.609
−0.157
4.61E−05

37622700
37622736
37625624

SUPT20H
37583947-
37584689-
37584793-
Inc
0.420
0.779
0.359
3.13E−21

37584688
37584792
37586328

SYNE1
152615263-
152621776-
152621917-
Unc
0.784
0.778
−0.006
6.13E−01

152621775
152621916
152623003

SYNJ2BP
70842489-
70855187-
70855324-
Unc
0.876
0.869
−0.007
8.71E−01

70855186
70855323
70883616

SYNRG
35879175-
35880282-
35880318-
Inc
0.460
0.836
0.377
2.57E−20

35880281
35880317
35880640

TAF1
70678217-
70679000-
70679102-
Exc
0.253
0.082
−0.171
1.03E−07

70678999
70679101
70679401

TAF2
120756634-
120757121-
120757277-
Inc
0.069
0.176
0.107
1.20E−04

120757120
120757276
120758944

TAMM41
11871339-
11874477-
11874626-
Unc
0.124
0.122
−0.002
9.01E−01

11874476
11874625
11880695

TANGO2
20043537-
20049053-
20049230-
Exc
0.985
0.855
−0.130
2.86E−05

20049052
20049229
20050860

TANGO2
20040108-
20040883-
20041075-
Exc
0.456
0.293
−0.163
4.78E−05

20040882
20041074
20043465

TANGO2
20040108-
20040960-
20041075-
Exc
0.585
0.412
−0.173
2.36E−06

20040959
20041074
20043465

TARBP2
53898600-
53898919-
53899047-
Exc
0.810
0.650
−0.160
1.16E−04

53898918
53899046
53899432

TAS2R14
11126321-
11187381-
11187485-
Exc
0.455
0.165
−0.290
5.30E−09

11187380
11187484
11199618

TAZ
153647963-
153648044-
153648086-
Exc
0.874
0.620
−0.254
1.12E−05

153648043
153648085
153648370

TBC1D14
7008454-
7011604-
7011676-
Exc
0.857
0.729
−0.128
2.05E−06

7011603
7011675
7012379

TBC1D17
50386150-
50386230-
50386334-
Exc
0.994
0.892
−0.102
3.08E−11

50386229
50386333
50386907

TBC1D25
48399831-
48403257-
48403412-
Exc
0.691
0.459
−0.232
3.35E−04

48403256
48403411
48417284

TBC1D32
121482203-
121491551-
121491674-
Unc
0.890
0.885
−0.006
9.13E−01

121491550
121491673
121526220

TBC1D5
17550098-
17665341-
17665406-
Exc
0.806
0.498
−0.308
3.67E−13

17665340
17665405
17783972

TBCE
235543465-
235564818-
235564903-
Unc
0.805
0.814
0.009
9.68E−01

235564817
235564902
235577747

TBCEL
120918377-
120924260-
120924442-
Unc
0.813
0.805
−0.008
7.85E−01

120924259
120924441
120925760

TBCK
107114928-
107115875-
107115912-
Exc
0.936
0.549
−0.387
6.40E−56

107115874
107115911
107133906

TBCK
107173165-
107176104-
107176205-
Inc
0.047
0.406
0.360
4.86E−30

107176103
107176204
107181593

TBPL1
134273869-
134274323-
134274564-
Inc
0.633
0.887
0.253
9.06E−04

134274322
134274563
134301219

TBX15
119466227-
119467269-
119467441-
Exc
0.972
0.815
−0.157
3.14E−06

119467268
119467440
119469132

TCERG1
145888809-
145889630-
145889724-
Exc
0.227
0.120
−0.107
9.87E−04

145889629
145889723
145890003

TCF20
42557365-
42564615-
42564743-
Unc
0.243
0.233
−0.010
9.77E−01

42564614
42564742
42565852

TCF7L2
114917829-
114918426-
114918477-
Unc
0.770
0.780
0.010
7.78E−01

114918425
114918476
114920377

TCF7L2
114917829-
114919679-
114919752-
Unc
0.516
0.525
0.009
9.75E−01

114919678
114919751
114920377

TCF7L2
114917829-
114919679-
114919752-
Unc
0.338
0.334
−0.004
6.21E−01

114919678
114919751
114925313

TEAD2
49858677-
49859216-
49859228-
Exc
0.413
0.183
−0.230
6.40E−11

49859215
49859227
49860508

TENM2
167182198-
167302991-
167303201-
Unc
0.873
0.878
0.005
6.28E−01

167302990
167303200
167379592

TENM2
167631627-
167638739-
167638760-
Unc
0.143
0.138
−0.005
8.43E−01

167638738
167638759
167642044

TEP1
20849561-
20849712-
20849846-
Exc
0.602
0.343
−0.258
1.09E−05

20849711
20849845
20850071

TEP1
20839792-
20840892-
20841017-
Exc
0.758
0.466
−0.293
1.63E−09

20840891
20841016
20841169

TET2
106068137-
106111517-
106111663-
Unc
0.732
0.724
−0.008
9.36E−01

106111516
106111662
106155053

TFB2M
246714605-
246719875-
246720024-
Unc
0.873
0.864
−0.009
9.05E−01

246719874
246720023
246727647

TFDP1
114277602-
114285938-
114286060-
Exc
0.923
0.820
−0.103
5.57E−17

114285937
114286059
114287434

TFDP1
114277602-
114285938-
114286221-
Exc
0.853
0.685
−0.168
1.24E−15

114285937
114286220
114287434

TFDP2
141724387-
141772957-
141772992-
Exc
0.260
0.116
−0.144
1.48E−04

141772956
141772991
141811902

TFDP2
141697525-
141712380-
141712428-
Unc
0.864
0.869
0.005
9.77E−01

141712379
141712427
141724282

TFDP2
141697525-
141713862-
141713984-
Unc
0.857
0.847
−0.010
6.43E−01

141713861
141713983
141724282

TFPI
188368498-
188394091-
188394213-
Exc
0.214
0.058
−0.156
1.45E−10

188394090
188394212
188418926

TGFBR2
30648470-
30664691-
30664766-
Inc
0.247
0.361
0.114
1.28E−15

30664690
30664765
30686238

TGIF1
3450069-
3450323-
3450504-
Unc
0.727
0.736
0.009
6.27E−01

3450322
3450503
3456351

THADA
43625279-
43657352-
43657442-
Unc
0.858
0.859
0.000
9.41E−01

43657351
43657441
43712372

THAP6
76442190-
76446946-
76447072-
Exc
0.949
0.794
−0.155
2.70E−04

76446945
76447071
76452169

THAP9-AS1
83816928-
83819142-
83819216-
Inc
0.865
0.971
0.106
2.38E−05

83819141
83819215
83821229

THBS3
155173097-
155173304-
155173331-
Exc
0.984
0.861
−0.123
1.84E−05

155173303
155173330
155174850

THBS3
155169905-
155170242-
155170402-
Exc
0.930
0.744
−0.186
2.81E−24

155170241
155170401
155170687

THOC2
122757135-
122757495-
122757561-
Exc
0.188
0.077
−0.111
1.23E−03

122757494
122757560
122757637

THTPA
24025553-
24025952-
24026249-
Unc
0.291
0.297
0.005
9.10E−01

24025951
24026248
24027903

THTPA
24025553-
24025952-
24026244-
Unc
0.270
0.263
−0.008
9.94E−01

24025951
24026243
24027903

TIA1
70454955-
70455476-
70455595-
Inc
0.210
0.532
0.322
1.88E−12

70455475
70455594
70456190

TIA1
70451762-
70452460-
70452526-
Inc
0.123
0.374
0.251
2.51E−14

70452459
70452525
70454866

TIAL1
121339523-
121339983-
121340359-
Inc
0.068
0.278
0.210
5.41E−34

121339982
121340358
121341433

TIAL1
121339523-
121339983-
121340051-
Inc
0.072
0.178
0.106
8.55E−12

121339982
121340050
121341433

TIMM17B
48752385-
48752635-
48752785-
Inc
0.105
0.216
0.111
1.53E−05

48752634
48752784
48754041

TIMM21
71816345-
71822380-
71822443-
Exc
1.000
0.836
−0.164
2.93E−14

71822379
71822442
71822540

TJAP1
43445971-
43446397-
43446457-
Unc
0.181
0.180
−0.001
9.49E−01

43446396
43446456
43465618

TJP1
30011343-
30011981-
30012221-
Unc
0.317
0.310
−0.007
9.42E−01

30011980
30012220
30012561

TLK2
60600539-
60601597-
60601693-
Unc
0.413
0.423
0.010
9.00E−01

60601596
60601692
60613530

TM7SF3
27128592-
27129193-
27129291-
Inc
0.836
0.966
0.129
2.07E−09

27129192
27129290
27133498

TMCO4
20067435-
20072025-
20072145-
Exc
0.711
0.348
−0.364
6.18E−05

20072024
20072144
20072948

TMEM11
21102154-
21114249-
21114541-
Exc
0.327
0.206
−0.121
1.46E−05

21114248
21114540
21117403

TMEM119
108986174-
108987940-
108988322-
Unc
0.306
0.302
−0.004
6.73E−01

108987939
108988321
108991745

TMEM120A
75616747-
75616856-
75616921-
Exc
0.963
0.574
−0.389
1.44E−31

75616855
75616920
75617035

TMEM126B
85339733-
85342189-
85342361-
Inc
0.622
0.779
0.157
7.27E−10

85342188
85342360
85342730

TMEM126B
85339733-
85340176-
85340307-
Inc
0.053
0.198
0.145
1.01E−05

85340175
85340306
85342730

TMEM161B
87524346-
87536630-
87536734-
Unc
0.824
0.818
−0.006
8.70E−01

87536629
87536733
87564537

TMEM175
926329-
941497-
941943-
Unc
0.531
0.525
−0.007
9.38E−01

941496
941942
944208

TMEM18
675631-
675758-
676239-
Inc
0.104
0.246
0.143
1.52E−06

675757
676238
677288

TMEM194A
57458523-
57463017-
57463090-
Exc
0.855
0.568
−0.287
1.77E−04

57463016
57463089
57464602

TMEM230
5090092-
5092146-
5092252-
Unc
0.508
0.505
−0.003
9.86E−01

5092145
5092251
5093388

TMEM234
32682953-
32683038-
32683179-
Inc
0.094
0.210
0.116
9.14E−05

32683037
32683178
32686731

TMEM260
57085482-
57088249-
57088421-
Exc
0.884
0.727
−0.157
9.42E−04

57088248
57088420
57092099

TMEM260
57082746-
57083901-
57084016-
Exc
0.964
0.804
−0.161
1.21E−05

57083900
57084015
57085311

TMEM39B
32541424-
32542765-
32542920-
Exc
0.772
0.276
−0.496
2.72E−08

32542764
32542919
32557275

TMEM62
43461876-
43470805-
43470910-
Exc
0.978
0.786
−0.192
7.18E−07

43470804
43470909
43473378

TMOD2
52073372-
52074918-
52075026-
Exc
0.993
0.862
−0.131
1.39E−04

52074917
52075025
52090393

TMUB2
42264478-
42265044-
42265112-
Exc
0.898
0.675
−0.223
4.21E−06

42265043
42265111
42265274

TMUB2
42266668-
42266779-
42266957-
Unc
0.846
0.849
0.004
9.41E−01

42266778
42266956
42267868

TMUB2
42266668-
42266792-
42266957-
Unc
0.844
0.848
0.003
9.51E−01

42266791
42266956
42267868

TMX3
66367723-
66368982-
66369028-
Exc
0.967
0.821
−0.146
5.98E−29

66368981
66369027
66377257

TOM1
35713955-
35717952-
35718013-
Exc
0.931
0.817
−0.114
2.97E−10

35717951
35718012
35719020

TOR1AIP2
179821947-
179834571-
179834990-
Unc
0.810
0.814
0.005
9.93E−01

179834570
179834989
179846373

TOR3A
179052189-
179054763-
179055029-
Unc
0.886
0.890
0.004
9.77E−01

179054762
179055028
179057045

TP53BP2
224002056-
224005908-
224006040-
Unc
0.108
0.118
0.010
8.29E−01

224005907
224006039
224008921

TP53INP1
95942957-
95944298-
95944336-
Exc
0.573
0.361
−0.212
1.18E−09

95944297
95944335
95952087

TP53TG1
86971001-
86974359-
86974550-
Exc
0.583
0.415
−0.168
1.27E−04

86974358
86974549
86974620

TPD52L1
125569530-
125578244-
125578305-
Inc
0.338
0.440
0.102
1.32E−04

125578243
125578304
125583979

TPD52L2
62505170-
62507169-
62507229-
Exc
0.868
0.741
−0.126
3.05E−32

62507168
62507228
62514071

TPRA1
127294349-
127294592-
127294653-
Exc
0.909
0.621
−0.288
4.41E−39

127294591
127294652
127294782

TPT1-AS1
45957371-
45957895-
45957974-
Inc
0.259
0.514
0.255
6.01E−04

45957894
45957973
45963869

TPT1-AS1
45963956-
45964893-
45965038-
Inc
0.792
0.941
0.149
2.04E−04

45964892
45965037
45965166

TPT1-AS1
45963956-
45964849-
45965038-
Inc
0.835
0.950
0.116
4.16E−04

45964848
45965037
45965166

TRA2A
23561460-
23561740-
23562052-
Unc
0.101
0.104
0.003
9.31E−01

23561739
23562051
23571407

TRAPPC12
3469467-
3481463-
3481567-
Exc
0.973
0.858
−0.115
6.99E−05

3481462
3481566
3482616

TREX2
152719967-
152720335-
152720512-
Exc
0.465
0.347
−0.119
9.05E−04

152720334
152720511
152720999

TRIM16
15546131-
15554405-
15555261-
Inc
0.791
0.955
0.164
1.23E−05

15554404
15555260
15580489

TRIM37
57076821-
57078959-
57079103-
Unc
0.841
0.835
−0.005
9.69E−01

57078958
57079102
57089688

TRIM65
73887429-
73887894-
73887960-
Inc
0.430
0.645
0.214
1.65E−04

73887893
73887959
73888091

TRIO
14502767-
14504502-
14504703-
Exc
0.987
0.870
−0.117
1.47E−17

14504501
14504702
14507230

TRIP10
6745006-
6746040-
6746208-
Exc
0.353
0.207
−0.146
9.68E−08

6746039
6746207
6746462

TRIP12
230724291-
230725122-
230725248-
Inc
0.564
0.760
0.195
1.78E−18

230725121
230725247
230744697

TRMU
46751486-
46751887-
46751970-
Unc
0.826
0.836
0.010
9.49E−01

46751886
46751969
46752738

TROVE2
193038765-
193039684-
193039750-
Inc
0.039
0.308
0.269
3.64E−15

193039683
193039749
193044949

TROVE2
193028907-
193029004-
193029353-
Unc
0.156
0.148
−0.008
9.76E−01

193029003
193029352
193038163

TRPC1
142510001-
142511666-
142511810-
Exc
0.886
0.735
−0.151
1.77E−04

142511665
142511809
142521010

TRPM4
49661517-
49669298-
49669473-
Exc
1.000
0.794
−0.206
4.10E−04

49669297
49669472
49671516

TRPT1
63991440-
63991572-
63991683-
Exc
0.955
0.795
−0.160
2.78E−12

63991571
63991682
63991756

TRPT1
63991440-
63991572-
63991635-
Exc
0.927
0.704
−0.223
2.99E−11

63991571
63991634
63991756

TSEN15
184023998-
184041291-
184041433-
Exc
0.766
0.618
−0.149
5.24E−09

184041290
184041432
184041960

TSEN15
184023998-
184041291-
184041329-
Exc
0.636
0.451
−0.186
4.32E−08

184041290
184041328
184041960

TSEN15
184023998-
184039750-
184039867-
Inc
0.032
0.171
0.139
1.01E−12

184039749
184039866
184041290

TSPAN5
99403327-
99407889-
99408036-
Unc
0.851
0.857
0.006
8.52E−01

99407888
99408035
99428828

TSR1
2239025-
2239331-
2239435-
Exc
0.967
0.825
−0.142
2.43E−09

2239330
2239434
2239624

TSTD3
99973986-
99979239-
99979413-
Exc
0.692
0.476
−0.216
3.86E−05

99979238
99979412
99979507

TUBG2
40812726-
40814991-
40815071-
Exc
0.929
0.811
−0.119
1.94E−04

40814990
40815070
40815394

TULP3
3043728-
3046797-
3046896-
Exc
0.947
0.671
−0.276
1.33E−24

3046796
3046895
3047279

TULP3
3018747-
3029929-
3030089-
Unc
0.766
0.765
−0.001
9.89E−01

3029928
3030088
3031427

TXNDC11
11792182-
11794308-
11794421-
Exc
0.897
0.758
−0.139
3.52E−06

11794307
11794420
11815432

TXNDC11
11815527-
11824501-
11824631-
Exc
0.896
0.728
−0.168
8.33E−07

11824500
11824630
11827837

TXNL4A
77737702-
77746602-
77746751-
Inc
0.109
0.212
0.102
2.71E−13

77746601
77746750
77748239

U2AF1
44520630-
44521476-
44521543-
Unc
0.143
0.143
0.001
9.72E−01

44521475
44521542
44524424

U2AF1L4
36235323-
36235527-
36235640-
Exc
0.519
0.093
−0.426
1.77E−15

36235526
36235639
36236025

U2AF1L4
36235323-
36235527-
36235594-
Exc
0.538
0.066
−0.471
1.56E−18

36235526
36235593
36236025

UACA
70968931-
70969447-
70969480-
Exc
0.936
0.753
−0.183
3.76E−17

70969446
70969479
70970437

UBA7
49849977-
49850081-
49850172-
Exc
0.971
0.826
−0.145
6.17E−08

49850080
49850171
49850494

UBE2A
118709364-
118715470-
118715560-
Exc
0.886
0.683
−0.203
1.92E−45

118715469
118715559
118716550

UBE2D1
60121162-
60121255-
60121287-
Exc
0.992
0.865
−0.126
1.19E−14

60121254
60121286
60123368

UBN2
138921844-
138936702-
138936804-
Exc
0.910
0.653
−0.257
4.56E−04

138936701
138936803
138943233

UBP1
33444397-
33450182-
33450290-
Inc
0.356
0.568
0.212
2.16E−16

33450181
33450289
33450727

UBQLN1
86280061-
86281265-
86281349-
Exc
0.813
0.711
−0.102
1.70E−10

86281264
86281348
86284099

UBQLN1
86280061-
86281265-
86281310-
Exc
0.687
0.557
−0.130
2.08E−08

86281264
86281309
86284099

UCHL5
192993077-
192997005-
192997086-
Unc
0.119
0.122
0.003
9.32E−01

192997004
192997085
192997214

UFD1L
19459332-
19462993-
19463126-
Exc
0.821
0.658
−0.164
4.55E−06

19462992
19463125
19466605

UNC5B
73048490-
73048715-
73048748-
Exc
0.964
0.839
−0.125
2.93E−08

73048714
73048747
73050671

UPF3A
115048419-
115051734-
115051876-
Unc
0.532
0.530
−0.002
9.49E−01

115051733
115051875
115051993

UPF3A
115048419-
115051777-
115051876-
Unc
0.630
0.622
−0.008
9.23E−01

115051776
115051875
115051993

UPP1
48134425-
48141421-
48141468-
Unc
0.195
0.185
−0.010
7.14E−01

48141420
48141467
48146469

URGCP
43927085-
43927389-
43927416-
Exc
0.925
0.790
−0.136
8.53E−05

43927388
43927415
43946160

URGCP
43927085-
43927389-
43927411-
Exc
0.900
0.708
−0.191
2.51E−05

43927388
43927410
43946160

USMG5
105152224-
105153956-
105154152-
Exc
0.530
0.311
−0.220
1.87E−06

105153955
105154151
105155502

USP24
55557800-
55558494-
55558590-
Exc
0.990
0.881
−0.108
2.57E−08

55558493
55558589
55559609

USP25
17177578-
17181128-
17181205-
Exc
0.983
0.835
−0.148
1.91E−13

17181127
17181204
17183455

USP3
63824907-
63826002-
63826118-
Unc
0.101
0.094
−0.006
8.98E−01

63826001
63826117
63829223

USP33
78207434-
78211106-
78211285-
Inc
0.414
0.558
0.144
9.65E−05

78211105
78211284
78225327

USP53
120134029-
120135225-
120135378-
Exc
0.631
0.332
−0.300
1.17E−16

120135224
120135377
120138704

USP8
50774263-
50776472-
50776559-
Inc
0.466
0.594
0.127
1.87E−06

50776471
50776558
50781997

VAMP7
155119276-
155125286-
155125344-
Exc
0.957
0.830
−0.127
4.67E−13

155125285
155125343
155127775

VCAN
82808216-
82815168-
82818129-
Exc
0.685
0.357
−0.328
7.07E−14

82815167
82818128
82841355

VDR
48272899-
48276477-
48276558-
Unc
0.878
0.876
−0.002
7.96E−01

48276476
48276557
48298737

VEGFA
43746656-
43748469-
43748592-
Unc
0.115
0.123
0.009
8.73E−01

43748468
43748591
43749692

VEGFA
43746656-
43748469-
43748523-
Unc
0.140
0.145
0.005
9.83E−01

43748468
43748522
43749692

VEZT
95645848-
95650326-
95650399-
Inc
0.510
0.668
0.157
2.20E−07

95650325
95650398
95650925

VIPAS39
77920446-
77923438-
77923757-
Unc
0.130
0.125
−0.005
9.28E−01

77923437
77923756
77923837

VPS13D
12395885-
12398288-
12398363-
Unc
0.126
0.117
−0.009
9.68E−01

12398287
12398362
12401836

VPS29
110934009-
110937340-
110937352-
Inc
0.356
0.468
0.113
3.40E−06

110937339
110937351
110939853

WARS
100828259-
100841620-
100841744-
Unc
0.507
0.515
0.007
9.35E−01

100841619
100841743
100842596

WARS
100835596-
100840473-
100840582-
Unc
0.249
0.240
−0.009
5.31E−01

100840472
100840581
100841619

WBP1
74685799-
74686605-
74686690-
Exc
0.239
0.112
−0.127
6.92E−05

74686604
74686689
74686769

WDFY2
52234800-
52249306-
52249380-
Exc
0.833
0.606
−0.226
2.21E−06

52249305
52249379
52277731

WDR27
170062521-
170063659-
170063746-
Unc
0.353
0.358
0.005
9.09E−01

170063658
170063745
170064261

WHSC1
1936990-
1941381-
1941506-
Unc
0.739
0.741
0.001
9.07E−01

1941380
1941505
1952798

WNK1
971437-
980431-
980515-
Unc
0.768
0.770
0.002
9.77E−01

980430
980514
987380

XIAP
122993756-
123019481-
123020390-
Unc
0.893
0.896
0.003
9.33E−01

123019480
123020389
123022468

XPNPEP3
41265120-
41266052-
41266144-
Unc
0.230
0.223
−0.008
9.33E−01

41266051
41266143
41277773

YEATS2
183476754-
183479295-
183479403-
Exc
1.000
0.892
−0.108
1.05E−06

183479294
183479402
183479884

YIPF1
54354660-
54354917-
54355137-
Exc
0.384
0.070
−0.314
1.42E−15

54354916
54355136
54355385

YME1L1
27425315-
27431316-
27431415-
Exc
0.897
0.774
−0.123
6.50E−26

27431315
27431414
27434356

YTHDF2
29064851-
29068915-
29070499-
Unc
0.891
0.896
0.006
7.03E−01

29068914
29070498
29095440

YWHAB
43514528-
43516186-
43516384-
Unc
0.100
0.103
0.003
7.26E−01

43516185
43516383
43530171

YWHAB
43514528-
43516289-
43516384-
Unc
0.151
0.150
−0.001
8.69E−01

43516288
43516383
43530171

YY1AP1
155649304-
155650207-
155650248-
Exc
0.923
0.816
−0.107
4.12E−04

155650206
155650247
155657861

YY1AP1
155649304-
155650173-
155650248-
Exc
0.845
0.673
−0.172
1.08E−03

155650172
155650247
155657861

ZBTB38
141122874-
141157110-
141157208-
Unc
0.214
0.213
0.000
9.84E−01

141157109
141157207
141161230

ZBTB38
141122874-
141157085-
141157208-
Unc
0.211
0.202
−0.009
7.68E−01

141157084
141157207
141161230

ZBTB8OS
33093146-
33097428-
33097481-
Exc
0.713
0.581
−0.132
9.29E−05

33097427
33097480
33099245

ZC2HC1A
79610749-
79624225-
79624342-
Inc
0.062
0.219
0.156
3.70E−06

79624224
79624341
79627455

ZC3H11A
203764923-
203765421-
203765730-
Inc
0.201
0.555
0.354
2.19E−13

203765420
203765729
203770702

ZC3H11A
203764923-
203765421-
203765625-
Inc
0.351
0.673
0.322
5.26E−13

203765420
203765624
203770702

ZCCHC6
88932192-
88933873-
88933974-
Exc
0.924
0.819
−0.104
2.10E−04

88933872
88933973
88934498

ZCCHC6
88940430-
88941286-
88941407-
Unc
0.159
0.154
−0.005
9.59E−01

88941285
88941406
88943254

ZCCHC8
122974011-
122975009-
122975115-
Exc
0.977
0.868
−0.110
1.26E−03

122975008
122975114
122977261

ZDHHC16
99213421-
99213556-
99213604-
Exc
0.810
0.587
−0.223
1.09E−12

99213555
99213603
99214470

ZDHHC20
21950795-
21952800-
21952878-
Inc
0.085
0.281
0.197
1.13E−23

21952799
21952877
21955572

ZDHHC7
85015601-
85022369-
85022480-
Exc
0.536
0.415
−0.121
3.36E−08

85022368
85022479
85023909

ZEB1
31676196-
31676649-
31676728-
Unc
0.233
0.235
0.002
9.27E−01

31676648
31676727
31749965

ZFAND1
82627350-
82629484-
82629524-
Exc
0.621
0.382
−0.239
4.40E−12

82629483
82629523
82630416

ZFAND5
74975704-
74978386-
74978523-
Exc
0.559
0.450
−0.109
4.90E−08

74978385
74978522
74979611

ZFAS1
47897108-
47897440-
47897502-
Exc
0.660
0.536
−0.125
2.58E−49

47897439
47897501
47905581

ZFAT
135621123-
135622713-
135622899-
Unc
0.792
0.792
0.000
9.29E−01

135622712
135622898
135649703

ZFX
24170948-
24179832-
24179960-
Unc
0.264
0.261
−0.003
9.35E−01

24179831
24179959
24190831

ZMIZ1
81067329-
81070681-
81070942-
Exc
0.635
0.512
−0.124
1.40E−05

81070680
81070941
81072398

ZMYM1
35545044-
35558921-
35559043-
Unc
0.546
0.542
−0.004
9.83E−01

35558920
35559042
35559514

ZMYM4
35734687-
35790961-
35791007-
Exc
0.939
0.631
−0.309
4.74E−12

35790960
35791006
35824525

ZMYM5
20426331-
20436539-
20436607-
Exc
0.911
0.689
−0.222
6.25E−05

20436538
20436606
20437589

ZMYM5
20409830-
20411796-
20411962-
Exc
0.914
0.557
−0.358
1.76E−06

20411795
20411961
20425494

ZNF140
133660148-
133677573-
133677640-
Unc
0.502
0.500
−0.002
9.78E−01

133677572
133677639
133682095

ZNF160
53589575-
53594666-
53594783-
Exc
0.605
0.362
−0.244
3.05E−04

53594665
53594782
53594889

ZNF207
30687987-
30688487-
30688535-
Exc
0.935
0.477
−0.459
1.66E−186

30688486
30688534
30689932

ZNF207
30692507-
30693684-
30693777-
Inc
0.629
0.872
0.243
9.12E−73

30693683
30693776
30694790

ZNF217
52185804-
52188260-
52188393-
Unc
0.836
0.835
−0.001
9.72E−01

52188259
52188392
52192265

ZNF248
38145266-
38145363-
38145461-
Exc
0.985
0.762
−0.223
1.31E−04

38145362
38145460
38146112

ZNF260
37006602-
37016057-
37016276-
Unc
0.879
0.886
0.008
8.79E−01

37016056
37016275
37019120

ZNF266
9530895-
9544741-
9544912-
Unc
0.564
0.568
0.004
8.76E−01

9544740
9544911
9545473

ZNF280D
56996466-
56999280-
56999349-
Exc
0.954
0.846
−0.108
6.55E−04

56999279
56999348
56999460

ZNF280D
56996466-
56999280-
56999342-
Exc
0.942
0.822
−0.120
9.46E−04

56999279
56999341
56999460

ZNF3
99675057-
99677159-
99677280-
Unc
0.818
0.824
0.007
9.83E−01

99677158
99677279
99679257

ZNF346
176471535-
176477752-
176477938-
Unc
0.903
0.899
−0.004
9.51E−01

176477751
176477937
176489058

ZNF37A
38383419-
38383859-
38384153-
Unc
0.530
0.521
−0.009
9.87E−01

38383858
38384152
38384465

ZNF384
6787627-
6787829-
6787877-
Exc
0.781
0.593
−0.188
2.07E−08

6787828
6787876
6788111

ZNF419
58002966-
58003481-
58003580-
Unc
0.617
0.624
0.007
9.78E−01

58003480
58003579
58004223

ZNF426
9640313-
9641661-
9641744-
Unc
0.898
0.901
0.003
8.37E−01

9641660
9641743
9643520

ZNF512
27822921-
27823558-
27823683-
Exc
0.970
0.865
−0.106
1.55E−05

27823557
27823682
27824222

ZNF516
74074513-
74082483-
74082551-
Inc
0.831
1.000
0.169
7.19E−08

74082482
74082550
74083421

ZNF529
37039225-
37042779-
37042880-
Unc
0.104
0.111
0.008
9.72E−01

37042778
37042879
37045571

ZNF532
56530983-
56532536-
56532618-
Inc
0.796
0.928
0.132
9.81E−04

56532535
56532617
56532701

ZNF585B
37681053-
37689841-
37689957-
Unc
0.897
0.896
−0.001
9.20E−01

37689840
37689956
37697941

ZNF638
71558996-
71575557-
71577402-
Unc
0.860
0.858
−0.001
9.30E−01

71575556
71577401
71582848

ZNF655
99158319-
99159511-
99160118-
Unc
0.765
0.762
−0.003
9.61E−01

99159510
99160117
99161485

ZNF720
31765222-
31770678-
31770788-
Exc
0.925
0.725
−0.200
9.99E−04

31770677
31770787
31803950

ZNF75A
3355644-
3358313-
3358837-
Unc
0.782
0.778
−0.004
9.35E−01

3358312
3358836
3361752

ZNF767
149317129-
149318137-
149318264-
Unc
0.844
0.835
−0.009
9.22E−01

149318136
149318263
149318350

ZSCAN32
3440518-
3443649-
3443815-
Unc
0.854
0.852
−0.001
9.08E−01

3443648
3443814
3447191

ZZZ3
78105288-
78107069-
78107132-
Exc
0.980
0.864
−0.117
2.20E−08

78107068
78107131
78107206

Differential Splicing Analysis to Identify Drug-Responding Sequences from RNA Sequencing

For differential splicing analysis as shown in FIG. 21B, a Cochran-Mantel-Haenszel test was applied followed by FDR (False-Discovery-Rate) correction. A FDR<0.1 and Δψ>=0.1 was considered as an inclusion-response after treatment (FIG. 21B). Any triplet with a FDR<0.1 and Δψ≤=−0.1 was considered as an exclusion-response after treatment (FIG. 21B). Any exon triplet, whose ψ before-treatment was in a range from 0.1 to 0.9 and the ψ change after treatment was less than 0.01, was considered to be an unchanged-response. For the Pearson correlation analysis shown in FIG. 2C, the grey zone indicated a 9500 confident interval. The p values were then adjusted by Bonferroni correction. For the splicing strength comparison illustrated in FIG. 3C, the maximum entropy was compared amongst the inclusion, exclusion and unchanged groups at each splice Junction, using an unpaired Welch's t test followed by Bonferroni correction. For the boxplots shown in FIG. 3C, the middle lines inside boxes indicate the medians. The lower and upper hinges correspond to the first and third quartiles. Each box extends to 1.5 times inter-quartile range (IQR) from the upper and lower hinges respectively. Outliers were not shown. For RT-PCR comparison, an unpaired Student's t test was applied. For the distance comparison shown in FIG. 4B), the Kolmogorov-Smirnov (K-S) test was applied, where all tests were two-tailed. In all plots, the error bars indicate the 95% confident interval and the significance levels were marked by * having p<0.05, ** p<0.01 and *** p<0.001, where the significance levels always refer to the adjusted p values if adjusted as described above. Training of CNN Model to Predict Potentially Responsive Genes

The CNN model (as shown in FIGS. 4A and 4B, and FIGS. 5A1, 5A2, 5B and 5C) consisted of two layers of convolutions with a total of 2.50 million trainable parameters optimized for predicting splicing changes after being trained using RNASeq values for effect on exon triplet splicing after Compound (I) treatment.

The two convolutional layers and one hidden layer (see FIGS. 5A1 and 5A2) were trained using the Basset framework⁴¹. The training set consisted of 178 inclusion-responded, 476 exclusion-responded and 268 unchanged exon triplets. The validation sets consisted of 51 inclusion-responded, 136 exclusion-responded and 76 unchanged exon triplets. The test set consisted of 25 inclusion-responded, 68 exclusion-responded and 38 unchanged exon triplets. The three sets were assigned randomly in Python using seed of 122. For each exon-triplet, the sequences consisting of an exonic 25 nucleotide sequence and an intronic 75 nucleotide sequence within the UI₁, I₁X, XI₂and I₂D regions (see FIG. 2A) were concatenated and then one-hot coded into an input matrix with a size of 4×400. The first round of convolution was applied with fifty 4×5 weight matrices, converting the input matrix into a 50×396 convoluted matrix, in which each row represented the convolution of one weight matrix.

The convolution matrix was nonlinearly transformed using a rectified linear unit (ReLU) function, with the maximum pool stage taking the maximum of two adjacent positions of each row, shrinking the output matrix to a size of 50×198. The second round of matrix convolution then applied fifty 4×2 weight matrices, followed by the same ReLU transformation and maximum pool of the first round. The output was converted to a 1×500 matrix to initiate the hidden layer, where a fully connected network was built with 90% dropout rate. The output from the hidden layer was ReLU transformed again and was then linearly transformed into a vector of three values, representing the three different treatment responses. The final sigmoid nonlinearity mapped each element in the vector to a value between 0 and 1, considered as the probability of small molecule splicing modulator compound responsiveness. In each Epoch of training, an average of the area under the curve (AUC) was measured on the validation set across the prediction of three treatment responses. The training and validation loss in terms of binary cross-entropy were measured on the training set and validation set respectively. The training process stopped if there was no improvement in the AUC average over 10 consecutive Epochs. In this study, training was stopped at the 12^thEpoch to avoid overfitting (see FIG. 5B).

The CNN model obtained an average accuracy for an Area-Under-Curve (AUC) of 0.82 (as shown in FIG. 5C), identifying 39 5-mer CNN Motifs (as shown in FIG. 6A1-6A7) that suggest genes having similar motifs would also be affected by Compound (I) splicing modulation. The 39 CNN Motifs were identified based on their higher probability to cause a splicing reaction in the presence of Compound (I), yielding a prediction of whether the isoform produced will be the result of either an exclusion of an exon or inclusion of an exon or poison exon or whether there will be no change in the isoform produced. The 39 CNN Motifs present in wildtype or mutant genes described herein may cause changes or no change in isoform results in other genes not described herein depending on the structure of the small molecule splicing compound tested.

Without being limited by theory, the 39 CNN Motifs obtained using the CNN Model described herein may suggest other equivalents that may be obtained within the scope of the deep learning algorithm underlying the CNN Model, enabling others of ordinary skill in the art to predict or allow the prediction of the effect of other small molecule splicing compounds to modulate the production of one or more mature RNA isoforms from other wildtype or mutant gene transcripts than those described or predicted herein. In other words, the in vitro and in vivo minigene data provided herein demonstrates that the use of all 39 CNN Motifs in the CNN Model were sufficient and efficient to make correct and accurate predictions.

CNN Motif Ranking

The 39 CNN Motifs may be ranked according to a predicted probability for modulating the production of one or more mature RNA isoforms from a wildtype or mutant gene transcript. Two analytic methods were used to rank the degree of Motif probability to predict an effect on splicing in the presence of a small molecule splicing compound. In the first instance, the analytic method used reset each Motifs activation probability level to the average level of all Motif activations. As shown in FIGS. 3A1-3A2, the 12 CNN Motifs having AUC changes greater than 0.1 were identified and ordered according to the AUC change before and after the reset. In the second instance, the analytic method used reset each Motifs activation level to zero. As shown in FIGS. 3B1-3B2, the 13 CNN Motifs having AUC changes greater than 0.05 were identified and ordered according to the AUC change before and after the reset.

The 39 CNN Motifs may be ranked according to positional importance for modulating the production of one or more mature RNA isoforms from a wildtype or mutant gene transcript. Two analytic methods were used to rank the positional importance of each Motif to predict an effect on splicing in the presence of a small molecule splicing compound. In the first instance, the AUC analytic method used reset each nucleotide's position activation level to the average activation level of that position. As shown in FIG. 3A3, the positional importance for the 12 CNN Motifs was ranked by the AUC change before and after the reset. In the second instance, the AUC analytic method used the highest activation of each nucleotide position to identify and order the Motifs. As shown in FIG. 3B3, the Motif positional importance for the 13 CNN Motifs was ranked according to the highest activation of each nucleotide position as shown in the heatmap results.

Moreover, without theoretical limitation, the ranking of the 39 Motifs used in the CNN Model according to the description herein and other embodiments may be ordered by those of ordinary skill in the art using a variety of analytic and mathematic modeling to predict or allow the prediction of the effect of other small molecule splicing compounds to modulate the production of one or more mature RNA isoforms from other wildtype or mutant gene transcripts than those described or predicted herein.

Positional Importance in the CNN Model

To examine each motif contribution in classification, the validation set was used as model input. For each motif whose positional importance was to be measured, the position-wise output of the first convolutional layer from that motif was manually set as the mean of all the convolutional output. The model was then used without tuning other parameters and the new loss, measured by binary cross-entropy, was calculated. The importance of the motif at that tuned position was measured as the difference between the new loss of the model and the original loss of the model. All the positions of that motif were similarly investigated.

Determining the Standardized Probability from CNN Model Prediction

To determine the drug response class (inclusion, exclusion or unchanged) using the CNN Model prediction, the raw prediction score from the Model was standardized. For each class, a cutoff representing 95% specificity for that response was identified on the validation set. The intermediate score of each class was calculated as the raw prediction score divided by the cutoff of that response class. The standardized probability for each response was then calculated as the intermediate score divided by the sum of intermediate scores of the three classes.

Identification of Enrichment Motif Using K-Mer Enrichment Analysis

The sequences of adjacent nucleotides from the −3 to +7 position of the 5′ splice sites of the middle exons for inclusion, exclusion and unchanged exon triplets were extracted. For each class response, 5-mer enrichment was estimated against the other two classes using Discriminative Regular Expression Motif Elicitation (DREME) from THE MEME Suite (PMID: 21543442) with the parameter “-p, -n, -dna -e 0.05 and -k 5”.

The 5-mer sequence enrichment analysis of adjacent nucleotides from the −3 to +7 position in the Exon X 5′ splice site also agreed with the 39 CNN Motifs identified by the CNN model (as shown in FIG. 6A1-6A7). These results suggest that 5′splice site sequences containing the CNN Motifs are predictively involved in non-canonical U1-5′splice site interaction.

CNN Model Splice Site Strength Analysis

To determine the effect of the CNN Motifs on the splicing of responsive triplets, the strength of the four splice sites UI₁, I₁X, XI₂and I₂D within the triplets was evaluated. Splice site strength for each motif was measured using a maximum entropy model⁷⁷. As described, the measurement used was either the short sequence of 9 nucleotides and 23 nucleotides for the flanking splice junctions, as determined from the 5′ or 3′ end, respectively. The resulting analysis found that exon triplets with inclusion responses had significantly lower strength in the Exon X 5′ splice site compared to the exon triplets with unchanged response (as shown in FIG. 3C). Consistent with previous findings that support the role of this class of splicing modulator compounds in promoting the recruitment of U1 snRNP in non-canonical ending exons^46,56, these data suggest that weak 5′ splice sites are more sensitive to treatment with Compound (I).

CNN Model Prediction

To evaluate the reproducibility of the model, random initialization of the training process was implemented 1,000 times. It was found that the performance of all models was tightly distributed and aligned with the original model (FIG. 12A). In addition, all of the top 10 first-layer filters contributing to the performance of the CNN model were highly correlated with those of the 1,000 random-initialized models (average Pearson correlation R2=0.55, FIG. 12B), suggesting that the deep learning framework was robust.

The 39 5-mer motifs (CNN Motifs) were identified from the first layer of the CNN model were identified (FIGS. 6A1-6A7). The treatment response was not determined by any of these motifs independently, all 39 CNN Motifs are used in the CNN Model to interrogate genes of interest. As such, the CNN model utilizes the synergistic effect of all 39 Motifs on a given sequence to make the Class decision. Thirteen motifs (see FIGS. 3B1-3B2) explained 92.62% of the AUC, each of which altered more than 0.105 of AUC for at least one class of prediction (FIG. 5C). Analysis of these motifs revealed that the sequence in proximity to, and in many cases encompassing, the 5′ splice site of the middle exon had the largest influence in modulating treatment response (FIGS. 3A, 3B and 3C). These results emphasized the importance of the 5′ splice site in determining treatment outcome. In silico saturation mutagenesis further supported these findings, revealing that base contribution to the treatment outcomes peaked around the 5′ splice sites of the middle exons, with distinct patterns amongst sequences with inclusion, exclusion and unchanged responses (FIG. 3C).

Table 17 lists the motifs (Motif) shown in FIGS. 6A1-6A7, with constant and most dominant nucleotides as shown in the LOGO plot. The 39 CNN Motifs were those most frequent 5-mer sequences (5-mer) predicted by the CNN Model to affect splicing in the presence of Compound (I) toward an inclusion, exclusion or unchanged Effect.

TABLE 17

Motif
5-Mer
SEQ ID NO.
Effect

01
CTTAG
25
Unchanged

02
NNAGC
26
Exclusion

03
NCAGA
27
Exclusion

04
CCCTT
28
Inclusion

05
TNNCT
29
Exclusion

06
GCAGA
30
Unchanged

09
TNTGA
31
Exclusion

10
TGAGC
32
Exclusion

12
CTCTC
33
Exclusion

14
TNNNT
34
Inclusion

15
TTTTT
35
Inclusion

16
ATGGN
36
Unchanged

17
TCTCA
37
Unchanged

18
AAGCT
38
Inclusion

20
GTCAT
39
Exclusion

21
GAGAG
40
Exclusion

22
AGGAN
41
Unchanged

23
AGACC
42
Inclusion

25
AAGGT
43
Inclusion

26
GATTA
44
Inclusion

27
TCTTT
45
Unchanged

28
NNAGN
46
Inclusion

29
TCGTG
47
Exclusion

31
ANGAA
48
Exclusion

32
TTAAA
49
Inclusion

33
AGACT
50
Unchanged

34
GGGTG
51
Inclusion

35
TTCCC
52
Inclusion

37
AGTNA
53
Unchanged

38
TATGT
54
Exclusion

40
GGGAA
55
Exclusion

41
NTGNN
56
Exclusion

42
NTCCC
57
Exclusion

43
CAGGC
58
Exclusion

44
NTGTN
59
Exclusion

46
NTCCT
60
Unchanged

47
AACCT
61
Exclusion

48
ACTCN
62
Unchanged

49
CTGTA
63
Inclusion

Identification of ClinVar Therapeutic Targets Harboring Disease-Causing Mutations Amenable to Compound (I) Splicing Modulation

As shown in FIG. 4A, from 89,642 potential CV-pMUTs within 5 kb upstream or downstream of the mutated site, SpliceAI scores identified 17,956 (20.03%) splice site mutations that had the potential to disrupt pre-mRNA splicing in the gene and result in a disease. Out of those 17,956 CV-pMUTs, there were 14,272 (79.48%) leading to splicing disruption of the Ensembl-annotated splice sites (GRCh37 version 75). These CV-pMUT disrupting annotated splice sites were then used to train the CNN model to predict splicing alterations in mutated splice sites that could be corrected by Compound (I) treatment.

As shown in FIG. 4B, the CV-pMUTs disrupting annotated splice sites demonstrated that the identified flanking regions UI₁, I₁X, XI₂and I₂D were significantly closer to the splice junction than the CV-pMUTs that had no effect in disrupting annotated splice sites. Since about 98% of them were within 75 nucleotides of the splice site junction, the flanking regions were determined to include most of the targetable pathogenic splicing alterations for use in training the CNN model.

As illustrated in FIG. 4A, amongst the 14,272 CV-pMUTs predicted to disrupt annotated splice sites (corresponding to 11,616 exon triplets in 1,970 genes), the CNN model predicted that the altered splicing of 234 CV-pMUTs (1.64%) found in 295 exon triplets (2.54%) in 174 genes (8.83%) could be rescued by splicing modulation, toward either or both exon inclusion and exon exclusion, resulting from Compound (I) treatment.

SpliceAI Prediction for ClinVar Pathogenic Mutations

The VCF file recording ClinVar (version 20190325) mutations was downloaded. The pathogenic/likely pathogenic mutations were extracted and fed to SpliceAI (https://github.com/illumina/SpliceAI). In the prediction from SpliceAI, any mutation with any SpliceAI score greater than 0.2 was considered to be the result of altering splicing. As shown in Table 19, those mutations, together with the influenced splice junction (ISJ) and SpliceAI score were recorded.

Rescue Definition and Prediction

For an exon triplet, the coordinates of the two flanking domains of the middle exon for an exon triplet were compared to those ISJs discovered by SpliceAI. If either domain overlapped with an ISJ and the SpliceAI score indicated a splicing gain, the exon triplet was considered to likely promote exon inclusion as a result of the corresponding mutation. On the other hand, a 5′ splice site of the middle exon overlapping with an ISJ and having a SpliceAI score that indicated a splicing loss, the exon triplet was considered to likely promote exon skipping as a result of the corresponding mutation.

Three possible rescue outcomes were considered: 1) The mutated exon triplet was predicated (by SpliceAI) to cause exon skipping and the CNN model predicted an inclusion response after Compound (I) treatment; or, 2) The mutated exon triplet was predicted (by SpliceAI) to promote exon inclusion and the CNN model predicted an exclusion response after Compound (I) treatment; or, 3) the mutated exon triplet generated a pre-mature termination codon (PTC) inside the middle exon and the CNN model predicted an exclusion response after Compound (I) treatment without a reading frameshift after exclusion.

Allele Frequency From gnomAD

VCF files for both human exome and genome sequencing were downloaded from gnomAD (v2.1.1). The corresponding ClinVar mutations were located in the VCF files via their SNP IDs. If a short variant was found only in the exome or only in the genome sequencing VCF, the reported minor allele frequency was then used. If a short variant was found in both the exome and genome sequencing, the combined frequency was calculated as (AC1+AC2)/(AN1+AN2), where AC1 and AC2 were the allele counts for exome and genome sequencing, respectively, and AN1 and AN2 were the total sample sizes for exome and genome sequencing, respectively.

As described herein, wildtype genes were identified by RNA sequencing and ClinVar mutated genes were predicted by SpliceAI scores and the CNN model to harbor a mutation that will cause a splicing defect were analyzed, as described herein, to determine whether they could be responsive to Compound (I) splicing modulation. The CNN Model was used to predict whether the ClinVar SpliceAI identified splicing defect could be rescued by treatment with Compound (I) modulation of splicing toward either or both exon inclusion and exon exclusion. As described herein, certain genes were responsive to modulation of splicing as a result of treatment with Compound (I).

Table 18 lists for each mutated Gene (identified by ClinVar and Allele identification numbers) and associated Introns and Exon (where Intron 1 is upstream of the affected Exon and Intron 2 is downstream), predicted by SpliceAI scores based on frequency of occurrence (gnomAD Freq) and the CNN model, as described herein, that may be modulated by Compound (I) toward either or both exon inclusion and exon exclusion (Rescue).

TABLE 18

Clin

gnomAD

Gene
Rescue
VAR
Allele
Freq
Intron 1
Exon
Intron2

ABCA4
inclusion
236104
237676
−1
94502345-
94502701-
94502907-

94502700
94502906
94505598

ABCC9
inclusion
31947
40612
3.99E−06
21991105-
21995248-
21995406-

21995247
21995405
21997416

ABCC9
inclusion
31946
40611
−1
21991105-
21995248-
21995406-

21995247
21995405
21997416

ACADSB
inclusion
9199
24238
2.95E−05
124810703-
124812577-
124812677-

124812576
124812676
124813210

ADAM10
inclusion
88840
94409
−1
58904191-
58913670-
58913821-

58913669
58913820
58919898

AGK
inclusion
209129
205751
1.42E−05
141313979-
141315271-
141315366-

141315270
141315365
141321531

ALDH3A2
inclusion
189079
186958
−1
19559888-
19561034-
19561176-

19561033
19561175
19564439

ALDH3A2
inclusion
189079
186958
−1
19559888-
19561058-
19561176-

19561057
19561175
19564439

ALMS1
inclusion
191112
188916
−1
73646447-
73649985-
73650103-

73649984
73650102
73651557

ANTXR2
inclusion
2598
17637
−1
80899329-
80905032-
80905125-

80905031
80905124
80905972

APC
inclusion
411344
394701
−1
112116601-
112136976-
112137081-

112136975
112137080
112151191

APC
inclusion
411344
394701
−1
112128227-
112136976-
112137081-

112136975
112137080
112151191

APC
inclusion
411344
394701
−1
112128227-
112136976-
112137081-

112136975
112137080
112145822

APC
inclusion
433614
427251
−1
112146009-
112151192-
112151291-

112151191
112151290
112154662

APC
inclusion
486792
473576
−1
112151291-
112154663-
112155042-

112154662
112155041
112157592

APC
inclusion
411416
394347
−1
112151291-
112154663-
112155042-

112154662
112155041
112157592

APC
inclusion
428128
419618
−1
112157689-
112170648-
112170863-

112170647
112170862
112173249

APC
inclusion
428128
419618
−1
112164670-
112170648-
112170863-

112170647
112170862
112173249

ARMC9
inclusion
427935
419011
3.98E−06
232137792-
232141349-
232141489-

232141348
232141488
232143094

ASAH1
inclusion
55908
70551
−1
17916974-
17917081-
17917213-

17917080
17917212
17918885

ASPM
inclusion
402180
389111
−1
197062392-
197063214-
197063311-

197063213
197063310
197065127

ASPM
inclusion
210353
206745
−1
197091726-
197093240-
197093462-

197093239
197093461
197093999

ASPM
inclusion
21572
34424
−1
197094086-
197094176-
197094322-

197094175
197094321
197097619

ATM
inclusion
3044
18083
4.39E−05
108124767-
108126942-
108127068-

108126941
108127067
108128207

ATM
inclusion
181974
180483
2.78E−05
108183226-
108186550-
108186639-

108186549
108186638
108186737

ATM
inclusion
3035
18074
1.59E−05
108150336-
108151722-
108151896-

108151721
108151895
108153436

ATM
inclusion
230851
233909
4.01E−06
108098616-
108099905-
108100051-

108099904
108100050
108106396

ATM
inclusion
230851
233909
4.01E−06
108098616-
108099905-
108100051-

108099904
108100050
108114679

ATM
inclusion
135778
139490
3.99E−06
108202285-
108202606-
108202765-

108202605
108202764
108203488

ATRX
inclusion
560933
552266
−1
76907844-
76909588-
76909691-

76909587
76909690
76912049

BBS4
inclusion
585184
576240
−1
73002121-
73004585-
73004649-

73004584
73004648
73009118

BBS4
inclusion
585184
576240
−1
73002121-
73004585-
73004649-

73004584
73004648
73007631

BFSP1
inclusion
425558
413913
0.00E+00
17475675-
17477583-
17477669-

17477582
17477668
17479464

BMPR2
inclusion
425729
414116
−1
203242274-
203329532-
203329703-

203329531
203329702
203332241

BRCA1
inclusion
37604
46160
3.19E−05
41223256-
41226348-
41226539-

41226347
41226538
41228504

BRCA1
inclusion
37604
46160
3.19E−05
41223256-
41226348-
41226539-

41226347
41226538
41277287

BRCA1
inclusion
17660
32699
1.20E−05
41256974-
41258473-
41258551-

41258472
41258550
41276033

BRCA1
inclusion
17660
32699
1.20E−05
41256974-
41258473-
41258551-

41258472
41258550
41262481

BRCA1
inclusion
55131
69798
−1
41234593-
41242961-
41243050-

41242960
41243049
41251791

BRCA1
inclusion
55131
69798
−1
41234593-
41242961-
41243050-

41242960
41243049
41246760

BRCA1
inclusion
55131
69798
−1
41234593-
41242961-
41243050-

41242960
41243049
41243451

BRCA1
inclusion
55131
69798
−1
41234593-
41242961-
41243050-

41242960
41243049
41247862

BRCA1
inclusion
54471
69138
−1
41256974-
41258473-
41258551-

41258472
41258550
41276033

BRCA1
inclusion
54471
69138
−1
41256974-
41258473-
41258551-

41258472
41258550
41262481

BRCA1
inclusion
54471
69138
−1
41256974-
41258473-
41258551-

41258472
41258550
41267742

BRCA2
inclusion
38215
46771
4.03E−06
32953653-
32953887-
32954051-

32953886
32954050
32954143

BRCA2
inclusion
51711
66379
−1
32899322-
32900238-
32900288-

32900237
32900287
32900378

BRCA2
inclusion
52058
66726
−1
32900420-
32900636-
32900751-

32900635
32900750
32903579

CA5A
inclusion
127088
132598
1.66E−04
87935581-
87936031-
87936127-

87936030
87936126
87938391

CAPN3
inclusion
523316
514049
−1
42678484-
42679951-
42680085-

42679950
42680084
42681125

CD3D
inclusion
180674
178842
7.96E−06
118210210-
118211090-
118211309-

118211089
118211308
118211584

CD3D
inclusion
180674
178842
7.96E−06
118210622-
118211090-
118211309-

118211089
118211308
118213267

CD3D
inclusion
180674
178842
7.96E−06
118210210-
118211090-
118211309-

118211089
118211308
118213267

CDH1
inclusion
185583
184420
−1
68849663-
68853183-
68853329-

68853182
68853328
68855903

CDH23
inclusion
45989
55154
8.05E−06
73544178-
73544648-
73544858-

73544647
73544857
73545387

CERKL
inclusion
438052
431648
−1
182413332-
182413407-
182413585-

182413406
182413584
182414360

CFTR
inclusion
53750
68418
7.09E−06
117251863-
117254667-
117254768-

117254666
117254767
117267575

CFTR
inclusion
35857
44521
7.08E−06
117243837-
117246728-
117246808-

117246727
117246807
117250572

CFTR
inclusion
54012
68679
−1
117171169-
117174330-
117174420-

117174329
117174419
117175301

CHD7
inclusion
520773
511761
−1
61754612-
61757423-
61757623-

61757422
61757622
61757808

CLCN1
inclusion
447078
441048
1.41E−05
143021586-
143027865-
143027991-

143027864
143027990
143028324

CLMP
inclusion
50384
59506
3.98E−06
122944483-
122945410-
122945559-

122945409
122945558
122953792

CLMP
inclusion
50384
59506
3.98E−06
122944483-
122945410-
122945552-

122945409
122945551
122953792

CLMP
inclusion
50384
59506
3.98E−06
122944483-
122945410-
122945525-

122945409
122945524
122953792

CLN3
inclusion
56265
70904
4.00E−06
28498863-
28498983-
28499063-

28498982
28499062
28500610

CLN3
inclusion
56265
70904
4.00E−06
28498863-
28498983-
28499063-

28498982
28499062
28499911

CLN3
inclusion
56265
70904
4.00E−06
28498863-
28498983-
28499063-

28498982
28499062
28502802

CLN3
inclusion
56265
70904
4.00E−06
28498863-
28498983-
28499063-

28498982
28499062
28500610

CNGB3
inclusion
427674
417119
−1
87656915-
87660029-
87660116-

87660028
87660115
87666239

COG6
inclusion
493009
485965
7.10E−06
40254183-
40256308-
40256402-

40256307
40256401
40261639

COL11A1
inclusion
547210
537669
0.00E+00
103364330-
103364497-
103364551-

103364496
103364550
103377714

COL3A1
inclusion
101376
107122
−1
189863046-
189863400-
189863445-

189863399
189863444
189864010

COL4A3
inclusion
551759
541906
−1
228125834-
228128496-
228128661-

228128495
228128660
228131132

COL4A5
inclusion
38768
47373
5.55E−06
107863657-
107865033-
107865123-

107865032
107865122
107865905

COL4A5
inclusion
587202
578111
−1
107827756-
107829845-
107829978-

107829844
107829977
107834287

COL4A5
inclusion
587163
578120
−1
107829978-
107834288-
107834462-

107834287
107834461
107834790

COL4A5
inclusion
24409
35750
−1
107834462-
107834791-
107834875-

107834790
107834874
107838738

COL4A5
inclusion
24530
35871
−1
107850123-
107858141-
107858255-

107858140
107858254
107863488

COL4A5
inclusion
24550
35891
−1
107863657-
107865033-
107865123-

107865032
107865122
107865905

COL4A5
inclusion
24696
36037
−1
107920864-
107923909-
107923982-

107923908
107923981
107924114

COL4A5
inclusion
24773
36114
−1
107936156-
107938037-
107938152-

107938036
107938151
107939526

COL4A5
inclusion
24782
36123
−1
107938152-
107938497-
107938670-

107938496
107938669
107939526

COL5A2
inclusion
213101
209548
−1
189926342-
189927591-
189927645-

189927590
189927644
189927735

CSTB
inclusion
55958
70597
−1
45194212-
45194539-
45194641-

45194538
45194640
45196084

CTNS
inclusion
556587
548124
−1
3543562-
3558515-
3558647-

3558514
3558646
3559780

CTU2
inclusion
585016
576071
9.29E−06
88779314-
88779720-
88779856-

88779719
88779855
88780054

CUBN
inclusion
56321
70960
−1
17142239-
17145124-
17145237-

17145123
17145236
17146417

CWC27
inclusion
426071
414475
3.80E−06
64079807-
64081308-
64081407-

64081307
64081406
64082350

CYBB
inclusion
10933
25972
−1
37639376-
37642743-
37642854-

37642742
37642853
37651227

DCX
inclusion
158456
169903
−1
110644559-
110653263-
110653649-

110653262
110653648
110655365

DCX
inclusion
158456
169903
−1
110644559-
110653263-
110653649-

110653262
110653648
110653981

DCX
inclusion
158456
169903
−1
110644559-
110653263-
110653649-

110653262
110653648
110655197

DGKE
inclusion
548648
539159
−1
54923171-
54925283-
54925427-

54925282
54925426
54926056

DGUOK
inclusion
214286
210897
4.95E−05
74174034-
74177712-
74177860-

74177711
74177859
74184251

DGUOK
inclusion
214286
210897
4.95E−05
74174034-
74177754-
74177860-

74177753
74177859
74185272

DGUOK
inclusion
214286
210897
4.95E−05
74174034-
74177728-
74177860-

74177727
74177859
74185272

DMD
inclusion
501566
492990
−1
32717411-
32827610-
32827729-

32827609
32827728
32834584

DNAH5
inclusion
228251
229258
1.99E−05
13829814-
13830135-
13830323-

13830134
13830322
13830705

DNAH5
inclusion
572293
564698
1.99E−05
13701546-
13708232-
13708445-

13708231
13708444
13714513

DNAH9
inclusion
617523
608891
1.45E−04
11543702-
11547948-
11548017-

11547947
11548016
11550388

DYNC2H1
inclusion
437419
430981
4.15E−06
102996025-
102999639-
102999735-

102999638
102999734
103004283

DYNC2LI1
inclusion
518440
509032
1.32E−05
44023935-
44027980-
44028057-

44027979
44028056
44028777

EBF3
inclusion
488452
481314
−1
131676114-
131755522-
131755591-

131755521
131755590
131757197

EP300
inclusion
378053
380144
−1
41560135-
41562603-
41562671-

41562602
41562670
41564452

F10
inclusion
12059
27098
−1
113798410-
113801693-
113801801-

113801692
113801800
113803229

F13A1
inclusion
16524
31563
3.98E−06
6146006-
6152046-
6152183-

6152045
6152182
6167690

FBN1
inclusion
437420
430986
−1
48725186-
48726791-
48726911-

48726790
48726910
48729157

FUT8
inclusion
545467
535727
−1
66188740-
66190865-
66191042-

66190864
66191041
66199948

G6PC
inclusion
214465
211810
1.77E−05
41059646-
41061320-
41061436-

41061319
41061435
41062931

GAA
inclusion
188044
185936
4.03E−06
78082628-
78083744-
78083855-

78083743
78083854
78084525

GABRG2
inclusion
433102
426665
−1
161529680-
161530895-
161531033-

161530894
161531032
161569169

GABRG2
inclusion
433102
426665
−1
161528324-
161530895-
161531033-

161530894
161531032
161569169

GCK
inclusion
36224
44888
−1
44189664-
44190555-
44190675-

44190554
44190674
44191869

GLA
inclusion
180842
179870
−1
100653556-
100653773-
100653935-

100653772
100653934
100654731

GLA
inclusion
180842
179870
−1
100653556-
100653773-
100653935-

100653772
100653934
100655653

GNB5
inclusion
268098
263624
−1
52442123-
52446137-
52446274-

52446136
52446273
52471964

GNPTAB
inclusion
397556
384468
3.99E−06
102174400-
102179790-
102179996-

102179789
102179995
102182325

GNPTAB
inclusion
2761
17800
−1
102164936-
102173930-
102174065-

102173929
102174064
102174334

GPR143
inclusion
10517
25556
−1
9716707-
9727372-
9727467-

9727371
9727466
9728756

GPX4
inclusion
140615
150320
3.59E−05
1105510-
1105657-
1105809-

1105656
1105808
1106240

GRHPR
inclusion
548673
539143
3.98E−06
37425992-
37426535-
37426652-

37426534
37426651
37428480

GRN
inclusion
599616
590962
−1
42427709-
42428918-
42429164-

42428917
42429163
42429382

GRN
inclusion
599616
590962
−1
42428829-
42428918-
42429164-

42428917
42429163
42429382

GUCY2C
inclusion
31604
40288
3.99E−06
14822768-
14825807-
14825893-

14825806
14825892
14827558

GYPA
inclusion
17714
32753
3.60E−05
145039906-
145040839-
145040935-

145040838
145040934
145041642

HBB
inclusion
36337
45001
1.03E−04
5248030-
5248160-
5248270-

5248159
5248269
5248741

IDH1
inclusion
375891
362770
0.00E+00
209110149-
209113093-
209113385-

209113092
209113384
209116153

IDH1
inclusion
375893
362772
0.00E+00
209110149-
209113093-
209113385-

209113092
209113384
209116153

IFT57
inclusion
506288
497913
−1
107886712-
107910368-
107910491-

107910367
107910490
107925474

IL36RN
inclusion
40005
48518
9.55E−04
113817045-
113818429-
113818515-

113818428
113818514
113819700

KDSR
inclusion
427791
418321
2.83E−05
60999135-
61002490-
61002592-

61002489
61002591
61006032

KIAA0586
inclusion
208813
205374
1.38E−05
58924698-
58925191-
58925264-

58925190
58925263
58926560

KIAA0586
inclusion
208813
205374
1.38E−05
58924698-
58925191-
58925264-

58925190
58925263
58927703

KIAA1109
inclusion
487550
480599
−1
123145833-
123147862-
123147991-

123147861
123147990
123150275

KIF14
inclusion
503567
495007
−1
200530009-
200534197-
200534382-

200534196
200534381
200534572

KIT
inclusion
13843
28882
−1
55594094-
55594177-
55594288-

55594176
55594287
55595500

KMT2D
inclusion
547418
537993
−1
49441853-
49442442-
49442553-

49442441
49442552
49442887

KRIT1
inclusion
590717
581356
−1
91843294-
91843925-
91844092-

91843924
91844091
91851215

KRIT1
inclusion
590718
581357
−1
91843294-
91843925-
91844092-

91843924
91844091
91851215

LAMB3
inclusion
14543
29582
−1
209806122-
209806415-
209806479-

209806414
209806478
209807791

LDLR
inclusion
252233
246528
7.99E−06
11230910-
11231046-
11231199-

11231045
11231198
11233849

LIPA
inclusion
203361
199794
1.03E−04
90975767-
90982268-
90982340-

90982267
90982339
90983440

LMNA
inclusion
519180
509123
−1
156106228-
156106712-
156107024-

156106711
156107023
156107444

LMNA
inclusion
519180
509123
−1
156106820-
156106904-
156107024-

156106903
156107023
156107444

LMNA
inclusion
519180
509123
−1
156106820-
156106904-
156107024-

156106903
156107023
156108278

LMNA
inclusion
66854
77751
−1
156106228-
156106712-
156107024-

156106711
156107023
156107444

LMNA
inclusion
66854
77751
−1
156106820-
156106904-
156107024-

156106903
156107023
156107444

LMNA
inclusion
66854
77751
−1
156106820-
156106904-
156107024-

156106903
156107023
156108278

MCFD2
inclusion
2865
17904
1.19E−05
47135109-
47136162-
47136317-

47136161
47136316
47139681

MCFD2
inclusion
2865
17904
1.19E−05
47135109-
47136162-
47136317-

47136161
47136316
47143119

MCFD2
inclusion
2865
17904
1.19E−05
47135109-
47136162-
47136317-

47136161
47136316
47142861

MCFD2
inclusion
2865
17904
1.19E−05
47135109-
47136162-
47136317-

47136161
47136316
47168710

MLH1
inclusion
90285
95759
−1
37048555-
37053311-
37053354-

37053310
37053353
37053501

MLH1
inclusion
90285
95759
−1
37050397-
37053311-
37053354-

37053310
37053353
37053501

MLH1
inclusion
90415
95889
−1
37056036-
37058997-
37059091-

37058996
37059090
37061800

MLH1
inclusion
90415
95889
−1
37056036-
37058997-
37059091-

37058996
37059090
37067127

MLH1
inclusion
89616
95090
−1
37056036-
37061801-
37061955-

37061800
37061954
37067127

MLH1
inclusion
89616
95090
−1
37059091-
37061801-
37061955-

37061800
37061954
37067127

MLH1
inclusion
89979
95453
−1
37089175-
37090008-
37090101-

37090007
37090100
37090394

MMAB
inclusion
218326
215033
−1
110002982-
110006575-
110006669-

110006574
110006668
110011151

MMAB
inclusion
218326
215033
−1
110002982-
110006575-
110006669-

110006574
110006668
110009453

MMAB
inclusion
218326
215033
−1
110002982-
110006575-
110006669-

110006574
110006668
110007776

MPC1
inclusion
35561
44234
−1
166778942-
166779462-
166779595-

166779461
166779594
166780282

MSH2
inclusion
483664
472825
−1
47690294-
47693797-
47693948-

47693796
47693947
47698103

MSH2
inclusion
483724
472839
−1
47693948-
47698104-
47698202-

47698103
47698201
47702163

MTM1
inclusion
158960
169974
−1
149765035-
149783062-
149783173-

149783061
149783172
149787510

MTM1
inclusion
158960
169974
−1
149767151-
149783062-
149783173-

149783061
149783172
149787510

MTM1
inclusion
158966
169981
−1
149765035-
149783062-
149783173-

149783061
149783172
149787510

MTM1
inclusion
158966
169981
−1
149767151-
149783062-
149783173-

149783061
149783172
149787510

MYBPC3
inclusion
454301
461685
−1
47365176-
47367758-
47367922-

47367757
47367921
47368177

MYO7A
inclusion
228280
231385
7.19E−06
76891528-
76892426-
76892636-

76892425
76892635
76892996

NF1
inclusion
480206
478059
−1
29486112-
29490204-
29490395-

29490203
29490394
29508439

NF1
inclusion
480206
478059
−1
29486112-
29490204-
29490395-

29490203
29490394
29496908

NF1
inclusion
428998
420767
−1
29509684-
29527440-
29527614-

29527439
29527613
29528054

NF1
inclusion
431976
426213
−1
29546137-
29548868-
29548948-

29548867
29548947
29550461

NF1
inclusion
220498
222614
−1
29626625-
29652838-
29653271-

29652837
29653270
29654516

NF1
inclusion
220498
222614
−1
29592358-
29652838-
29653271-

29652837
29653270
29654516

NF1
inclusion
220498
222614
−1
29645583-
29652838-
29653271-

29652837
29653270
29654516

NF1
inclusion
185354
184694
−1
29653271-
29654517-
29654858-

29654516
29654857
29657313

NIPBL
inclusion
446431
439877
−1
36971139-
36972047-
36972144-

36972046
36972143
36975877

NPHP1
inclusion
3510
18549
1.06E−05
110919275-
110920625-
110920713-

110920624
110920712
110922264

NPHP1
inclusion
3510
18549
1.06E−05
110919275-
110920625-
110920710-

110920624
110920709
110922096

NPHP1
inclusion
3510
18549
1.06E−05
110919275-
110920625-
110920710-

110920624
110920709
110922264

NPHP1
inclusion
3510
18549
1.06E−05
110919275-
110920625-
110922308-

110920624
110922307
110922628

NPHP1
inclusion
3510
18549
1.06E−05
110919275-
110920625-
110920713-

110920624
110920712
110922096

NR3C2
inclusion
8564
23603
−1
149116014-
149181130-
149181270-

149181129
149181269
149356255

NR3C2
inclusion
8564
23603
−1
149116014-
149181130-
149181270-

149181129
149181269
149289416

NSD1
inclusion
573155
560277
5.96E−05
176710930-
176715820-
176715927-

176715819
176715926
176718954

OCA2
inclusion
965
16004
1.19E−05
28231790-
28234747-
28234813-

28234746
28234812
28259921

OCA2
inclusion
965
16004
1.19E−05
28231790-
28234747-
28234813-

28234746
28234812
28235721

OFD1
inclusion
41060
49482
−1
13753203-
13753367-
13753466-

13753366
13753465
13754226

OFD1
inclusion
41060
49482
−1
13753203-
13753367-
13753466-

13753366
13753465
13754596

OFD1
inclusion
41061
49483
−1
13753203-
13753367-
13753466-

13753366
13753465
13754226

OFD1
inclusion
41061
49483
−1
13753203-
13753367-
13753466-

13753366
13753465
13754596

OFD1
inclusion
41116
49538
−1
13757034-
13757121-
13757152-

13757120
13757151
13758207

OFD1
inclusion
41120
49542
−1
13757034-
13757121-
13757152-

13757120
13757151
13762533

OFD1
inclusion
41120
49542
−1
13757034-
13757121-
13757152-

13757120
13757151
13758207

OGT
inclusion
428572
420006
−1
70757923-
70764417-
70764486-

70764416
70764485
70766060

OGT
inclusion
428572
420006
−1
70757923-
70764417-
70764486-

70764416
70764485
70767756

ORC6
inclusion
253273
247699
1.63E−04
46726458-
46727005-
46727095-

46727004
46727094
46729473

ORC6
inclusion
253273
247699
1.63E−04
46726458-
46727005-
46727095-

46727004
46727094
46728850

ORC6
inclusion
253273
247699
1.63E−04
46726458-
46727005-
46727095-

46727004
46727094
46729928

OTC
inclusion
97286
103178
−1
38260682-
38262871-
38262994-

38262870
38262993
38267994

OTC
inclusion
97301
103193
−1
38262994-
38267995-
38268049-

38267994
38268048
38268128

OTC
inclusion
97091
102983
−1
38268279-
38271115-
38271253-

38271114
38271252
38280275

OTOGL
inclusion
39780
48379
5.82E−06
80733045-
80735728-
80735943-

80735727
80735942
80746074

PAFAH1B1
inclusion
159550
169377
−1
2576052-
2577354-
2577583-

2577353
2577582
2579798

PAFAH1B1
inclusion
159550
169377
−1
2576052-
2577354-
2577583-

2577353
2577582
2583457

PAH
inclusion
102892
108628
3.98E−06
103240730-
103245465-
103245535-

103245464
103245534
103246592

PARN
inclusion
190291
178830
4.38E−05
14700384-
14702138-
14702177-

14702137
14702176
14702914

PARN
inclusion
190291
178830
4.38E−05
14698084-
14702138-
14702177-

14702137
14702176
14702914

PDCD10
inclusion
468332
452270
−1
167402178-
167405022-
167405105-

167405021
167405104
167405402

PIGN
inclusion
101048
106813
8.03E−05
59807713-
59810539-
59810580-

59810538
59810579
59813141

PIGN
inclusion
264636
259229
1.77E−05
59777207-
59780367-
59780550-

59780366
59780549
59781793

PMS2
inclusion
237932
240133
3.98E−06
6031689-
6035165-
6035265-

6035164
6035264
6036956

PMS2
inclusion
192316
190109
−1
6022623-
6026390-
6027252-

6026389
6027251
6029430

POLG
inclusion
587863
580246
3.98E−05
89862331-
89862459-
89862582-

89862458
89862581
89863996

POMGNT1
inclusion
3988
19027
3.98E−06
46655662-
46656145-
46656190-

46656144
46656189
46656391

PPT1
inclusion
56191
70830
−1
40555185-
40557001-
40557072-

40557000
40557071
40557716

PPT1
inclusion
56191
70830
−1
40555255-
40557001-
40557072-

40557000
40557071
40557716

PRMT7
inclusion
266022
260845
1.44E−05
68345003-
68349800-
68349978-

68349799
68349977
68355328

PRMT7
inclusion
266022
260845
1.44E−05
68345150-
68349800-
68349978-

68349799
68349977
68355328

PRMT7
inclusion
266022
260845
1.44E−05
68349553-
68349828-
68349978-

68349827
68349977
68355328

PRMT7
inclusion
266022
260845
1.44E−05
68345003-
68349800-
68349978-

68349799
68349977
68358585

PTEN
inclusion
280031
264490
4.02E−06
89693009-
89711875-
89712017-

89711874
89712016
89717609

PTEN
inclusion
427622
416983
−1
89693009-
89711875-
89712017-

89711874
89712016
89717609

RAD51B
inclusion
221910
223600
4.03E−06
68289048-
68290259-
68290345-

68290258
68290344
68292180

RAD51B
inclusion
221910
223600
4.03E−06
68286571-
68290259-
68290345-

68290258
68290344
68292180

RAD51C
inclusion
128201
133658
1.19E−05
56801462-
56809845-
56809906-

56809844
56809905
56811478

RAD51C
inclusion
128201
133658
1.19E−05
56798174-
56809845-
56809906-

56809844
56809905
56811478

RAD51C
inclusion
128201
133658
1.19E−05
56801462-
56809842-
56809906-

56809841
56809905
56811478

RB1
inclusion
428730
420512
−1
48881543-
48916735-
48916851-

48916734
48916850
48919215

RB1
inclusion
527935
528310
−1
49050659-
49050837-
49050980-

49050836
49050979
49051490

RB1
inclusion
527935
528310
−1
49047527-
49050837-
49050980-

49050836
49050979
49051490

RHAG
inclusion
13066
28105
3.99E−06
49573544-
49574561-
49574635-

49574560
49574634
49574862

RNF216
inclusion
183356
181427
−1
5692142-
5751392-
5751471-

5751391
5751470
5752345

RTTN
inclusion
219187
217210
7.18E−06
67692085-
67695960-
67696038-

67695959
67696037
67697247

SCN1A
inclusion
190009
187855
−1
166905460-
166908229-
166908499-

166908228
166908498
166909361

SLC10A7
inclusion
623252
612215
8.47E−06
147204418-
147214081-
147214133-

147214080
147214132
147215081

SLC12A1
inclusion
8752
23791
1.42E−05
48541874-
48543812-
48543968-

48543811
48543967
48548007

SLC4A11
inclusion
1311
16350
1.20E−05
3208503-
3208905-
3209075-

3208904
3209074
3209157

SMS
inclusion
11623
26662
−1
21990109-
21990625-
21990690-

21990624
21990689
21995178

SPAST
inclusion
468575
451183
0.00E+00
32323961-
32339707-
32339895-

32339706
32339894
32340770

SPAST
inclusion
468575
451183
0.00E+00
32314675-
32339707-
32339895-

32339706
32339894
32340770

SPG11
inclusion
41362
49786
7.98E−06
44855500-
44856745-
44856897-

44856744
44856896
44858051

SPTA1
inclusion
544819
535240
3.19E−05
158585194-
158587327-
158587379-

158587326
158587378
158587828

SPTA1
inclusion
12865
27904
−1
158622444-
158623064-
158623216-

158623063
158623215
158624400

SPTA1
inclusion
544822
535243
−1
158624539-
158626354-
158626447-

158626353
158626446
158627266

SPTB
inclusion
544811
535260
−1
65268119-
65268472-
65268553-

65268471
65268552
65268943

SRD5A2
inclusion
3341
18380
4.88E−05
31754528-
31756441-
31756543-

31756440
31756542
31758672

STXBP1
inclusion
520996
511787
−1
130434396-
130435460-
130435541-

130435459
130435540
130438082

SYNGAP1
inclusion
375528
362330
−1
33400030-
33400462-
33400584-

33400461
33400583
33402928

TGFBR2
inclusion
12504
27543
−1
30715739-
30729876-
30730004-

30729875
30730003
30732911

TJP2
inclusion
397505
384407
7.96E−06
71840324-
71840938-
71841092-

71840937
71841091
71842680

TMEM138
inclusion
31190
40147
−1
61133689-
61135395-
61135471-

61135394
61135470
61135723

TMEM138
inclusion
31190
40147
−1
61133689-
61135395-
61135471-

61135394
61135470
61136068

TMPRSS6
inclusion
30802
39759
1.59E−05
37467073-
37469572-
37469686-

37469571
37469685
37470649

TP53
inclusion
80709
91600
3.98E−06
7577609-
7578177-
7578290-

7578176
7578289
7578370

TP53
inclusion
428868
420639
−1
7574034-
7576853-
7576927-

7576852
7576926
7577018

TP53
inclusion
428868
420639
−1
7576658-
7576853-
7576927-

7576852
7576926
7577018

TP53
inclusion
428868
420639
−1
7576585-
7576853-
7576927-

7576852
7576926
7577018

TP53
inclusion
428868
420639
−1
7569563-
7576853-
7576927-

7576852
7576926
7577018

TPO
inclusion
4045
19084
3.18E−05
1488627-
1491593-
1491764-

1491592
1491763
1497573

TRAPPC2
inclusion
11512
26551
0.00E+00
13734798-
13737990-
13738102-

13737989
13738101
13752162

TRAPPC2
inclusion
11512
26551
0.00E+00
13734798-
13737990-
13738102-

13737989
13738101
13752643

TRAPPC2
inclusion
11512
26551
0.00E+00
13734798-
13737990-
13738102-

13737989
13738101
13738546

TRAPPC2
inclusion
11512
26551
0.00E+00
13734798-
13737990-
13738102-

13737989
13738101
13752168

TRIM37
inclusion
5246
20285
8.62E−06
57140010-
57141716-
57141767-

57141715
57141766
57148183

TYR
inclusion
99582
105471
3.99E−06
88911941-
88924370-
88924587-

88924369
88924586
88960990

TYR
inclusion
99582
105471
3.99E−06
88911941-
88924370-
88924587-

88924369
88924586
88933430

UROD
inclusion
72
15111
3.98E−06
45480509-
45480612-
45480679-

45480611
45480678
45481008

VMA21
inclusion
208798
205359
−1
150565530-
150572103-
150572213-

150572102
150572212
150573387

VMA21
inclusion
208799
205360
−1
150565530-
150572103-
150572213-

150572102
150572212
150573387

VMA21
inclusion
208806
205367
−1
150565120-
150572103-
150572213-

150572102
150572212
150573387

VMA21
inclusion
208806
205367
−1
150565530-
150572103-
150572213-

150572102
150572212
150573387

VMA21
inclusion
208720
205332
−1
150565120-
150572103-
150572213-

150572102
150572212
150573387

VMA21
inclusion
208720
205332
−1
150565530-
150572103-
150572213-

150572102
150572212
150573387

VPS13B
inclusion
68084
78975
−1
100147366-
100147824-
100147962-

100147823
100147961
100148892

WDR35
inclusion
617905
609306
−1
20151246-
20153595-
20153740-

20153594
20153739
20166484

WDR35
inclusion
617905
609306
−1
20151246-
20153595-
20153740-

20153594
20153739
20160314

WDR73
inclusion
208470
204991
4.01E−06
85191186-
85191768-
85191857-

85191767
85191856
85195944

XPC
inclusion
260
15299
−1
14208754-
14209757-
14209881-

14209756
14209880
14211937

BRCA1
exclusion
55387
70054
3.98E−06
41215391-
41215891-
41215969-

41215890
41215968
41234420

BRCA1
exclusion
55387
70054
3.98E−06
41215391-
41215891-
41215969-

41215890
41215968
41277198

BRCA1
exclusion
55419
70086
−1
41215391-
41215891-
41215969-

41215890
41215968
41234420

BRCA1
exclusion
55419
70086
−1
41215391-
41215891-
41215969-

41215890
41215968
41277198

BRIP1
exclusion
578521
571401
3.98E−06
59876661-
59878614-
59878836-

59878613
59878835
59885827

BRIP1
exclusion
491400
485084
−1
59876661-
59878614-
59878836-

59878613
59878835
59885827

CDAN1
exclusion
3182
18221
−1
43026545-
43027298-
43027377-

43027297
43027376
43027458

CLN3
exclusion
56290
70929
2.47E−05
28488957-
28493798-
28493867-

28493797
28493866
28493946

COL6A1
exclusion
17169
32208
3.99E−06
47418086-
47418312-
47418348-

47418311
47418347
47418810

COL7A1
exclusion
17437
32476
−1
48619947-
48620042-
48620087-

48620041
48620086
48620445

CTSK
exclusion
8424
23463
−1
150778493-
150778578-
150778701-

150778577
150778700
150779161

EBP
exclusion
158530
170113
−1
48380296-
48382311-
48382461-

48382310
48382460
48385376

ERCC6
exclusion
1700
16739
−1
50701299-
50708584-
50708743-

50708583
50708742
50713929

F8
exclusion
10303
25342
−1
154129718-
154130326-
154130443-

154130325
154130442
154132180

FBN1
exclusion
547347
538033
3.98E−06
48707965-
48712884-
48713004-

48712883
48713003
48713754

FBN1
exclusion
36119
44783
−1
48707965-
48712884-
48713004-

48712883
48713003
48713754

FIG4
exclusion
447336
440905
2.48E−05
110113868-
110117968-
110118055-

110117967
110118054
110146290

FLT3
exclusion
16271
31310
4.01E−06
28589839-
28592604-
28592727-

28592603
28592726
28597486

GLA
exclusion
10768
25807
4.53E−05
100653935-
100654732-
100654789-

100654731
100654788
100655653

HFE
exclusion
407073
395090
−1
26091333-
26092955-
26093189-

26092954
26093188
26093346

HFE
exclusion
407073
395090
−1
26091333-
26092913-
26093189-

26092912
26093188
26093346

LHCGR
exclusion
492757
485710
0.00E+00
48950836-
48952815-
48952890-

48952814
48952889
48958365

LHCGR
exclusion
492757
485710
0.00E+00
48950836-
48952815-
48952890-

48952814
48952889
48956291

MAPT
exclusion
14253
29292
2.62E−05
44074031-
44087676-
44087769-

44087675
44087768
44091608

MAPT
exclusion
98218
104110
5.64E−06
44074031-
44087676-
44087769-

44087675
44087768
44091608

MAPT
exclusion
14254
29293
−1
44074031-
44087676-
44087769-

44087675
44087768
44091608

OTC
exclusion
97139
103031
−1
38226683-
38229049-
38229094-

38229048
38229093
38240612

SCN5A
exclusion
448976
442549
−1
38662463-
38663891-
38663981-

38663890
38663980
3867180 1

SDCCAG8
exclusion
212141
206783
−1
243449700-
243456393-
243456522-

243456392
243456521
243468014

SDCCAG8
exclusion
212141
206783
−1
243449700-
243456393-
243456522-

243456392
243456521
243456700

SDHD
exclusion
6903
21942
−1
111957684-
111958581-
111958698-

111958580
111958697
111959590

SDHD
exclusion
6903
21942
−1
111957684-
111958581-
111958698-

111958580
111958697
111959590

SDHD
exclusion
6903
21942
−1
111957684-
111958581-
111958698-

111958580
111958697
111965528

SNX10
exclusion
139565
143196
2.39E−05
26386087-
26400595-
26400682-

26400594
26400681
26404154

SNX10
exclusion
139565
143196
2.39E−05
26396748-
26400595-
26400682-

26400594
26400681
26404154

SNX10
exclusion
139565
143196
2.39E−05
26393805-
26400595-
26400682-

26400594
26400681
2640415 4

STK11
exclusion
216070
213437
−1
1219413-
1220372-
1220717-

1220371
1220716
1221211

TCIRG1
exclusion
5462
20501
4.03E−05
67806587-
67808735-
67808814-

67808734
67808813
67809219

TECTA
exclusion
228404
230005
1.99E−05
121038927-
121039386-
121039635-

121039385
121039634
121058540

TFR2
exclusion
21379
34231
−1
100229569-
100229705-
100229822-

100229704
100229821
100230623

TP53
exclusion
428868
420639
−1
7574034-
7576525-
7576585-

7576524
7576584
7576852

Table 19 lists those ClinVar pathogenic mutations predicted to be rescued by Compound (I) treatment selected based on top populational allele frequencies in gnomAD v2.1.1, as described herein, that may be modulated by Compound (I) toward either or both exon inclusion and exon exclusion.

TABLE 19

ATM, BRCA1, CA5A, DGUOK, DNAH9, GLA,

GPX4, GYPA, HBB, IL36RN, KDSR, LIPA, MYO7A,

NPHP1, NSD1, ORC6, PARN, PIGN, POLG,

SLC12A1, SPTA1, SRD5A2, TCIRG1, and TPO.

One aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method, wherein the gene transcript is a predicted wildtype or mutant gene transcript in a cell comprising, a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

One aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method, wherein Compound (I) modulates the production of one or more mature RNA isoforms from a mutant gene transcript in a cell, wherein the method comprises, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

One aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a predicted wildtype or mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the predicted wildtype or mutant gene transcript includes a nucleotide sequence selected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, and wherein the predicted wildtype or mutant gene transcript is transcribed from a gene selected from Table 8.

One aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a wildtype gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the wildtype gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate the production of one or more mature RNA isoforms from a mutant gene transcript in a cell comprising, contacting the cell with Compound (I), wherein the mutant gene transcript comprises, three exons and two introns operably linked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence other than a sequence selected from the group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript is transcribed from a gene selected from Table 19.

Identification of Potential Therapeutic Targets of Compound (I)

About 20% of all CV-pMUTs were predicted to alter splicing within 50 nucleotides of the mutation, and that about 80% of these disrupt Ensembl-annotated (GRCh37 version 75) splice sites (FIG. 4A). The responsive genes (Gene) containing the top 20 most frequent mutations (gnomAD v2.1.1) (Mutation) are shown in Table 20. The human diseases associated with the Mutations are shown in Table 14.

Table 20 lists ClinVar pathogenic mutations (ClinVar) predicted by Splice AI (Prediction) to be rescued by either Gain or Loss after Compound (I) treatment, with corresponding isoform change (Response) were selected based on top populational allele frequencies in gnomAD (v2.1.1) (Frequency).

TABLE 20

ClinVar Pathogenic Mutations

SpliceAI

Gene
Mutation
Frequency
ClinVar
Prediction
Response

ATM
c.2250G > A
4.39E−05
Synonymous
Loss
Inclusion

CA5A
c.555G > A
1.67E−04
Synonymous
Loss
Inclusion

DGUOK
c.591G > A
1.27E−04
Intronic/
Loss
Inclusion

Synonymous

DNAH9
c.1970 +
3.18E−04
Intronic
Loss
Inclusion

4A > G

GLA
c.639 +
4.53E−05
Intronic
Gain
Exclusion

919G > A

GPX4
c.476 +
3.65E−05
Intronic
Loss
Inclusion

5G > A

GYPA
c.232G > A
3.60E−05
Missense
Loss
Inclusion

HBB
c.92G > A
1.03E−04
Missense
Loss
Inclusion

IL36RN
c.115 +
1.00E−03
Intronic
Loss
Inclusion

6T > C

KDSR
c.879G > A
6.37E−05
Synonymous
Loss
Inclusion

LIPA
c.894G > A
8.28E−04
Synonymous
Loss
Inclusion

MYO7A
c.2904G > A
3.20E−05
Synonymous
Loss
Inclusion

NPHP1
c.1027G > A
6.37E−05
Missense
Loss
Inclusion

NSD1
c.6152 −
5.96E−05
Intronic
Loss
Inclusion

5T > G

ORC6
c.449 +
1.63E−04
Intronic
Loss
Inclusion

5G > A

PARN
c.659 +
4.63E−05
Intronic
Loss
Inclusion

4_659 +

7delAGTA

PIGN
c.963G > A
8.31E−05
Synonymous
Loss
Inclusion

POLG
c.3104 +
3.98E−05
Intronic
Loss
Inclusion

3A > T

SLC12A1
c.1942G > A
6.37E−05
Missense
Loss
Inclusion

SRD5A2
c.547G > A
1.59E−04
Missense
Loss
Inclusion

Minigene Validation of the CNN Model

To validate whether the CNN model correctly predicted mutated exon triplet response to Compound (I) using the minigene system and RT-PCR, the following rules were used to select suitable exon triplets: 1) Exon triplet total length, including introns, was less than 1.5 kb and suitable for cloning, 2) Exon triplet splicing changes were detectable in fibroblast RNASeq against Compound (I), where the response classes could be used as quality checks of minigene expression; and 3) Wild-type exon triplet splicing of the minigene recapitulated the response observed in the fibroblast RNASeq before and after treatment with Compound (I), thus confirming the splicing process in the minigene was intact.

Minigene splicing assays for certain genes having exon triplets harboring mutations were used to confirm the predictive accuracy of the CNN model results. The genes were chosen based on their genomic triplet length which enabled them to be cloned into a splice vector. Minigenes for CPSF7, SETD5 and PARP6 were developed (as shown in FIGS. 3E-3G, respectively) with alternatively spliced triplets that the CNN model had predicted would respond in the presence of Compound (I). One nucleotide in the 5′ splice site (in adjacent nucleotides from the +2 to +6 position) was randomly mutated for each minigene, resulting in mutations in the +3 position (CPSF7 and PARP6) and the +6 position (SETD5), then the response to treatment in both wild-type and mutant constructs was predicted by the CNN model and subsequently confirmed by RT-PCR. For example, FIG. 3E illustrates that the mutated CPSF7 minigene was predicted to be affected by the presence of Compound (I) toward inclusion and subsequently confirmed by RT-PCR. FIG. 3F indicates that the mutated SETD5 minigene was predicted to be affected by the presence of Compound (I) toward exclusion, which was subsequently confirmed by RT-PCR. FIG. 3G shows that the mutated PARP6 gene isolated from patient cells was predicted to be affected by the presence of Compound (I) toward inclusion, which was also subsequently confirmed by RT-PCR.

Results of Minigene Validation of CNN Model

In one example from Table 18, the IL36RN gene harbors the mutation c.115+6T>C, which is 6 nucleotides downstream of exon 3 and was annotated as an intronic mutation in a patient with psoriasis (ClinVar ID: 40005). SpliceAI predicted that this mutation would cause skipping of Exon 3 and the CNN model predicted that the mutated sequence would be responsive to Compound (I) treatment, promoting exon 3 inclusion.

Similarly, in another example from Table 18, the c.894G>A mutation located at the last nucleotide of exon 8 in LIPA was annotated as a synonymous mutation (ClinVar ID: 203361), leading to deficient activity of lysosomal acid lipase (LAL)^56,57,59,60and characterized by the accumulation of harmful amounts of lipids in cells and tissues throughout the body. Mutations in LIPA are expressed in two major phenotypes: the severe infantile-onset Wolman disease and the milder late-onset cholesterol ester storage disease (CESD)^58-60. The severity of the condition depends on the residual LAL activity⁵⁷. The c.894G>A LIPA gene mutation is the most common mutation in the LIPA gene, found in about 50% of individuals with LAL deficiency⁵⁸. This mutation is responsible for the milder disease CESD and leads to skipping of exon 8. SpliceAI predicted the mutation would cause exon 8 skipping while the CNN model predicted the mutated sequence would be responsive to Compound (I) treatment, promoting exon 8 inclusion (see FIG. 4C). To confirm the prediction for LIPA, a cell line (Coriell Cell Repository) carrying the c.894G>A mutation in the LIPA gene was treated with Compound (I) (60 μM) for 24 hours. As predicted and shown in FIG. 4C, the WT sequence was unaffected, but Compound (I) promoted the inclusion of exon 8 for the mutated gene, with cells showing a significant 10% increase in normal transcript levels.

In another example from Table 18, the ClinVar and CNN model predictions related to the CFTR gene carrying a c.2988G>A mutation (see FIG. 4D) were confirmed by stably expressing a minigene containing the full length CFTR coding sequence carrying the c.2988G>A mutation and flanking introns (EMG-MUT)⁶³in HEK293 cells. The c.2988G>A mutation was reported to cause skipping of exon 18 in the CFTR gene and is associated with abnormal CFTR function and a mild form of Cystic Fibrosis⁶⁴. The CNN model predicted that CFTR exon skipping would be rescued by Compound (I) treatment (as shown in FIG. 4D)⁵⁹. Using RT-PCR, the minigene was confirmed to harbor the mutation (EMG-MUT), showing only 5% exon 18 inclusion. As shown in FIG. 4D, treatment with Compound (I) (60 μM) for 24 hours significantly increased exon inclusion in the EMG-MUT.

In another example from Table 18, a minigene encompassing MLH1 exons 16 to 18 and flanking exon 17 intronic sequences, with the c.1989 G>A mutation was prepared. This mutation was predicted by SpliceA1 to cause skipping of exon 17 in the MLH1 gene. The CNN model predicted that the skipping of this exon would be rescued by Compound (I) treatment. The c.1989 G>A mutation in MLH1 is associated with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (MIM #120435). Individuals with MLH1 mutations also have an increased risk of cancers of the endometrium, ovaries, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain^14-16,65. In order to validate the treatment effect on the splicing of exon 17, transfected cell lines were treated with Compound (I) (60 μM) for 24 hours. As shown in FIG. 4E, the treatment significantly promoted exon 17 inclusion.

In another example from Table 18, several MAPT minigenes encompassing exons 9 to 11 and flanking exon 10 intronic sequences, with the three mutations listed in Table 17: c.1866+3 G>A, c.1865 G>A or c.1788 T>G were prepared. These mutations were predicted by SpliceA1 to promote inclusion of MAPT exon 10. The CNN model predicted that Compound (I) would promote exon 10 exclusion. An increase in MAPT exon 10 inclusion is responsible for familial frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17, MIM #600274). Alternative splicing of MAPT exon 10 is tightly regulated and generates two tau isoforms with three (3R tau, exon 10 skipped) or four (4R tau, exon 10 included) microtubule-binding repeats, the latter having an increased affinity for microtubules. Exon 10 is expressed only in adult human brain and 3R and 4R tau isoforms are expressed in approximately equal amounts. Mutations affecting exon 10 splicing result in an up to 6-fold excess of 4R tau and in an elevated 4R/3R ratio^68-72. Elevated 4R/3R ratio leads to saturation of microtubule binding sites and increase of unbound 4R tau which assembles into filaments. The most common mutation in MAPT gene is the C to T substitution in intron 10, c.1866+16C>T, commonly referred to as IVS10+16. This mutation increases inclusion of exon 10. The MAPT c.1866+16C>T mutation was not initially identified by SpliceAI to affect splicing, but the CNN model for this mutation predicted the treatment effect of Compound (I) on exon 10 splicing to promote exon 10 exclusion. The MAPT minigene carrying the c.1866+16C>T mutation was used to validate the CNN Model prediction. The use of Compound (I) treatment to affect splicing of MAPT exon 10 was validated in transfected cell lines treated with Compound (I) (60 μM) for 24 hours. As shown in FIG. 4F, the treatment significantly promoted exon 10 exclusion for all three mutations tested.

ELP1 Gene Modulation Using Kinetin

Splicing alterations identified at three 5′ splice site junctions in triplets of consecutive exons in the Elongator complex Protein 1 gene (ELP1), having a 5′ splice site mutation resulting in Exon 20 exclusion, after treatment with kinetin, a small molecule 6-furfurylaminopurine splicing modulator compound, have demonstrated corrective splicing^44,46-50,93A Percent Spliced In (PSI) change of 0.57 was assessed by RNA sequencing for ELP1 exon 20 splicing after kinetin treatment^44,46-50,93. 42 additional exon-usage differences in response to kinetin were observed: 11 of the usage differences promoted inclusion of the middle exon and 31 usage differences induced skipping of the middle exon^44,46-50,93.

Kinetin is a naturally occurring small molecule splicing modulator compound with a safe absorption, distribution, metabolism, and excretion (ADME) profile; however, extremely high doses are necessary to achieve inclusion of Exon 20 in vivo^44,46-50,93. As described herein, in vitro and in vivo splicing assays in various cell lines, including patient cells, have identified Compound (I) as a potent and efficacious small molecule splicing modulator compound.

ELP1 Gene Modulation Using Compound (I)

Compound (I) was evaluated in vivo to determine whether splicing correction can lead to a concomitant increase in ELP1 protein. In brief, TgFD9 transgenic mice, which carry the human ELP1 gene with a Exon 20 splice mutation, were treated by oral gavage once daily for 7 days with Compound (I) as a suspension in 0.5% HPMC, 0.1% Tween 80 at a dose of 10, 30, 60 or 100 mg/kg. The mice used for this study were housed in an animal facility, provided with access to food and water ad libitum, and maintained on a 12-hour light/dark cycle. For routine genotyping, genomic DNA was prepared from tail biopsies and PCR was carried out to detect the TgFD9 transgene using the following primers—forward 5′-GCCATTGTACTGTTTGCGACT-3′; reverse, 5′-TGAGTGTCACGATTCTTTCTGC-3′. Mice were sacrificed 1 hour after the last dose.

Brain, liver, lung, kidney, heart and skin tissues were removed and snap frozen in liquid nitrogen. Tissues were homogenized in ice-cold QIAzol Lysis Reagent (Qiagen), using Qiagen TissueLyser II (Qiagen). Total RNA was extracted using the QIAzol reagent procedure. The yield, purity and quality of the total RNA for each sample were determined using a Nanodrop ND-1000 spectrophotometer. Full-length and mutant ELP1 mRNA expression was quantified by quantitative real-time PCR (qRT-PCR) analysis using CFX384 Touch Real-Time PCR Detection System (BioRad). Reverse transcription and qPCR were carried out using One Step RT-qPCR (BioRad). The mRNA levels of full-length ELP1, mutant Δ20 ELP1 and GAPDH were quantified using Taqman-based RT-qPCR with a cDNA equivalent of 25 ng of starting RNA in a 20-μl reaction. To amplify the full-length ELP1 isoform, FL ELP1 forward primer 5′-GAGCCCTGGTTTTAGCTCAG-3′; reverse primer 5′-CATGCATTCAAATGCCTCTTT-3′, and FL ELP1 probe 5′-TCGGAAGTGGTTGGACAAACTTATGTTT-3′ were used. To amplify the mutant (Δ20) ELP1 spliced isoforms, Δ20 ELP1 forward primer, 5′-CACAAAGCTTGTATTACAGACT-3′; reverse primer 5′-GAAGGTTTCCACATTTCCAAG -3′ and Δ20 ELP1 probe 5′-CTCAATCTGATTTATGATCATAACCCTAAGGTG-3′ were used. The ELP1 forward and reverse primers were each used at a final concentration of 0.4 μM. The ELP1 probes were used at a final concentration of 0.15 μM. Mouse GAPDH mRNA was amplified using 20× gene expression PCR assay (Life Technologies, Inc.). RT-qPCR was carried out at the following temperatures for indicated times: Step 1: 48° C. (15 min); Step 2: 95° C. (15 min); Step 3: 95° C. (15 sec); Step 4: 60° C. (1 min); Steps 3 and 4 were repeated for 39 cycles. The Ct values for each mRNA were converted to mRNA abundance using actual PCR efficiencies. ELP1 FL and Δ20 mRNAs were normalized to GAPDH and vehicle controls and plotted as fold change compared to vehicle treatment. Data were analyzed using SDS software.

Compound (I) In Vivo ELP1 Protein Quantification

Tissue samples were collected, snap frozen in liquid nitrogen, weighed, and homogenized on the TissueLyzer II (Qiagen) in RIPA buffer (Tris-HCl 50 mM, pH 7.4; NaCl 150 mM; NP-40 1%; sodium deoxycholate 0.5%; SDS 0.1%) containing a cocktail of protease inhibitors (Roche) at a tissue weight to RIPA buffer volume of 50 mg/mL. The samples were then centrifuged for 20 min at 14,000×g in a microcentrifuge. The homogenates were transferred to a 96-well plate and diluted in RIPA buffer to ˜1 mg/mL for ELP1-HTRF and ˜0.5 mg/mL for total protein measurement using the BCA protein assay (Pierce). Samples were run in duplicate and averaged. For the ELP1-HTRF assay, 35 μL of tissue homogenate were transferred to a 384-well plate containing 5 μL of the antibody solution (1:50 dilution of anti-ELP1 D2 and anti-ELP1 cryptate from Cisbio). The plate was incubated overnight at room temperature. Fluorescence was measured at 665 nm and 620 nm on an EnVision multilabel plate reader (Perkin Elmer). Total protein content was quantified in each tissue homogenate using the BCA assay. The total protein normalized change in ELP1 protein signal for Compound (I) and vehicle treated tissue sample was calculated as ratio of the signal in the presence of the test compound (e.g., Compound (I)) over the signal in the absence of the Compound (I) (vehicle control).

Treatment increased full-length ELP1 transcript in a dose-dependent manner and led to at least a two-fold increase in functional ELP1 protein in brain, liver, kidney, heart and skin (FIGS. 7A-7E). The treatment was found to be well tolerated with no weight loss or adverse effects observed in the treated groups. The level of splicing correction correlated with Compound (I) tissue distribution (FIGS. 7F-7G). These results demonstrated that treatment with Compound (I), which corrects splicing of the ELP1 transcript, significantly increased the level of functional protein in vivo in all tissues, including the brain (FIGS. 7A-7B).

Materials and Methods
HEL-293 Cell Culture

HEK-293T (ATCC) cells were cultured in Dulbecco's modified Eagle's medium (11995-065, D-MEM, Gibco) supplemented with 10% fetal bovine serum (FBS, 12306C, SIGMA) and 1% penicillin/streptomycin (30-009-CI, Corning).

Minigene Generation and Site Direct Mutagenesis

Wild-type and mutant double-stranded DNA (dsDNA) fragments, selected based on low nucleotide length and exon-skipping probability, were ordered through GENEWIZ (FragmentGENE). Adenosine was enzymatically attached to DNA fragment 3′ ends with Taq Polymerase in the presence of 200 nM dATP and 2 mM MgCl₂at 70° C. for 30 min. Fragments were ligated into linearized pcDNA™3.1/V5-His TOPO® TA plasmid (K480001 ThermoFisher Scientific) according to manufacturer's instructions. After colony selection and sequence confirmation, each plasmid was finally purified using MIDIprep kit (740410, NucleoBond® Xtra Midi, Takara, Mountain View, Calif.). Concentrations were determined using a nanodrop spectrometer.

Wild-Type and Mutant CFTR Minigene

HEK-293 cells stably transfected with the expression minigenes (EMGs) for the full-length coding sequence and flanking intron sequence of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) (courtesy of Dr. Garry R. Cutting, Johns Hopkins University school of Medicine, Baltimore, Md.) were cultured in D-MEM supplemented with 10% FBS (FBS), 1% penicillin/streptomycin and 0.1 mg/mL Hygromycin (SIGMA).

Wild-Type and Mutant ELP1 and LIPA Culture in Patient Cells

Patient human fibroblast cells GM04663 (Coriell Cell Repository) carrying the c.2204+6T>C mutation in ELP1 and patient human fibroblast cells GM03111 (Coriell Cell Repository) carrying the c.894G>A mutation in LIPA and human wild type fibroblasts (Coriell Cell Repository) were used for the RNA sequence and were cultured in D-MEM supplemented with 10% FBS and 1% penicillin/streptomycin.

HEK293 Transfection

HEK293T cells were seeded in 6-well culture plates at 1.20×10⁶cells/well in D-MEM, 10% FBS, without antibiotics and incubated overnight to reach approximately 90% confluence. Transfection was performed with FuGENE® HD Transfection Reagent (E2311, Promega) using the FuGENE-DNA ratio at 3.5:1 and following manufacturer protocol. After 4 hours of incubation at 37° C., cells were plated at a density of 3×10⁴cells/well in a poly-L-lysine coated 96-well plate for the dual luciferase minigene assay or at the density of 8.5×10⁵cells/well into 6-well plates for minigene transfection. After 16 hours incubation at 37° C., Compound (I) or DMSO was added at the desired concentrations as described in the next paragraph and kept in culture for other 24 hours.

Fibroblast Cell Lines

Six different human fibroblast cell lines from healthy individuals were obtained from Coriell Institute and cultured in D-MEM (Gibco) supplemented with 10% FBS and 1% penicillin/streptomycin. Cells were counted and plated in order to achieve semi-confluence after eight days. Twenty-four hours after plating, the medium was changed and cells were treated with Compound (I) or DMSO to a final concentration of 30 μM and 0.5%, respectively. DMSO was used as vehicle. The concentration of Compound (I) was chosen to induce splicing changes and ELP1 protein increase. After seven days of treatment, cells were collected, and RNA was extracted using the QIAzol Reagent following the manufacturer's instructions. RNASeq libraries were prepared using the strand-specific dUTP method^24,90,91.

The six different wildtype (WT) human fibroblast cell lines shown in Table 22 included three wildtype human fibroblast cell lines from three caucasian males (10, 12, and 32 years of age) and three caucasian females (3 month, 11, and 11 years of age).

TABLE 22

Wildtype (WT) Human Fibroblast Cell Lines

Coriell #
Genotype
Sex
Age
Race

AG16409
WT
Male
12 years
Caucasian

GM03348
WT
Male
10 years
Caucasian

GM08402
WT
Male
32 years
Caucasian

GM01652
WT
Female
11 years
Caucasian

GM02036
WT
Female
11 years
Caucasian

GM00041
WT
Female
3 months
Caucasian

RNA Isolation and RT-PCR Analysis

After treatment, the cells were collected and RNA was extracted with QIAzol Lysis Reagent (79306, Qiagen) following the manufacturer's instructions. The yields of the total RNA for each sample were determined using a Nanodrop ND-1000 spectrophotometer.

Reverse transcription was performed using 0.5-1 μg of total RNA, Random Primers (C1181, Promega), Oligo(dT)15 Primer (SEQ ID NO: 103) (C1101, Promega), and Superscript III reverse transcriptase (18080093, ThermoFisher Scientific) according to the manufacturer's protocol. cDNA was used to perform PCR reaction in a 20-25 μL volume, using GoTaq® green master mix (MT123, Promega). The primers and melting temperature (Tm) used were according to the manufacturer's protocol. To measure minigene splicing, forward and reverse primers were designed to include the TOPO/V5 plasmid vector and flanking exon sequence in order to avoid endogenous gene detection. PCR reaction was performed as follows: 32 cycles of (95° C. for 30 s, T_mfor 30 s, 72° C. for 30 s), products were resolved on a 1.5-3% agarose gel, depending on the dimension of the bands to be separated, and visualized using ethidium bromide staining.

Ratios between isoforms having the middle exon included or excluded were obtained using the integrated density value (IDV) for each correspondent band, and then assessed using Alpha 2000™ Image Analyzer and quantified by ImageJ software. The level of exon inclusion was calculated as previously described⁴, where the relative density value of the band represents inclusion and is expressed as a percentage. Validation of the semi-quantitative RT-PCR method for the measurement of exon inclusion was performed using RT-qPCR⁴.

RNA Sequencing

Briefly, RNA sample quality (based on RNA Integrity Number, or RIN) and quantity was determined using the Agilent 2200 TapeStation, with between 100-1000 ng of total RNA used for library preparation. Each RNA sample was spiked with 1 μL of diluted (1:100) External RNA Controls Consortium (ERCC) RNA Spike-In Mix (4456740, ThermoFisher Scientific), alternating between mix 1 and mix 2 for each well in the batch. Samples were then enriched for mRNA using polyA capture, followed by stranded reverse transcription and chemical shearing to make appropriate stranded cDNA inserts. Libraries were finished by adding Y-adapters, with sample specific barcodes, followed by between 10-15 rounds of PCR amplification. Libraries were evaluated for final concentration and size distribution by Agilent 2200 TapeStation and/or qPCR, using Library Quantification Kit (KK4854, Kapa Biosystems), and multiplexed by pooling equimolar amounts of each library prior to sequencing. Pooled libraries were 50 base pair paired-end sequenced on Illumina HiSeq 2500 across multiple lanes. Real time image analysis and base calling were performed on the HiSeq 2500 instrument using the HiSeq Sequencing Control Software (HCS) and FASTQ files demultipled using CASAVA software version 1.8. RNASeq reads were mapped to the human genome Ensembl GRCh37 by STAR v2.5.2a allowing 5% mismatch^24,90,91. The exon triplet index was built according to transcriptome Ensembl GRCh37 version 75. Reads spliced at each exon triplet splice junction were calculated by STAR on the fly.

Differential Splicing Analysis

For each exon triplet in a certain biological replicate, the ψ (Percent Splice In) value was calculated as (0.5*(R1+R2)/(0.5*(R1+R2)+R3). The average ψ was calculated for treated and untreated conditions, followed by calculation of ψ change. For a certain exon triplet in a certain biological replicate, a 2×2 table was created, where the four cells of the table represent number of reads supporting middle exon inclusion and skipping before and after treatment. Thus, for each exon triplet, a total of six 2×2 tables were created for each of the six biological replicates. A Cochran-Mantel-Haenszel test was applied to test whether an association between treatment and splicing across all replicates (namely whether the cross-replicate odds ratio is 1 or not) could be determined. For each exon triplet, a p value for the Cochran-Mantel-Haenszel test was reported. Benjamini-Hochberg false-discovery-rate (BH FDR) correction was finally applied top values of all triplets.

The primers and melting temperature (Tm) that were used for RNA Isolation and RT-PCR Analysis are shown in Table 20A AND 20B.

TABLE 20A

Forward Primers

SEQ

ID

Gene
Forward 5′-3′
NO
Tm

ELP1
CCTGAGCAGCAATCATGTG
111
58 C°

KLC1
CGCAGTGGTTCCTTTAGC
112
60 C°

LPIN1
GCTGTGATTTACCCTCAGTCAGC
113
64 C°

HSD17B4
GCAGAAAGAGGAGCGTTA
114
56 C°

SLC4A7
GCTACAGAGGACTGGACG
115
60 C°

LRRC28
GATATAGTGCTGCAGCGTGC
116
60 C°

AFMID
GCCTTTCTTCCTGTTCTTTCACG
117
60 C°

CD99P1
CGACCCAGCACCTCTTAATTC
118
62 C°

CRYZ
GCACTGCTGGTACTGAGGAAG
119
64 C°

IP6K2
AACAAGCCAAGGAGCCAAGA
120
62 C°

EVC
TGCCCTGAAGCTGATGAAGG
121
62 C°

EPB41L2
GGAGAAGTACCTGATGCCGAC
122
60 C°

CYLD
GATGGTTCTACACAGCCACC
123
62 C°

MEGF6
CTGGTTTGGAGAGGCCTGTG
124
60 C°

MYEF2
GTACCGTGGTGCGATGACTA
125
60 C°

ASXL1
GCCTCGAGTTGTCCTGACTC
126
60 C°

SPTAN1
CGATCGTCAGGGTTTTGTGC
127
60 C°

COPS8
CTGAGGGACAGTCTGGGGTT
128
60 C°

PDZD11
GTCAGTGAGCGGAGTCTGAG
129
60 C°

KTN1
AGGCAGAGATGGAACGATCT
130
60 C°

SPPL2A
TCATGGTTGAACTCGCAGCT
131
60 C°

LIPA
CCCAGAGTGCGTTTTTGAA
132
60 C°

CFTR
GCAGTGATTATCACCAGC
133
58 C°

PTEN
TTGCACAATATCCTTTTGAAGACCA
134
60 C°

CPSF7
ATTGCCCTTGACCCAGAGTT
135
60 C°

SETD5
TGTGGTGGAATTGCCCTTAC
136
60 C°

MLH1
GTGGAATTGCCCTTGAGC
137
60 C°

PARP6
GGAATTGCCCTTGATCATCT
138
60 C°

MAPT
ACCCAAGTCGCCGTCTTCCGCC
139
60 C°

TABLE 20B

Reverse Primers

SEQ

ID

Gene
Reverse 5′-3′
NO
Tm

ELP1
TACATGGTCTTCGTGACATC
140
58 C°

KLC1
CACTGCTGCTGCTGTCG
141
60 C°

LPIN1
CTTAGCAGCCTGCGGCAGC
142
64 C°

HSD17B4
GTTGGCCACTGCTTTTCC
143
56 C°

SLC4A7
CTAGAACTGGACCTGTGCTCC
144
60 C°

LRRC28
CAACTATGTTATTTGAGTGCAGG
145
60 C°

AFMID
GGTGAGCACGTTGTCCTTCT
146
60 C°

CD99P1
CGGTGGAATCAGGCTGCTTG
147
62 C°

CRYZ
CTTTGCCATGGTGTCTCGTGG
148
64 C°

IP6K2
ATTCAGGCCACACTTCCCTG
149
62 C°

EVC
GGTGCCAGCGTCTGCTTC
150
62 C°

EPB41L2
CTCACTCTCACTGCTGCTG
151
60 C°

CYLD
CTTCCCAGTAGGGTGAAGTGAC
152
62 C°

MEGF6
GGGACGGACTGCAACCTCA
153
60 C°

MYEF2
TCTGACAAATATCTGGTTGCCT
154
60 C°

ASXL1
TTCAGGCAGGAGGAAGAGGA
155
60 C°

SPTAN1
TTCTGGAGCACCTCAACCTG
156
60 C°

COPS8
ATGGAGCAAATATAAAGCTAGAAGC
157
60 C°

PDZD11
TGAGGAGGAATCCATGCTGG
158
60 C°

KTN1
TGCAAATCACCAGCTACCTTCT
159
60 C°

SPPL2A
TGAGGCACACACTCATTACTGA
160
60 C°

LIPA
CCCAGTCAAAGGCTTGAAAC
161
60 C°

CFTR
GGAGGAAATATGCTCTCAAC
162
58 C°

PTEN
TTAGCATCTTGTTCTGTTTGTGGA
163
60 C°

CPSF7
GAGCGAATAACCTGGATCAGC
164
60 C°

SETD5
GCAGAATTGCCCTTCTGATA
165
60 C°

MLH1
CACTGTGCTGGATATCTGCTG
166
60 C°

PARP6
AATTGCCCTTCTGCAGTTTG
167
60 C°

MAPT
CACCTTGCTCAGGTCAACTGGT
168
60 C°

In Vitro and In Vivo Compound (1) Treatment

Compound (I) (>9900 pure) was mixed in 100% DMSO to yield 40 mM stock solutions. Working solutions (10×) were prepared by dilution to 500 DMSO in phosphate-buffered saline (PBS, GIBCO). The final DMSO concentration in the treated or untreated cells was 0.5%. Kinetin was purchased from Sigma (K3253).

Cells to be treated with Compound (I) were seeded at the appropriate density in specific vessels to reach semiconfluency at the time of treatment. BEK293T cells transfected with minigenes were seeded in 6 wells and patient fibroblasts were seeded in 10 cm dishes using the described media. The following day, the media was changed with regular growth media supplemented with Compound (I) or DMSO working solutions to obtain final concentrations of 60 μM Compound (I) and 0.05% DMSO. The concentration of 60 μM for dosing Compound (I) was chosen to maximize the possible effect on splicing. Cells were collected for RNA extraction 24 hours after compound or DMSO addition.

Compound (I) ELP1 Dual-Luciferase Splicing Assay

The Rluc-FD-Fluc plasmid used for the dual-luciferase splicing assay was derived using the ELP1 FD minigene^44,45,93containing the ELP1 genomic sequence spanning exon 19-21 inserted into spcDNA3.1/V5-His Topo (Invitrogen). The firefly luciferase (FLuc) coding sequence was inserted immediately after exon 21 and Renilla luciferase (RLuc) upstream of exon 19. Characterization of the assay demonstrated that RLuc was expressed each time a transcript was generated from the reporter plasmid, while FLuc was only expressed when exon 20 was included in the transcript, thereby keeping FLuc in-frame. Evaluation of FLuc/RLuc expression provided the percent exon inclusion in the splicing assays. To perform the dual-luciferase assay, HEK-293T cells were transfected with the minigene plasmid and treated with Compound (I) for 24 hours as described above. After treatment, cells were washed once in PBS and lysed for 25 minutes at room temperature using 50 μL/well of passive lysis buffer (E1941, Promega). Luciferase activity was measured in each sample (20 μL) using the Dual-Luciferase® Reporter Assay reagents (Promega) and the GloMax® 96 Microplate Luminometer (Promega), following manufacturer's instruction, in a 96 well format⁴⁹. The integration time on the luminometer was set at 10-seconds. Compound (I) and kinetin were serially diluted in DMSO and PBS to generate concentration-response curves over eight concentrations, with each point run in quadruplicate. Cells cultured in the presence of 0.5% DMSO were used as controls and run in each plate in quadruplicate.

Minigene Protein Isolation and Western Blot Analysis

Protein extracts were obtained by homogenizing cells in RIPA buffer (Tris-HCl 50 mM, pH 7.4; NaCl 150 mM; NP-40 1%; sodiumdeoxycholate 0.5%; SDS 0.1%, 1 mM DTT) containing protease and phosphatase inhibitor cocktail (Roche). Insoluble debris were discarded after centrifugation and protein concentration was determined using Pierce® BCA Protein Assay Kit (Thermo Scientific). For LIPA WB, 30 μg of protein lysate was separated on NuPage 10% Bis-Tris gel (Invitrogen) and transferred into nitrocellulose membrane (Thermo Scientific). Membrane was blocked in Odyssey blocking buffer (Licor biosciences) for 1 h at room temperature and incubated overnight at 4° C. with a mouse monoclonal antibody against LIPA (Abnova clone 9G7F12, 1:200) and with a rabbit polyclonal antibody against actin (Sigma, 1:5000). Membranes were washed 3 times in PBS with 0.1% tween 20 and incubated with IRDye secondary antibodies (Licor biosciences) for 1 h at room temperature. Protein bands were visualized by Odyssey CLx imager (Licor biosciences).

Compound (I) Treatment in a LIPA Cell Model

Wolman disease and CESD are both caused by mutations in LIPA. Wolman is lethal in infancy, whereas CESD patients have some residual enzyme activity and therefore have a milder clinical course. Patients with only 3% of the normal level of LIPA transcript have the much milder disease CESD.

Patient fibroblasts carrying the major LIPA splicing mutation, c.894G>A were treated with 60 μM of Compound (I) for seven days (FIG. 8A). The treatment led to a 10% increase in functional LAL enzyme in mutated cells (FIG. 8B). Given that a 3% increase in residual LAL enzyme activity is enough to distinguish Wolman disease, which is lethal in infancy, from the much milder CESD, a 10% increase in functional LAL can be predicted to have clinical benefit, and Compound (I) increased exon 8 inclusion and lead to a 10% increase in functional protein in a patient cell line, suggesting high potential therapeutic efficacy.

CFTR Minigene Preparation

For CFTR WB, 40 μg of protein lysate was separated on 7.5% Criterion TGX protein gel (BioRad) and transferred to a PVDF membrane using a Trans-Blot Turbo Transfer System (BioRad). After blocking in 5% non-fat dry milk (BioRad), the membrane was probed with mouse monoclonal anti-CFTR antibody (1:5000 in PBST) that recognizes amino acids 1204-1211 (596, CFFT, North Carolina Chapel Hill). Rabbit monoclonal anti-Na+K+ ATPase (Abcam) (1:50,000 in PBST) was used as a loading control. Secondary antibodies were anti-mouse (1:150,000 GE Healthcare) and anti-rabbit (1:100,000 GE Healthcare), respectively. Blots were exposed on film using ECL Primer Western Blotting Detection Reagent (GE Healthcare)

Creation of 293-Flp-In and CFBE-Flp-In Stable Cell Lines

WT CFTR-EMG-i14-i18, CFTR-EMG-i14-i18 harboring c.2988G>A, Flp-In-CFBE, and Flp-In-293 cells stably expressing WT-EMG and c.2988G>A EMG were generated. Both Flpin-293 and Flp-In-CFBE cells lack endogenous CFTR expression (CFBE41o-) and contain a single Flp recombinase target site. Co-transfection of EMG plasmid with pOG44 (a plasmid encoding Flp recombinase) allowed for genomic integration at the FRT site. Hygromycin was used for stable cell selection.

CFTR Functional Assessment

Assessment of CFTR channel function and response to Compound (I) was performed in CFBEs stably expressing c.2988G>A. Briefly, CFBE stable cell lines were plated on snapwell filters. When transepithelial resistance reached ˜200Ω (˜ 5-7 days) as measured using Voltammeter (Physiologic Instruments), cells were treated with Compound (I) at varying doses (0.3 μM to 10 μM) for next 3 days. Filters were mounted in Ussing chambers (Physiological Instruments). A high chloride solution was added to the basolateral chamber and a low chloride solution was added to the apical chamber. After equilibration of currents, 10 μM forskolin (Selleckchem) was added to the basolateral side to activate CFTR channels via cAMP signaling. Currents were allowed to plateau, followed by acute addition of 10 μM ivacaftor at apical side for CFTR potentiation (Selleckchem). Inhibition of CFTR was performed using 10 μM Inh-172 (Selleckchem) added to the apical chamber. FIG. 9C shows a drop in short-current (ΔIsc), defined as the current inhibited by Inh-172 after sustained Isc responses were achieved upon stimulation with forskolin alone or sequentially with ivacaftor, was a quantifiable measurement assigned to CFTR channel function.

Validation of CFTR as a Therapeutic Target for Compound (I)

To evaluate the efficacy of Compound (I) to correct CFTR aberrant splicing caused by the c.2988G>A mutation (FIG. 9) in a Flp-In-293 stable cell line expressing c.2988G>A CFTR-EMG-i14-i18 were generated to contain full-length introns 14 and 16, and abridged introns 15, 17 and 18. The c.2988G>A variant is located in the last nucleotide position of exon 18 and results in a synonymous change (Gln996Gln) at the protein level. RT-PCR using CFTR specific primers revealed about 3% normal spliced transcript in the Flp-In-293 stable cells expressing 2988G>A (FIG. 9B). Treatment with Compound (I) at 60 μM for 5 days increased exon 18 inclusion by 10% (FIG. 9B) confirming the CNN model prediction. Further, the results suggested that an optimized form of the SMC can be beneficial for other forms of FTD caused by gain of function mutations in exon 10, such as P301L, P301S or the S305N, since treatment could reduce the level of mutated transcript.

Compound (I) Treatment in a CFTR Cell Model

CFTR protein levels was assessed in Flp-In-293 cells stably expressing the c.2988G>A splicing variant after treatment with Compound (I) for 5 days. FIG. 9A shows that the WT CFTR EMG_il4-i18 control cell line produced predominantly the higher molecular weight, complex-glycosylated mature protein (band C˜170 kDa) as well as some lower molecular weight, core-glycosylated immature protein (band B). Flp-In-293 c.2988G>A stable cells treated with DMSO produce ˜3% of WT complex-glycosylated mature CFTR protein while treatment with 60 μM of Compound (I) for 5 days increased the amount of mature CFTR protein to ˜20% of WT (FIG. 9B).

The ability of Compound (I) to rescue chloride channel function was also assessed. CF bronchial epithelial (CFBE) cell lines was generated to stably express the splicing mutation c.2988G>A. Cells were grown in monolayers on filters and treated with increasing doses of Compound (I) (0.3 μM-10 μM) or DMSO for 3 days. Chloride channel function was assessed by measuring short circuit current (I_sc) on treated CFBE cells. Forskolin was added to initiate CFTR channel activity via cAMP-mediated signaling, with further channel activation by Ivacaftor and inhibition with Inh-172, a CFTR-specific inhibitor (FIG. 9C, representative Isc tracing). CFTR-specific change in current (ΔI_sc±SD) allows for measurement of chloride channel function (FIG. 9C). Residual CFTR channel activity was observed in DMSO treated CFBE stable cells expressing c.2988G>A (ΔI_sc=12.3±2.7 μA/cm², FIG. 9C). Significant recovery of CFTR function (˜3 fold) was observed following treatment with Compound (I) at 1, 3, 6, and 10 μM for 3 days, with a maximal increase in CFTR function achieved using 3 μM of Compound (I) (ΔI_sc=37.168±4.32 μA/cm², FIG. 9C). Importantly, the acute addition of Ivacaftor resulted in ˜2 fold improvement in CFTR function in Compound (I) treated cells. These results showed that Compound (I) treatment alone increased chloride channel function to ˜20% of WT, and to ˜30% of WT in combination with Ivacaftor. Given that slight residual CFTR function can lead to a mild form of CF, the increase in chloride channel function to 20% of WT by treatment with Compound (I) can be a prediction of clinical significance and indicates that the splicing-targeted approach of the present disclosure is potentially efficacious.

Compound (I) Treatment in an ELP1 Minigene

Compound (I) corrected splicing of ELP1 in a minigene system. In vivo splicing correction of ELP1 in a humanized transgenic mouse model led to an increase of ELP1 protein in all tissues, including the brain (FIGS. 7A-7B).

Results

The results demonstrated herein indicate that the identification of splicing potential for a SMC can provide druggable targets, where even a small increase in functional protein may provide a dramatic therapeutic effect for a neurologic disease phenotype. To determine the potential of Compound (I) to correct splicing of other genes, the machine learning approach using sequence signatures to predict targetable splicing defects was developed as described. The resulting CNN Model identified 39 CNN Motifs important for drug response, with 2 sets of 12 and 13 CNN Motifs accounting for most of the Compound (I) sensitivity when the CNN Motif is located close to the 5′ splice site. Evaluation of splice site strength in drug responsive triplets where middle exon inclusion is increased showed that such exons generally have weaker 5′ splice sites.

The CNN Model predictions of the present disclosure (combined with the fact that kinetin and analog Compound (I) are shown herein to promote the recognition of ELP1 exon 20 through recruitment of U1 snRNP at the 5′ splice site) strongly suggesting that small molecule compounds can act by promoting, either directly or indirectly, the recognition of weakly defined exons.

Application of the CNN Model to all ClinVar pathogenic mutations that disrupt splicing, identified 214 human disease-causing mutations in 155 unique genes as potential therapeutic targets of Compound (I), proving that a deep learning model such as the CNN described herein provide a powerful approach to explore novel therapeutic targets for drugs that modify RNA splicing. As such, the treatment effect on splicing was validated for several disease-causing mutations using patient cell lines and minigenes, and demonstrated the potential therapeutic feasibility of targeting splicing in patients with cystic fibrosis (CFTR), cholesterol ester storage disease (LIPA), Lynch syndrome (MLH1) and familial frontotemporal dementia (MAPT), amongst others. These findings could have significant impact for patients carrying these mutations.

It will be appreciated that, although specific aspects have been described herein for purposes of illustration, the present description is not to be limited in scope by the specific illustrations and examples herein disclosed. These illustrations and examples are intended to merely represent several aspects of the invention. Any equivalent aspects of the illustrations and examples are also intended to be within the scope of the present description. Indeed, various modifications of the aspects of the illustrations and examples, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description, modification of which is intended to be within the scope.

All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

REFERENCES

1. Cooper, T. A., Wan, L. & Dreyfuss, G. RNA and disease. Cell 136, 777-793 (2009).

2. Ritchie, D. B., Schellenberg, M. J. & MacMillan, A. M. Spliceosome structure: piece by piece. Biochim. Biophys. Acta 1789, 624-633 (2009).

3. Monani, U. R., et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet. 8, 1177-1183 (1999).

4. Cuajungco, M. P., et al. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am. J. Hum. Genet. 72, 749-758 (2003).

5. Flanigan, K. M., et al. Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum. Mutat. 30, 1657-1666 (2009).

6. Juan-Mateu, J., et al. Interplay between DMD point mutations and splicing signals in Dystrophinopathy phenotypes. PLoS One 8, e59916 (2013).

7. Thornton, C. A. Myotonic dystrophy. Neurol. Clin. 32, 705-719, viii (2014).

8. Pros, E., et al. NF1 mutation rather than individual genetic variability is the main determinant of the NF1-transcriptional profile of mutations affecting splicing. Hum. Mutat. 27, 1104-1114 (2006).

9. Bottillo, I., et al. Functional analysis of splicing mutations in exon 7 of NF1 gene. BMC Med. Genet. 8, 4 (2007).

10. Tzetis, M., Efthymiadou, A., Doudounakis, S. & Kanavakis, E. Qualitative and quantitative analysis of mRNA associated with four putative splicing mutations (621+3A->G, 2751+2T->A, 296+1G->C, 1717-9T->C-D565G) and one nonsense mutation (E822X) in the CFTR gene. Hum. Genet. 109, 592-601 (2001).

11. Cabello, G. M., Cabello, E. J., Jr., Fernande, O. & Harris, A. The 3120+1G->A splicing mutation in CFTR is common in Brazilian cystic fibrosis patients. Hum. Biol. 73, 403-409 (2001).

12. Giorgi, G., et al. Validation of CFTR intronic variants identified during cystic fibrosis population screening by a minigene splicing assay. Clin. Chem. Lab. Med. 53, 1719-1723 (2015).

13. Goina, E., Fernandez-Alanis, E. & Pagani, F. Approaches to study CFTR pre-mRNA splicing defects. Methods Mol. Biol. 741, 155-169 (2011).

14. Rhine, C. L., et al. Hereditary cancer genes are highly susceptible to splicing mutations. PLoS Genet 14, e1007231 (2018).

15. Srebrow, A. & Kornblihtt, A. R. The connection between splicing and cancer. J. Cell Sci. 119, 2635-2641 (2006).

16. Skotheim, R. I. & Nees, M. Alternative splicing in cancer: noise, functional, or systematic? Int. J. Biochem. Cell Biol. 39, 1432-1449 (2007).

17. Dlamini, Z., Mokoena, F. & Hull, R. Abnormalities in alternative splicing in diabetes: therapeutic targets. J. Mol. Endocrinol. 59, R93-R107 (2017).

18. Juan-Mateu, J., Villate, O. & Eizirik, D. L. MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research. Eur. J. Endocrinol. 174, R225-238 (2016).

19. Bamshad, M. J., et al. The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions. Am. J. Med. Genet. A 158A, 1523-1525 (2012).

20. Sanders, S. J., et al. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron 87, 1215-1233 (2015).

21. Fresard, L., et al. Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nat. Med. 25, 911-919 (2019).

22. Landrum, M. J., et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42, D980-985 (2014).

23. Jaganathan, K., et al. Predicting Splicing from Primary Sequence with Deep Learning. Cell 176, 535-548 e524 (2019).

24. Johnson, N. T., Dhroso, A., Hughes, K. J. & Korkin, D. Biological classification with RNA-seq data: Can alternatively spliced transcript expression enhance machine learning classifiers? RNA 24, 1119-1132 (2018).

25. Paggi, J. M. & Bejerano, G. A sequence-based, deep learning model accurately predicts RNA splicing branchpoints. RNA 24, 1647-1658 (2018).

26. Wang, J. & Wang, L. Deep Learning of the Back-splicing Code for Circular RNA Formation. Bioinformatics (2019).

27. Palacino, J., et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat. Chem. Biol. 11, 511-517 (2015).

28. Hua, Y., et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24, 1634-1644 (2010).

29. Passini, M. A., et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci. Transl. Med. 3, 72ra18 (2011).

30. Aartsma-Rus, A. & van Ommen, G. J. Antisense-mediated exon skipping: a versatile tool with therapeutic and research applications. RNA 13, 1609-1624 (2007).

31. Dal Mas, A., Rogalska, M. E., Bussani, E. & Pagani, F. Improvement of SMN2 pre-mRNA processing mediated by exon-specific U1 small nuclear RNA. Am. J. Hum. Genet. 96, 93-103 (2015).

32. Havens, M. A., Duelli, D. M. & Hastings, M. L. Targeting RNA splicing for disease therapy. Wiley interdisciplinary reviews. RNA 4, 247-266 (2013).

33. Sinha, R., et al. Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. Nucleic Acids Res. 46, 4833-4844 (2018).

34. Vigevani, L. & Valcarcel, J. Molecular biology. A splicing magic bullet. Science 345, 624-625.

35. Naryshkin, N. A., et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345, 688-693.

36. Woll, M. G., et al. Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy. J. Med. Chem. 59, 6070-6085 (2016).

37. Ratni, H., et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J. Med. Chem. 61, 6501-6517 (2018).

38. Esteva, A., et al. A guide to deep learning in healthcare. Nat. Med. 25, 24-29 (2019).

39. Ozaki, K., et al. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nature genetics 32, 650-654 (2002).

40. Golub, T. R., et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531-537 (1999).

41. Kelley, D. R., Snoek, J. & Rinn, J. L. Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks. Genome Res. 26, 990-999 (2016).

42. Chiriboga, C. A., et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 86, 890-897 (2016).

43. Cheung, A. K., et al. Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). J. Med. Chem. 61, 11021-11036 (2018).

44. Slaugenhaupt, S. A., et al. Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum. Mol. Genet. 13, 429-436 (2004).

45. Yoshida, M., et al. Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia. Proc. Natl. Acad. Sci. U.S.A. 112, 2764-2769 (2015).

46. Hims, M. M., et al. Therapeutic potential and mechanism of kinetin as a treatment for the human splicing disease familial dysautonomia. J. Mol. Med. (Berl.) 85, 149-161 (2007).

47. Axelrod, F. B., et al. Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatr. Res. 70, 480-483 (2011).

48. Gold-von Simson, G., et al. Kinetin in familial dysautonomia carriers: implications for a new therapeutic strategy targeting mRNA splicing. Pediatr. Res. 65, 341-346 (2009).

49. Salani, M., et al. Development of a Screening Platform to Identify Small Molecules That Modify ELP1 Pre-mRNA Splicing in Familial Dysautonomia. SLAS Discov, 2472555218792264 (2018).

50. Morini, E., et al. ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia. Am. J. Hum. Genet. (2019).

51. Hims, M. M., et al. A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect. Genomics 90, 389-396 (2007).

52. Wang, E. T., et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470-476 (2008).

53. Sakuma, M., Iida, K. & Hagiwara, M. Deciphering targeting rules of splicing modulator compounds: case of TG003. BMC Mol. Biol. 16, 16 (2015).

54. Chiara, M. D., et al. Identification of proteins that interact with exon sequences, splice sites, and the branchpoint sequence during each stage of spliceosome assembly. Mol. Cell. Biol. 16, 3317-3326 (1996).

55. Yeo, G. & Burge, C. B. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J. Comput. Biol. 11, 377-394 (2004).

56. Bowden, K. L., et al. Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease. J. Biol. Chem. 286, 30624-30635 (2011).

57. Reiner, Z., et al. Lysosomal acid lipase deficiency—an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 235, 21-30 (2014).

58. Saito, S., Ohno, K., Suzuki, T. & Sakuraba, H. Structural bases of Wolman disease and cholesteryl ester storage disease. Mol. Genet. Metab. 105, 244-248 (2012).

59. Zhang, B. & Porto, A. F. Cholesteryl ester storage disease: protean presentations of lysosomal acid lipase deficiency. J. Pediatr. Gastroenterol. Nutr. 56, 682-685 (2013).

60. Aslanidis, C., et al. Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. Genomics 33, 85-93 (1996).

61. Scott, S. A., et al. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology 58, 958-965 (2013).

62. Sosnay, P. R., et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat. Genet. 45, 1160-1167 (2013).

63. Masvidal, L., et al. Assessing the residual CFTR gene expression in human nasal epithelium cells bearing CFTR splicing mutations causing cystic fibrosis. Eur. J. Hum. Genet. 22, 784-791 (2014).

64. Sharma, N., et al. Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions. Hum. Mutat. 35, 1249-1259 (2014).

65. Lee, M., et al. Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites. Am. J. Hum. Genet. 100, 751-765 (2017).

66. Sharma, N., et al. Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis. PLoS Genet 14, e1007723 (2018).

67. Pande, M., et al. Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry. Fam. Cancer 11, 441-447 (2012).

68. Hutton, M., et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702-705 (1998).

69. Spillantini, M. G., et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. U.S.A. 95, 7737-7741 (1998).

70. Hong, M., et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914-1917 (1998).

71. Connell, J. W., et al. Quantitative analysis of tau isoform transcripts in sporadic tauopathies. Brain Res. Mol. Brain Res. 137, 104-109 (2005).

72. Neumann, M., et al. A new family with frontotemporal dementia with intronic 10+3 splice site mutation in the tau gene: neuropathology and molecular effects. Neuropathol. Appl. Neurobiol. 31, 362-373 (2005).

73. McCague, A. F., et al. Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis. Am. J. Respir. Crit. Care Med. 199, 1116-1126 (2019).

74. Ramsey, B. W., et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365, 1663-1672 (2011).

75. Keating, D., et al. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N. Engl. J. Med. 379, 1612-1620 (2018).

76. Wainwright, C. E., et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N. Engl. J. Med. 373, 220-231 (2015).

77. Taylor-Cousar, J. L., et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N. Engl. J. Med. 377, 2013-2023 (2017).

78. Davies, J. C., et al. VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N. Engl. J. Med. 379, 1599-1611 (2018).

79. Heaney, D. L., Flume, P., Hamilton, L., Lyon, E. & Wolff, D. J. Detection of an apparent homozygous 3120G>A cystic fibrosis mutation on a routine carrier screen. J. Mol. Diagn. 8, 137-140 (2006).

80. Ibrahim, E. C., et al. Weak definition of IKBKAP exon 20 leads to aberrant splicing in familial dysautonomia. Hum. Mutat. 28, 41-53 (2007).

81. Mitchell, R. J., Farrington, S. M., Dunlop, M. G. & Campbell, H. Mismatch repair genes hMEH and hMSH2 and colorectal cancer: a HuGE review. Am. J. Epidemiol. 156, 885-902 (2002).

82. Gottschalk, L. B., et al. Creation and characterization of an airway epithelial cell line for stable expression of CFTR variants. J Cyst Fibros 15, 285-294 (2016).

83. Raraigh, K. S., et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet (2018).

84. Bailey, T. L. DREME: motif discovery in transcription factor ChIP-seq data. Bioinformatics 27, 1653-1659 (2011).

85. Collins, R. L., et al. A structural variation reference for medical and population genetics. Nature 581, 444-451 (2020).

86. Karczewski, K. J., et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434-443 (2020).

87. Dowty, J. G., et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum. Mutat. 34, 490-497 (2013).

88. Dachsel, J. C., et al. Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol. 113, 601-606 (2007).

89. Whitwell, J. L., et al. Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations. Neurology 73, 1058-1065 (2009).

90. Jiang, L., et al. Synthetic spike-in standards for RNA-seq experiments. Genome Res. 21, 1543-1551 (2011).

91. Dobin, A., et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15-21 (2013).

92. Yeo, G. & Burge, C. B. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J. Comput. Biol. 11, 377-394 (2004).

93. Morini, E., et al. ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia. Am J. Human Genetics. 104(4), 638-650 (April 2019).

94. CNN Model Source Code on GitHub: https://github.com/talkowski-lab/SMC_CNN_Model

RNA Splicing Modulation

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