Patent Application
20230227912
The contents of the electronic sequence listing (PCTIL2020051188-SQL Corrected_MIL-P-002-US_ST25.txt; Size: 96,635 bytes; and Date of Creation: Apr. 4, 2023) is herein incorporated by reference in its entirety. No new matter is added by this incorporation.
The present invention relates to compositions, methods and biomarkers for diagnostics, monitoring and therapy of various health and complex malignant and/or neurodegenerative disease conditions, utilizing the techniques of data mining, computational biology, artificial intelligence and molecular biology.
Aberrations such as chromosomal translocations, trans-splicing, fusions and gene variants are frequently found in human disorders. Chromosomal translocations may result in a chimeric gene expressing a fusion transcript which is then translated into a fusion protein that affects normal regulatory pathways. Cancer is one of the most prominent examples of such disorder. Liquid biopsy is a newly emerging technique for cancer diagnostics and being widely accepted because of its non-invasive approach and many advantages over biopsy-based diagnostics [1]. This technique uses circulating cell-free nucleic acid fragment, namely circulating cell-free DNA (cfDNA) fragments and/or circulating free RNA (cfRNA). CfDNA is free floating small fragments of nucleic acids/DNA in the blood plasma that are not associated with cells or cell fragments. CfDNA has been shown to be present in patients with various types of neoplasms and is not thought to be directly related to metastasis. This cfDNA may be analyzed for specific genetic markers of neoplasm with varying degrees of specificity and sensitivity. CfDNA that are released into the blood stream by the tumor tissue can be screened for the cancer specific mutations for diagnostics of cancers. Unlike biopsy-based diagnosis, liquid biopsy can be repeated multiple times, which gives a profile of real time mutations in tumor and, more importantly, represents tumor heterogeneity [2]. One of the main challenges in liquid biopsy is to detect rare mutation in cfDNA which is accompanied with large amount of wild type cfDNA fragments. Rate of mutation varies among different cancer types and cancer grades and, thus, its availability in blood cfDNA is directly correlated. These mutations can be missed during cfDNA isolation step or at the detection level, where it may not get sequenced on next generation sequencing platform or amplified on droplet PCR due to its rare availability. These detection errors can then lead to false negative diagnostics [3]. Matthew W., et. al. in 2016 showed that it is possible to identify tissues contributing to cell-free DNA by looking at their fragmentation patterns, instead of looking for specific mutations in the DNA [4]. Recent studies suggested that cfDNA analysis may be useful for diagnostics for additional health and complex-disease conditions, such as neurodegenerative disorders.
Current methods and systems for analyzing the genetic markers of humans and providing tailor-made therapeutic means are still very limited. Therefore, there is an urgent, unmet need in game-changing technologies based on data mining and computational biology which will enable generating a characterization of the condition and generating a therapy model configured to correct the condition, thus providing tailored and personalized treatment solutions.
The invention provides a novel powerful method for identifying, monitoring and treating a condition in a subject, wherein said condition is associated with omics-discoverable features.
In one embodiment, the invention provides method for identifying a condition in a subject, wherein said condition is characterized by omics-discoverable features; the method comprising:
The invention further provides a method for treating a condition in a subject, wherein said condition is characterized by omics-discoverable features, the method comprising:
The invention further provides therapeutic means for use in the treatment of a neurodegenerative disorder characterized by omics-discoverable features in a subject, wherein said therapeutic means are identified by applying a pre-computed treatment model designed to identify the therapeutic means suitable for treating said neurodegenerative disorder; and, wherein said identifying of the therapeutic means comprises the steps of:
The invention further provides therapeutic means for use in the treatment of a malignant disorder characterized by omics-discoverable features in a subject, wherein said therapeutic means are identified by applying a pre-computed treatment model designed to identify the therapeutic means suitable for treating said malignant disorder; and, wherein said identifying of the therapeutic means comprises the steps of:
The invention further provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:1-32.
The invention further provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:33-64.
The invention yet further provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:65-77.
The invention yet further provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:78-85.
The invention yet further provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO: 86-114.
The invention yet further provides an isolated nucleotide sequence selected from the group consisting of nucleotide sequences set forth as SEQ ID NO:1-114.
Exemplary non-limited embodiments of the disclosed subject matter will be described, with reference to the following description of the embodiments, in conjunction with the figures. The figures are generally not shown to scale and any sizes are only meant to be exemplary and not necessarily limiting, corresponding or like elements are optionally designated by the same numerals or letters.
The present invention is now described more fully hereinafter. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art.
In one embodiment of the invention, provided a method for identifying a condition in a subject, wherein said condition is characterized by omics-discoverable features; the method comprising:
In one embodiment, the method of the invention further includes a step of isolating circulating cell-free nucleic acids from the biological sample. In the context of the invention, the phrase “a method of identifying a condition” is meant to be understood, without limitation, as diagnostic means, namely a method for diagnosing, recognizing, detecting and monitoring various characteristics of a certain disease or a condition.
As used herein, the phrase “pre-computed sequence data” refers, without limitation, to a pre-computed set of nucleotide sequences found in databases or generated using some heuristic or combination as random sequences; or merged as parts of sequences to a set of novel sequences, including separated and merged exons, introns, genes, pseudogenes or any genomic sequences and/or chimeric RNA sequences or fusion genes sequences that cannot be mapped to human genome linearly; and genomic “integrations” of pathogens to human genome.
As used herein the term “omics” refers, without limitation to genomics, proteomics, metagenomics, methylomics, epigenomics, and metabolomics. As used herein the term “biological sample” refers, without limitation to any biological material collected from a subject. A non-limiting list of biological samples of the invention includes blood, serum, plasma, urine, saliva, amniotic fluid, feces, synovial fluid, peritoneal fluid, pleural fluid, lymphatic fluid, mucus, and cerebrospinal fluid (CSF), or any other body fluid or acceptable body tissue. In one embodiment, the biological sample is a liquid biological sample. In another embodiment, the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva and cerebrospinal fluid (CSF). As used herein, the term “circulating cell-free nucleic acids” refers, without limitation to degraded nucleic acid fragments released to the blood plasma or other body fluids. In one embodiment, the circulating cell-free nucleic acids are selected from the group consisting of circulating cell-free RNA, circulating cell-free DNA, circulating cell free nucleic acid complexes, and circulating cell-free microRNA. In another embodiment, the circulating cell-free nucleic acids is circulating cell-free DNA. As used herein, the term “sequence” refers, without limitation to oligonucleotide or polynucleotide. As used herein, the terms “nucleic acid”, “nucleic acid sequence”, “nucleotide”, “nucleic acid molecule” or “polynucleotide” are intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), natural occurring, mutated, synthetic DNA or RNA molecules, and analogs of the DNA or RNA generated using nucleotide analogs. It can be single-stranded or double-stranded. Such nucleic acids or polynucleotides include, but are not limited to, coding sequences of structural genes, anti-sense sequences, and non-coding regulatory sequences that do not encode mRNAs or protein products. These terms also encompass a gene. The term “gene”, “allele” or “gene sequence” is used broadly to refer to a DNA (deoxynucleic nucleic acids) associated with a biological function. Thus, genes may include introns and exons as in the genomic sequence or may comprise only a coding sequence as in cDNAs, and/or may include cDNAs in combination with regulatory sequences. Thus, according to the various aspects of the invention, genomic DNA, cDNA or coding DNA may be used.
As used herein, the term “neurodegenerative disorder” refers, without limitation to a range of conditions which primarily affect the neurons in the human brain and tend to worsen over time. In one embodiment, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, dementia, and Parkinson's disease. In one embodiment the neurodegenerative disorder is Alzheimer's disease.
As used herein, the term “malignant disorder” refers, without limitation to a condition in which abnormal cells divide without control and can invade nearby tissues. Malignant cells can also spread to other parts of the body through the blood and lymph systems. In the context of the invention, “malignant disorder” can be replaced by any of the following terms: cancer, neoplasm, tumor or any other acceptable term that relates to pathological conditions accompanied by abnormal cell growth. A non-limiting list of malignant disorders of the invention includes sarcoma, carcinoma, melanoma, glioma, glioblastoma, lymphoma, astrocytoma, Grade I—pilocytic astrocytoma, Grade II—Low-grade astrocytoma, Grade III—anaplastic astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, medulloblastoma, and meningioma and any other tumor type.
According to some embodiments, the sequence associated with said condition is a gene fusion. The term “gene fusion” refers to a chimeric genomic DNA resulting from the fusion of at least a portion of a first gene to a portion of a second gene. The point of transition between the sequences from the first gene in the fusion to the sequences from the second gene in the fusion is referred to as the “breakpoint” or “fusion point” and/or “chimeric junction site”. Transcription of the gene fusion results in a chimeric mRNA and/or chimeric RNA transcript. As used herein in, the term “chimeric RNA transcript” refers, without limitation, to single-stranded sequences of RNAs transcribed from various locations in the total genome corresponding to exons and/or introns from two different genes or non-linear combination of exons/introns of the same gene; two copies of the same gene; regions of pathogen genome, which fuse together to produce a single RNA transcript and/or a single cell free DNA molecule. Two unrelated genomic loci on different chromosomes may produce a chimeric transcript through a genomic rearrangement event or due to trans-splicing. Similarly, a read-through transcript of two adjacent genomic loci may produce chimeric RNAs. As used herein, the term “gene” refers, without limitation, to a polynucleotide (e.g., a DNA segment), that encodes a polypeptide and includes regions preceding and following the coding regions as well as intervening sequences (introns) between individual coding segments (exons).
According to some embodiments, the at least one sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO:1-32. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of sequences set forth as SEQ ID NO: 1-32.
According to some embodiments, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 33-64.
According to some embodiments, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 65-77.
According to some embodiments, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 78-85.
According to some embodiments, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 86-114.
As used herein, “sequence identity” or “identity” in the context of two nucleic acid sequences makes reference to the residues in the two sequences that are the same when aligned for maximum correspondence over a specified comparison window. The term further refers hereinafter to the amount of characters which match exactly between two different sequences. Hereby, gaps are not counted, and the measurement is relational to the shorter of the two sequences. It is further within the scope that the terms “similarity” and “identity” additionally refer to local homology, identifying domains that are homologous or similar (in nucleotide sequence). It is acknowledged that bioinformatics tools such as BLAST, SSEARCH, FASTA, and HMMER calculate local sequence alignments which identify the most similar region between two sequences. For domains that are found in different sequence contexts in different proteins, the alignment should be limited to the homologous domain, since the domain homology is providing the sequence similarity captured in the score. According to some aspects the term similarity or identity further includes a sequence motif, which is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance.
In the context of the invention, the phrase “omics-discoverable features” is meant to be understood as a characteristic that can be identified and/or recognized and/or measured by means of “omics” as defined above. In one embodiment, the omics-discoverable feature is selected from the group consisting of genomics-discoverable features, proteomics-discoverable features, metagenomics-discoverable features, methylomics-discoverable features, epigenomics-discoverable features, and metabolomics-discoverable features. The non-limiting list of omics-discoverable features of the invention include chimeras, chimeric RNAS, gene-gene fusions, sense-antisense (SAS) chimeras, genomic integrations, aberrations, inversions, and other genomic alterations.
According to some embodiments, the invention provides a method for treating a condition in a subject, wherein said condition is characterized by omics-discoverable features, the method comprising:
In one embodiment, the method further comprises the step of isolating circulating cell-free nucleic acids from the biological sample. As described herein, isolation of cell-free nucleic acids may be done by any suitable technique known in the art, commercially available or using in-house developed tools and proprietary technology. In one embodiment, the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, amniotic fluid, feces, synovial fluid, peritoneal fluid, tissue biopsy, pleural fluid, lymphatic fluid, mucus, and cerebrospinal fluid (CSF). In another embodiment, the biological sample is a liquid biological sample. In one embodiment, the circulating cell-free nucleic acids is selected from the group consisting of circulating cell-free RNA, circulating cell-free DNA, circulating cell free nucleic acid complexes, and circulating cell-free microRNA.
According to some embodiments, the condition associated with omics-discoverable features is a neurodegenerative disorder. In one embodiment, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, Prion disease, Motor neuron diseases (MND), Huntington's disease (HD), Spinocerebellar ataxia (SCA), and Spinal muscular atrophy (SMA).
According to some embodiments, the condition associated with omics-discoverable features is a malignant disorder. In one embodiment, the malignant disorder is selected from the group consisting of sarcoma, carcinoma, melanoma, glioma, glioblastoma, lymphoma, astrocytoma, Grade I—pilocytic astrocytoma, Grade II—Low-grade astrocytoma, Grade III—anaplastic astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, medulloblastoma, and meningioma and other tumor types.
According to some embodiments, in the method of the invention, the at least one sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO:1-32. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of sequences set forth as SEQ ID NO: 1-32.
According to some embodiments, in the method of the invention, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 33-64.
According to some embodiments, in the method of the invention, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 65-77.
According to some embodiments, in the method of the invention, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 78-85.
According to some embodiments, in the method of the invention, the sequence associated with the condition of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 86-114.
According to some embodiments, in the method of the invention, omics-discoverable features are selected from the group consisting of genomics-discoverable features, proteomics-discoverable features, metagenomics-discoverable features, methylomics-discoverable features, epigenomics-discoverable features, and metabolomics-discoverable features. In another embodiment, omics-discoverable features are selected from chimeras, chimeric RNAS, gene-gene fusions, sense-antisense (SAS) chimeras, Genomic integrations, aberrations, inversions, and other genomic alterations.
According to some embodiments, in the method of the invention, the therapeutic means are selected from the group consisting of an investigational drug, an approved drug, a food supplement, phototherapy, radiation therapy, surgical intervention, non-invasive image-guided procedure, multi-step treatment protocol, immune-therapy, biological treatment, or any combination thereof.
According to some embodiments, in the method of the invention, the subject is a human subject.
According to some embodiments, in the method of the invention, the subject is a non-human subject.
According to some embodiments the invention provides therapeutic means for use in the treatment of a malignant disorder characterized by omics-discoverable features in a subject, wherein said therapeutic means are identified by applying a pre-computed treatment model designed to identify the therapeutic means suitable for treating said autoimmune disease; and, wherein said identifying of the therapeutic means comprises the steps of:
In one embodiment, identifying of the therapeutic means comprises the step of isolating circulating cell-free nucleic acids from the biological sample.
In one embodiment, therapeutic means are selected from the group consisting of an investigational drug, an approved drug, a food supplement, phototherapy, radiation therapy, surgical intervention, non-invasive image-guided procedure, multi-step treatment protocol, immune-therapy or a combination thereof.
In one embodiment, the malignant disorder is selected from the group consisting of sarcoma, carcinoma, melanoma, glioma, glioblastoma, lymphoma, astrocytoma, Grade I—pilocytic astrocytoma, Grade II—Low-grade astrocytoma, Grade III—anaplastic astrocytoma, chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, medulloblastoma, and meningioma and any other tumor type.
According to some embodiments the invention provides therapeutic means for use in the treatment of a neurodegenerative disorder characterized by omics-discoverable features in a subject, wherein said therapeutic means are identified by applying a pre-computed treatment model designed to identify the therapeutic means suitable for treating said autoimmune disease; and, wherein said identifying of the therapeutic means comprises the steps of:
In one embodiment, identifying of the therapeutic means comprises the step of isolating circulating cell-free nucleic acids from the biological sample. In one embodiment, therapeutic means are selected from the group consisting of an investigational drug, an approved drug, a food supplement, phototherapy, radiation therapy, surgical intervention, non-invasive image-guided procedure, multi-step treatment protocol, or a combination thereof. In one embodiment, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, Prion disease, Motor neuron diseases (MND), Huntington's disease (HD), Spinocerebellar ataxia (SCA), and Spinal muscular atrophy (SMA).
In one embodiment, provided therapeutic means for use a medicament.
According to some embodiments, in the therapeutic means of the invention, the at least one sequence associated with the disorder of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO:1-32. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of sequences set forth as SEQ ID NO: 1-32.
According to some embodiments, in the therapeutic means of the invention, the at least one sequence associated with the disorder of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 33-64.
According to some embodiments, in the therapeutic means of the invention, the at least one sequence associated with the disorder of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 65-77.
According to some embodiments, in the therapeutic means of the invention, the at least one sequence associated with the disorder of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 78-85.
According to some embodiments, in the therapeutic means of the invention, the at least one sequence associated with the disorder of the invention is selected from the group consisting of sequences having at least 75% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In another embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the sequence associated with said condition is selected from the group consisting of sequences having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In one embodiment, the at least one sequence associated with the condition of the invention is selected from the group consisting of nucleotide sequences set forth as SEQ ID NO: 86-114.
According to some embodiments, in the therapeutic means of the invention, the subject is a human subject.
According to some embodiments, in the therapeutic means of the invention, the subject is a non-human subject.
According to some embodiments, the invention provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:1-32. In another embodiment, the invention provides an isolated nucleotide sequence having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the invention provides an isolated nucleotide sequence having 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32. In another embodiment, the invention provides an isolated nucleotide sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 1-32.
According to some embodiments, the invention provides an isolated nucleotide sequence selected from the group consisting of sequences set forth as SEQ ID NO: 1-32.
According to some embodiments, the invention provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:33-64. In another embodiment, the invention provides an isolated nucleotide sequence having 750-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In another embodiment, the invention provides an isolated nucleotide sequence having 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64. In another embodiment, the invention provides an isolated nucleotide sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 33-64.
According to some embodiments, the invention provides an isolated nucleotide sequence selected from the group consisting of sequences set forth as SEQ ID NO: 33-64.
According to some embodiments, the invention provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:65-77. In another embodiment, the invention provides an isolated nucleotide sequence having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In another embodiment, the invention provides an isolated nucleotide sequence having 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77. In another embodiment, the invention provides an isolated nucleotide sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 65-77.
According to some embodiments, the invention provides an isolated nucleotide sequence selected from the group consisting of sequences set forth as SEQ ID NO: 65-77.
According to some embodiments, the invention provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:78-85. In another embodiment, the invention provides an isolated nucleotide sequence having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In another embodiment, the invention provides an isolated nucleotide sequence having 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85. In another embodiment, the invention provides an isolated nucleotide sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 78-85.
According to some embodiments, the invention provides an isolated nucleotide sequence selected from the group consisting of sequences set forth as SEQ ID NO: 78-85.
According to some embodiments, the invention provides an isolated nucleotide sequence having at least 75% sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:86-114. In another embodiment, the invention provides an isolated nucleotide sequence having 75%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In another embodiment, the invention provides an isolated nucleotide sequence having 80%-98%, 85%-98%, 87%-98%, 90%-98%, and 95%-98% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114. In another embodiment, the invention provides an isolated nucleotide sequence having at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity to the nucleotide sequence set forth as SEQ ID NO: 86-114.
According to some embodiments, the invention provides an isolated nucleotide sequence selected from the group consisting of sequences set forth as SEQ ID NO: 86-114.
In one embodiment, the method of the invention utilizes the most comprehensive chimeric transcript repository, ChiTaRS 5.0 (http://chitars.md.biu.ac.il/), with 111,582 annotated entries from eight species. The repository includes unique information correlating chimeric breakpoints with 3D chromatin contact maps, generated from public datasets of chromosome conformation capture techniques (Hi-C). The repository comprises curated information on druggable fusion targets matched with chimeric breakpoints, which are applicable to precision medicine in cancers; as well as chimeric RNAs in various cell-lines and, novel chimeras in Alzheimer's disease, schizophrenia, dyslexia and other diseases. ChiTaRS stands out as a unique server that integrates EST and mRNA sequences, literature resources, with RNA-sequencing data, expression level and tissue specificity of chimeric transcripts in various tissues and organisms.
According to some embodiments, the method of cfDNA analysis is based on deep Illumina sequencing procedure as well as BGI sequencing and/or other deep sequencing procedures of cfDNA and/or circulating cell free RNA (cfRNA) extracted from patients' blood plasma (using dedicated Quiagen and/or other kits), followed by the efficient Bioinformatics analysis using in-house developed tool, method and apparatus.
As used herein, the term “therapeutic means” refers, without limitation, to the remedial agents or methods for the treatment of health-disease conditions or disorders. A non-limiting list of therapeutic means of the invention includes investigational drug, an approved drug, food supplement, phototherapy, radiation therapy, surgical intervention, hyperbaric oxygen, non-invasive image-guided procedures, multi-step treatment protocol, or any combination of the above. A non-limiting list of therapeutic means of the invention further includes probiotic-based therapeutic means, phage-based therapeutic means, small-molecule-based therapeutic means, prebiotic-based therapeutic means, clinical measures, mouth derived microbiome or any other clinically acceptable therapeutics. The therapeutic means of the invention can be, without limitation, newly discovered therapeutic means and/or known therapeutic means that are already in clinical use.
According to some embodiments, diagnostics associated with the condition can be assessed using one or more of: a behavioral survey instrument (e.g., a Patient Health Questionnaire-9 (PHQ-9) survey, a patient health questionnaire-2 (PHQ-2) survey, an instrument derived from an edition of the Diagnostic and Statistical Manual (DSM) of mental disorders, an instrument derived from the Social Communication Questionnaire (SCQ), a Clinical Global Impression (CGI) scale, a Brief Psychiatric Rating Scale, etc.); a motor skills based assessment, a blood cell analysis of a biological sample, imaging based method, stress testing, motion testing, biopsy, and any other standard method.
In the examples below, if an abbreviation is not defined above, it has its generally accepted meaning.
The chimeric RNAs are predicted using 10 Alzheimer's disease brain samples and 10 Alzheimer's disease cell free DNA samples vs. 10 normal brain controls and 10 normal blood samples. Using our method, we identified unique fusions found only in Alzheimer's disease samples.
Reference is now made to Table 1, listing fusion gene and chimeric transcripts predicted in neurodegenerative disease including Alzheimer's disease and dementia.
Glioblastoma cell line LN229, astrocytoma grade-IV cell line CCFSTTG1 and ovarian cancer cell line OVCAR3 were grown in-vitro. Nucleosomal bound DNA from the cell lines was obtained by the means of micro-coccal nuclease (MNase) digestion and cfDNA isolated from the culture media. Nucleosomal DNA fragments and media cfDNA were sequenced using the next generation sequencing platform and are screened for similar fragmentation pattern between the nucleosomal DNA and cfDNA obtained from the cells media of each cell line. The specificity of this fragmentation pattern is assessed by comparing the nucleosomal DNA and cfDNA of different cell lines.
Reference is now made to Table 2, listing unique hotspots on different human chromosomes that make profiling of the tissue origin using nucleosome positioning at these regions.
cfDNA is isolated and sequenced as previously described from biological samples of subjects afflicted with conditions associated with hypoxia. Reference is now made to Table 3, listing regions of the druggable mitochondrial fusions with human genome: that were observed in hypoxia conditions as a result of mitophagy, that is the selective degradation of mitochondria by autophagy processes. It often occurs to defective mitochondria following damage or stress or hypoxia of human cells.
CfDNA was isolated and sequenced as previously described from biological samples of cancer patients and normal controls. Reference is now made to Table 4 listing regions of the predicted druggable kinase genomic fusions.
25 cfDNA samples of cancer patients and 15 cfDNAs of healthy controls were analyzed. NGS analyses of cfDNA samples were produced to identify gene-gene fusions that found in cancer patients and absent in normal controls. Next, fusions that incorporate kinases and may be targeted by chemotherapy drugs using the prediction method (ChiPPI) were identified. All the druggable kinase fusions are summarized in Table 5.
cfDNA fragment size distribution was examined in 41 samples obtained from glioma (n=27) patients and healthy (n=14) individuals by performing High Sensitivity Bioanalyzer DNA 1000 assay. As demonstrated on
These results indicate that GBM patient's plasma cfDNA show multiple fragment sizes such as 166 bp, 332 bp, 498 bp and 2000 bp; and healthy persons detectable plasma cfDNA shows mostly 166 bp fragments and rarely 332 bp fragments. Therefore, estimation of plasma cfDNA size enrichment may help in glioma liquid biopsy for distinguishing GBM patient's plasma cfDNA from healthy individuals.
In this study, a high level of variable sizes cfDNA fragmentation (˜166 bp, ˜332 bp, and ˜498 bp) was observed in the GBM patients compared to healthy individuals, who had less cfDNA fragmentation.
Apoptotic fragmentation of cfDNA generates ˜166 bp, ˜332 hp, and ˜498 bp of reference DNA sizes. Amongst, ˜166 hp DNA is produced majorly, which is mononucleotide digestion equal to ˜147 bp of DNA wrapped around a nucleosome plus the stretch of DNA on Histone H1 linking two nucleosome cores. The longer fractions produced di-, tri-, or poly-nucleosomes nuclease action.
In three GBM patients, we observed the presence of 2000 bp DNA fragments along with the smaller fragments. The mechanism through which these fragments originate in the blood is still unknown. Less and consistent fragmentation of DNA in healthy controls and high and variable size fragmentation in the GBM patients underlines the use of studying fragmentation pattern as a marker in cancer screening and clinical outcome monitoring in the GBM patients was observed. Lastly, the observation of 8000 bp DNA fragments in two GBM patients represents DNA contamination. The plasma DNA fragments with size 8000 bp or more are typically referred to as the PBMCs genomic DNA contamination occurred during the plasma sample processing. PBMCs lysis occurred due to a lack of/insufficient preservation process, releases the large DNA fragments around 8000 bp in the sample. This genomic DNA contamination can be avoided by taking simple measures such as immediate processing of plasma after blood collection, in case of storage of blood sample, it can be stored for a maximum of 2 hours by keeping it on ice, and the separated plasma after centrifugation, if not used immediately, should be stored at −80° C. in the refrigerator.
Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
As used herein the terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.
The term “consisting of” means “including and limited to”.
As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
It will be understood that when an element is referred to as being “on,” “attached” to, “connected” to, “coupled” with, “contacting,” etc., another element, it can be directly on, attached to, connected to, coupled with and/or contacting the other element or intervening elements can also be present. In contrast, when an element is referred to as being, for example, “directly on,” “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature can have portions that overlap or underlie the adjacent feature.
It will be understood that, although the terms first, second, etc., may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. Rather, these terms are only used to distinguish one element, component, region, layer and/or section, from another element, component, region, layer and/or section.
Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
Certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
As used herein, the term “non-linear reads” refers to nucleotide sequences which do not map linearly to the target genome. A non-limiting list of non-linear reads of the invention includes genomic integrations; exon-exon combinations; exon-intron combinations and/or any other sequence parts merged together
As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
By “patient” or “subject” is meant to include any mammal. A “mammal,” as used herein, refers to any animal classified as a mammal, including but not limited to, humans, experimental animals including monkeys, rats, mice, and guinea pigs, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like.
“Treating” or “treatment” of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e., causing regression of the disease or its clinical symptoms, and/or monitoring the disease and early diagnostics of the disease.
Druggability, is a term used in drug discovery to describe a biological target such as a protein that is known to bind or is predicted to bind with high affinity to a drug. Furthermore, the binding of the drug to a druggable target alters the function of the target with a therapeutic benefit to the patient. The term “drug” herein includes small molecules (low molecular weight organic substances) but also has been extended to include biologic medical products such as therapeutic monoclonal antibodies. In at least one embodiment, the gene fusion or gene variant can be used to identify a druggable target.
Certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
This application is the U.S. national phase of PCT Application No. PCT/IL2020/051188 filed Nov. 17, 2020, which claims the benefit of U.S. provisional application Ser. No. 62/936,537 filed Nov. 17, 2019, the disclosures of which are hereby incorporated in their entirety by reference herein.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2020/051188 | 11/17/2020 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62936537 | Nov 2019 | US |
