Modulators of YAP1 expression

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0352USSEQ_ST25.txt created Jan. 31, 2020, which is 814 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

The present embodiments provide methods, compounds, and compositions useful for inhibiting YAP1 expression, which can be useful for treating, preventing, or ameliorating a cancer associated with YAP1.

BACKGROUND

Yes-associated protein (YAP1) is a transcriptional coactivator that is frequently activated in multiple human cancer types due to alterations in the tumor suppressive ‘Hippo’ pathway or its amplification. YAP1 is the downstream regulator of the Hippo pathway and promotes tumor growth through both tumor autonomous and immune-regulatory mechanisms. An active Hippo pathway is tumor suppresive and phosphorylates YAP1, resulting in its inactivation. When the Hippo pathway is inactive, YAP1 is dephosphorylated and translocated into the nucleus where it promotes expression of multiple genes.

SUMMARY

Certain embodiments provided herein are directed to potent and tolerable compounds and compositions useful for inhibiting YAP1 expression, which can be useful for treating, preventing, ameliorating, or slowing progression of cancer associated with YAP1.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank and NCBI reference sequence records are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

It is understood that the sequence set forth in each SEQ ID NO contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Compounds described by ION number indicate a combination of nucleobase sequence, chemical modification, and motif.

Unless otherwise indicated, the following terms have the following meanings:

“2′-deoxynucleoside” means a nucleoside comprising 2′-H(H) furanosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

“2′-O-methoxyethyl” (also 2′-MOE and 2′-O(CH₂)₂—OCH₃) refers to an O-methoxy-ethyl modification at the 2′ position of a furanosyl ring. A 2′-O-methoxyethyl modified sugar is a modified sugar.

“2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means a nucleoside comprising a 2′-MOE modified sugar moiety.

“2′-substituted nucleoside” or “2-modified nucleoside” means a nucleoside comprising a 2′-substituted or 2′-modified sugar moiety. As used herein, “2′-substituted” or “2-modified” in reference to a sugar moiety means a sugar moiety comprising at least one 2′-substituent group other than H or OH.

“3′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 3′-most nucleotide of a particular compound.

“5′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 5′-most nucleotide of a particular compound.

“5-methylcytosine” means a cytosine with a methyl group attached to the 5 position.

“About” means within ±10% of a value. For example, if it is stated, “the compounds affected about 70% inhibition of YAP1”, it is implied that YAP1 levels are inhibited within a range of 60% and 80%.

“Administration” or “administering” refers to routes of introducing a compound or composition provided herein to an individual to perform its intended function. An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

“Administered concomitantly” or “co-administration” means administration of two or more compounds in any manner in which the pharmacological effects of both are manifest in the patient. Concomitant administration does not require that both compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive. Concomitant administration or co-administration encompasses administration in parallel or sequentially.

“Amelioration” refers to an improvement or lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain embodiments, amelioration includes a delay or slowing in the progression or severity of one or more indicators of a condition or disease. The progression or severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art.

“Animal” refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

“Antibody,” as used in this disclosure, refers to an immunoglobulin or a fragment or a derivative thereof, and encompasses any polypeptide comprising an antigen-binding site, regardless of whether it is produced in vitro or in vivo. The term includes, but is not limited to, polyclonal, monoclonal, monospecific, polyspecific, non-specific, humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, and grafted antibodies. Unless otherwise modified by the term “intact,” as in “intact antibodies,” for the purposes of this disclosure, the term “antibody” also includes antibody fragments such as Fab, F(ab′)2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to bind, for example, CTLA-4 or PD-L1 specifically. Typically, such fragments would comprise an antigen-binding domain.

“Anti-CTLA-4 antibody” refers to an antibody or antigen binding fragment thereof that specifically binds a CTLA-4 polypeptide. Exemplary anti-CTLA-4 antibodies are described for example at U.S. Pat. Nos. 6,682,736; 7,109,003; 7,123,281; 7,411,057; 7,824,679; 8,143,379; 7,807,797; and 8,491,895 (Tremelimumab is 11.2.1, therein), which are herein incorporated by reference. Tremelimumab (U.S. Pat. No. 6,682,736) is an exemplary anti-CTLA-4 antibody. Tremelimumab VL, VH, and CDR amino acid sequences are provided at SEQ ID NOs: 1-8, herein.

“Anti-OX40 antibody” refers to an antibody or antigen binding fragment thereof that specifically binds OX40. OX40 antibodies include monoclonal and polyclonal antibodies that are specific for OX40 and antigen-binding fragments thereof. In certain aspects, anti-OX40 antibodies as described herein are monoclonal antibodies (or antigen-binding fragments thereof), e.g., murine, humanized, or fully human monoclonal antibodies. In one particular embodiment, the OX40 antibody is an OX40 receptor agonist, such as the mouse anti-human OX40 monoclonal antibody (9B12) described by Weinberg et al., J Immunother 29, 575-585 (2006). In another embodiment, an OX40 antibody is MEDI0562 as described in US 2016/0137740, incorporated herein by reference. MEDI0562 VH and VL amino acid sequences are provided at SEQ ID NOs: 25-26, herein. In other embodiments, the antibody which specifically binds to OX40, or an antigen-binding fragment thereof, binds to the same OX40 epitope as mAb 9B12.

“Anti-PD-L1 antibody” refers to an antibody or antigen binding fragment thereof that specifically binds a PD-L1 polypeptide. Exemplary anti-PD-L1 antibodies are described for example at US2013/0034559, U.S. Pat. Nos. 8,779,108 and 9,493,565 which are herein incorporated by reference. Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody. Durvalumab VL, VH, and CDR amino acid sequences are provided at SEQ ID NOs: 9-16, herein. Other anti-PD-L1 antibodies include BMS-936559 (Bristol-Myers Squibb) and MPDL3280A (atezolizumab) (Roche).

“Anti-PD-1 antibody” refers to an antibody or antigen binding fragment thereof that specifically binds a PD-1 polypeptide. Exemplary anti-PD-1 antibodies are described for example at U.S. Pat. Nos. 7,521,051; 8,008,449; 8,354,509; 9,073,994; 9,393,301; 9,402,899; and 9,439,962, which are herein incorporated by reference. Exemplary anti-PD-1 antibodies include, without limitation, nivolumab, pembrolizumab, pidilizumab, and AMP-514.

“Antigen-binding domain,” “antigen-binding fragment,” and “binding fragment” refer to a part of an antibody molecule that comprises amino acids responsible for the specific binding between the antibody and the antigen. In instances, where an antigen is large, the antigen-binding domain may only bind to a part of the antigen. A portion of the antigen molecule that is responsible for specific interactions with the antigen-binding domain is referred to as “epitope” or “antigenic determinant.” An antigen-binding domain typically comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH), however, it does not necessarily have to comprise both. For example, a so-called Fd antibody fragment consists only of a VH domain, but still retains some antigen-binding function of the intact antibody. Binding fragments of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab′, F(ab′)2, Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as “Fab” fragments, and a “Fc” fragment, having no antigen-binding activity but having the ability to crystallize. Digestion of antibodies with the enzyme, pepsin, results in the a F(ab′)2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites. The F(ab′)2 fragment has the ability to crosslink antigen. “Fv” when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. “Fab” when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CH1 domain of the heavy chain.

“mAb” refers to monoclonal antibody. Antibodies of the present disclosure comprise without limitation whole native antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab′, single chain V region fragments (scFv), fusion polypeptides, and unconventional antibodies.

“Antisense activity” means any detectable and/or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound to the target.

“Antisense compound” means a compound comprising an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, oligonucleotides, ribozymes, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

“Antisense inhibition” means reduction of target nucleic acid levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound.

“Antisense mechanisms” are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing.

“Antisense oligonucleotide” means an oligonucleotide having a nucleobase sequence that is complementary to a target nucleic acid or region or segment thereof. In certain embodiments, an antisense oligonucleotide is specifically hybridizable to a target nucleic acid or region or segment thereof.

“Bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety. “Bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

“Branching group” means a group of atoms having at least 3 positions that are capable of forming covalent linkages to at least 3 groups. In certain embodiments, a branching group provides a plurality of reactive sites for connecting tethered ligands to an oligonucleotide via a conjugate linker and/or a cleavable moiety.

“Cell-targeting moiety” means a conjugate group or portion of a conjugate group that is capable of binding to a particular cell type or particular cell types.

“cEt” or “constrained ethyl” means a bicyclic furanosyl sugar moiety comprising a bridge connecting the 4′-carbon and the 2′-carbon, wherein the bridge has the formula: 4′-CH(CH₃)—O-2′.

“cEt nucleoside” means a nucleoside comprising a cEt modified sugar moiety.

“Chemical modification” in a compound describes the substitutions or changes through chemical reaction, of any of the units in the compound relative to the original state of such unit. “Modified nucleoside” means a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase. “Modified oligonucleotide” means an oligonucleotide comprising at least one modified internucleoside linkage, a modified sugar, and/or a modified nucleobase.

“Chemically distinct region” refers to a region of a compound that is in some way chemically different than another region of the same compound. For example, a region having 2′-O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2′-O-methoxyethyl modifications.

“Chimeric antisense compounds” means antisense compounds that have at least 2 chemically distinct regions, each position having a plurality of subunits.

“Chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more sterorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

“Cleavable bond” means any chemical bond capable of being split. In certain embodiments, a cleavable bond is selected from among: an amide, a polyamide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, a di-sulfide, or a peptide.

“Cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

“Complementary” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Nucleobase matches or complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) and guanine (G) unless otherwise specified. Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches. By contrast, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

“Conjugate group” means a group of atoms that is attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

“Conjugate linker” means a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

“Conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

“Contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

“Designing” or “Designed to” refer to the process of designing a compound that specifically hybridizes with a selected nucleic acid molecule.

“Diluent” means an ingredient in a composition that lacks pharmacological activity, but is pharmaceutically necessary or desirable. For example, the diluent in an injected composition can be a liquid, e.g. saline solution.

“Differently modified” means chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified DNA nucleoside are “differently modified,” even though the DNA nucleoside is unmodified. Likewise, DNA and RNA are “differently modified,” even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified. For example, a nucleoside comprising a 2′-OMe modified sugar and an unmodified adenine nucleobase and a nucleoside comprising a 2′-OMe modified sugar and an unmodified thymine nucleobase are not differently modified.

“Dose” means a specified quantity of a compound or pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dose may require a volume not easily accommodated by a single injection. In such embodiments, two or more injections may be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reaction in an individual. In other embodiments, the compound or pharmaceutical agent is administered by infusion over an extended period of time or continuously. Doses may be stated as the amount of pharmaceutical agent per hour, day, week or month.

“Dosing regimen” is a combination of doses designed to achieve one or more desired effects.

“Double-stranded antisense compound” means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex, and wherein one of the two said oligomeric compounds comprises an oligonucleotide.

“Effective amount” means the amount of compound sufficient to effectuate a desired physiological outcome in an individual in need of the compound. The effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual's medical condition, and other relevant factors.

“Efficacy” means the ability to produce a desired effect.

“Expression” includes all the functions by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation.

“Gapmer” means an oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.”

“Hybridization” means the annealing of oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an oligonucleotide and a nucleic acid target.

“Immediately adjacent” means there are no intervening elements between the immediately adjacent elements of the same kind (e.g. no intervening nucleobases between the immediately adjacent nucleobases).

“Individual” means a human or non-human animal selected for treatment or therapy.

“Inhibiting the expression or activity” refers to a reduction or blockade of the expression or activity relative to the expression of activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.

“Internucleoside linkage” means a group or bond that forms a covalent linkage between adjacent nucleosides in an oligonucleotide. “Modified internucleoside linkage” means any internucleoside linkage other than a naturally occurring, phosphate internucleoside linkage. Non-phosphate linkages are referred to herein as modified internucleoside linkages.

“Lengthened oligonucleotides” are those that have one or more additional nucleosides relative to an oligonucleotide disclosed herein, e.g. a parent oligonucleotide.

“Linked nucleosides” means adjacent nucleosides linked together by an internucleoside linkage.

“Linker-nucleoside” means a nucleoside that links an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of a compound. Linker-nucleosides are not considered part of the oligonucleotide portion of a compound even if they are contiguous with the oligonucleotide.

“Mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned. For example, nucleobases including but not limited to a universal nucleobase, inosine, and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with respect to nucleobase to which it hybridized. As another example, a nucleobase of a first oligonucleotide that is not capable of hybridizing to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned is a mismatch or non-complementary nucleobase.

“Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating YAP1 RNA can mean to increase or decrease the level of YAP1 RNA and/or YAP1 protein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, a YAP1 compound can be a modulator that decreases the amount of YAP1 RNA and/or YAP1 protein in a cell, tissue, organ or organism.

“MOE” means methoxyethyl.

“Monomer” refers to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides.

“Motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

“Natural” or “naturally occurring” means found in nature.

“Non-bicyclic modified sugar” or “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

“Nucleic acid” refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

“Nucleobase” means a heterocyclic moiety capable of pairing with a base of another nucleic acid. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally occurring nucleobase that is chemically modified. A “universal base” or “universal nucleobase” is a nucleobase other than a naturally occurring nucleobase and modified nucleobase, and is capable of pairing with any nucleobase.

“Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.

“Nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

“Oligomeric compound” means a compound comprising a single oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group.

“Oligonucleotide” means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another. Unless otherwise indicated, oligonucleotides consist of 8-80 linked nucleosides. “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified. “Unmodified oligonucleotide” means an oligonucleotide that does not comprise any sugar, nucleobase, or internucleoside modification.

“Parent oligonucleotide” means an oligonucleotide whose sequence is used as the basis of design for more oligonucleotides of similar sequence but with different lengths, motifs, and/or chemistries. The newly designed oligonucleotides may have the same or overlapping sequence as the parent oligonucleotide.

“Parenteral administration” means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

“Pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an individual. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water-for-injection.

“Pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

“Pharmaceutical agent” means a compound that provides a therapeutic benefit when administered to an individual.

“Pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition may comprise one or more compounds or salt thereof and a sterile aqueous solution.

“Phosphorothioate linkage” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom. A phosphorothioate internucleoside linkage is a modified internucleoside linkage.

“Phosphorus moiety” means a group of atoms comprising a phosphorus atom. In certain embodiments, a phosphorus moiety comprises a mono-, di-, or tri-phosphate, or phosphorothioate.

“Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an oligomeric compound.

“Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time from minutes to indefinitely.

“Prodrug” means a compound in a form outside the body which, when administered to an individual, is metabolized to another form within the body or cells thereof. In certain embodiments, the metabolized form is the active, or more active, form of the compound (e.g., drug). Typically conversion of a prodrug within the body is facilitated by the action of an enzyme(s) (e.g., endogenous or viral enzyme) or chemical(s) present in cells or tissues, and/or by physiologic conditions.

“Reduce” means to bring down to a smaller extent, size, amount, or number.

“RefSeq No.” is a unique combination of letters and numbers assigned to a sequence to indicate the sequence is for a particular target transcript (e.g., target gene). Such sequence and information about the target gene (collectively, the gene record) can be found in a genetic sequence database. Genetic sequence databases include the NCBI Reference Sequence database, GenBank, the European Nucleotide Archive, and the DNA Data Bank of Japan (the latter three forming the International Nucleotide Sequence Database Collaboration or INSDC).

“Region” is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic.

“RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2, but not through RNase H, to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.

“Segments” are defined as smaller or sub-portions of regions within a nucleic acid.

“Side effects” means physiological disease and/or conditions attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality.

“Single-stranded” in reference to a compound means the compound has only one oligonucleotide. “Self-complementary” means an oligonucleotide that at least partially hybridizes to itself. A compound consisting of one oligonucleotide, wherein the oligonucleotide of the compound is self-complementary, is a single-stranded compound. A single-stranded compound may be capable of binding to a complementary compound to form a duplex.

“Sites” are defined as unique nucleobase positions within a target nucleic acid.

“Specifically hybridizable” refers to an oligonucleotide having a sufficient degree of complementarity between the oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids. In certain embodiments, specific hybridization occurs under physiological conditions.

“Specifically inhibit” with reference to a target nucleic acid means to reduce or block expression of the target nucleic acid while exhibiting fewer, minimal, or no effects on non-target nucleic acids. Reduction does not necessarily indicate a total elimination of the target nucleic acid's expression.

“Standard cell assay” means assay(s) described in the Examples and reasonable variations thereof

“Standard in vivo experiment” means the procedure(s) described in the Example(s) and reasonable variations thereof.

“Stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

“Sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. “Unmodified sugar moiety” or “unmodified sugar” means a 2′-OH(H) furanosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2′-H(H) moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and 4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′ position. “Modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate. “Modified furanosyl sugar moiety” means a furanosyl sugar comprising a non-hydrogen substituent in place of at least one hydrogen of an unmodified sugar moiety. In certain embodiments, a modified furanosyl sugar moiety is a 2′-substituted sugar moiety. Such modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars.

“Sugar surrogate” means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary compounds or nucleic acids.

“Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

“YAP1” means any nucleic acid or protein of YAP1. “YAP1 nucleic acid” means any nucleic acid encoding YAP1. For example, in certain embodiments, a YAP1 nucleic acid includes a DNA sequence encoding YAP1, an RNA sequence transcribed from DNA encoding YAP1 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding YAP1. “YAP1 mRNA” means an mRNA encoding a YAP1 protein. The target may be referred to in either upper or lower case.

“YAP1 specific inhibitor” refers to any agent capable of specifically inhibiting YAP1 RNA and/or YAP1 protein expression or activity at the molecular level. For example, YAP1 specific inhibitors include nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of YAP1 RNA and/or YAP1 protein.

“Target gene” refers to a gene encoding a target.

“Targeting” means the specific hybridization of a compound to a target nucleic acid in order to induce a desired effect.

“Target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” all mean a nucleic acid capable of being targeted by compounds described herein.

“Target region” means a portion of a target nucleic acid to which one or more compounds is targeted.

“Target segment” means the sequence of nucleotides of a target nucleic acid to which a compound is targeted. “5′ target site” refers to the 5′-most nucleotide of a target segment. “3′ target site” refers to the 3′-most nucleotide of a target segment.

“Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

“Therapeutically effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual.

“Treat” refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal.

Certain Embodiments

Certain embodiments provide methods, compounds and compositions for inhibiting YAP1 expression.

Certain embodiments provide compounds targeted to a YAP1 nucleic acid. In certain embodiments, the YAP1 nucleic acid has the sequence set forth in RefSeq or GENBANK Accession No. NM_001282101.1 (SEQ ID NO: 1) or NC_000011.10 truncated from nucleotides 102107001 to 102236000 (SEQ ID NO: 2), each of which is incorporated by reference in its entirety. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 9 to 80 linked nucleosides and having a nucleobase sequence comprising at least 9 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 80 linked nucleosides and having a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 11 to 80 linked nucleosides and having a nucleobase sequence comprising at least 11 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 11 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 12 to 80 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 12 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound is an antisense compound or oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleotides 2565-2580, 2566-2581, or 4600-4615 of SEQ ID NO: 1. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion complementary to an equal length portion within nucleotides 123590-123605, 117330-117345, 117761-117776, 117757-117772, 117758-117773, 117330-117345, 119672-119687, 123591-123606, 125625-125640, or 117755-117770 of SEQ ID NO: 2. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is complementary within nucleotides 2565-2580, 2566-2581, or 4600-4615 of SEQ ID NO: 1. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is complementary within nucleotides 123590-123605, 117330-117345, 117761-117776, 117757-117772, 117758-117773, 117330-117345, 119672-119687, 123591-123606, 125625-125640, or 117755-117770 of SEQ ID NO: 2. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion of any one of the nucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the modified oligonucleotide consists of 10 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 16 linked nucleosides and having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

In certain embodiments, a compound targeted to YAP1 is ION 1198440. Out of over 3,000 compounds that were screened as described in the Examples section below, ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872 emerged as the top lead compounds. In particular, ION 1198440 exhibited the best combination of properties in terms of potency and tolerability out of over 3,000 compounds.

In certain embodiments, any of the foregoing modified oligonucleotides has at least one modified internucleoside linkage, at least one modified sugar, and/or at least one modified nucleobase.

In certain embodiments, at least one nucleoside of any of the foregoing modified oligonucleotides comprises a modified sugar. In certain embodiments, the modified sugar comprises a 2′-O-methoxyethyl group. In certain embodiments, the modified sugar is a bicyclic sugar, such as a 4′-CH(CH₃)—O-2′ group, a 4′-CH₂—O-2′ group, or a 4′-(CH₂)₂—O-2′group.

In certain embodiments, at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage, such as a phosphorothioate internucleoside linkage.

In certain embodiments, at least one nucleobase of the foregoing modified oligonucleotides is a modified nucleobase, such as 5-methylcytosine.

In certain embodiments, any of the foregoing modified oligonucleotides has:

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 16 to 80 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides and has a nucleobase sequence consisting of the nucleobase sequence recited in any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863, wherein the modified oligonucleotide has:

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 810 and 1404, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of each wing segment comprises a cEt nucleoside; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in SEQ ID NO: 2868, wherein the modified oligonucleotide has a gapmer consisting of a 5′-region, a 3′-region, and a central region positioned between the 5′-region and the 3′-region wherein:

the 5′-region consists of 3 linked modified nucleosides, wherein each nucleoside of the 5′-region comprises a cEt nucleoside;

the 3′-region consists of 3 linked modified nucleosides, wherein each nucleoside of the 3′-region comprises a cEt nucleoside;

the central region consists of 10 linked nucleosides, wherein the second nucleoside from the 5′ end of the central region comprises a 2′-O-methyl modified sugar moiety and the first and third through tenth nucleosides from the 5′ end of the central region each comprises a 2′deoxynucleoside;

wherein each internucleoside linkage is a phosphorothioate linkage; and

wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence recited in SEQ ID NO: 2868; wherein the modified oligonucleotide comprises the sugar motif kkk-d-y-d(8)-kkk, wherein “k” indicates a cEt modified sugar moiety, “d” indicates an unmodified 2′-deoxyribosyl sugar moiety, and “y” indicates a 2′-O-methyl modified sugar moiety; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of ION 1197270 having the nucleobase sequence and chemical motif: TksTksAksAdsAysGdsTdsGdsTdsAdsTdsGdsTdsmCksAksGk, wherein “d” represents a 2′-deoxyribose sugar, “k” represents a cEt modified sugar, “y” represents a 2′-O-methyl sugar, “s” represents a phosphorothioate internucleoside linkage, and “mC” refers to a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the 5′ wing segment comprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a cEt nucleoside, a cEt nucleoside, and a 2′-O-methoxyethyl nucleoside in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the 5′ wing segment comprises a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein the 3′ wing segment comprises a 2′-O-methoxyethyl nucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

Certain embodiments provide a modified oligonucleotide, wherein the anion form of the modified oligonucleotide has the following chemical structure:

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or a salt thereof.

Certain embodiments provide a modified oligonucleotide according to the following chemical structure:

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or a salt thereof.

Certain embodiments provide a modified oligonucleotide according to the following chemical structure:

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Under certain conditions, certain compounds disclosed herein act as acids. Although such compounds may be drawn or described in protonated (free acid) form, or ionized and in association with a cation (salt) form, aqueous solutions of such compounds exist in equilibrium among such forms. For example, a phosphate linkage of an oligonucleotide in aqueous solution exists in equilibrium among free acid, anion and salt forms. Unless otherwise indicated, compounds described herein are intended to include all such forms. Moreover, certain oligonucleotides have several such linkages, each of which is in equilibrium. Thus, oligonucleotides in solution exist in an ensemble of forms at multiple positions all at equilibrium. Unless otherwise indicated, an oligonucleotide described herein and the term “oligonucleotide” are intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of a compound followed by the term “or a salt thereof” expressly includes all such forms that may be fully or partially protonated/de-protonated/in association with a cation. In certain instances, one or more specific cation is identified.

In any of the foregoing embodiments, the compound or oligonucleotide can be at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% complementary to a nucleic acid encoding YAP1.

In any of the foregoing embodiments, the compound can be single-stranded. In certain embodiments, the compound comprises deoxyribonucleotides. In certain embodiments, the compound is double-stranded. In certain embodiments, the compound is double-stranded and comprises ribonucleotides. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In any of the foregoing embodiments, the compound can consist of 8 to 80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked nucleosides. In certain embodiments, the compound comprises or consists of an oligonucleotide.

In certain embodiments, compounds or compositions provided herein comprise a salt of the modified oligonucleotide. In certain embodiments, the salt is a sodium salt. In certain embodiments, the salt is a potassium salt.

In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having at least one of an increase an alanine transaminase (ALT) or aspartate transaminase (AST) value of no more than 4 fold, 3 fold, or 2 fold over saline treated animals or an increase in liver, spleen, or kidney weight of no more than 30%, 20%, 15%, 12%, 10%, 5%, or 2% compared to control treated animals. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase of ALT or AST over control treated animals. In certain embodiments, the compounds or compositions as described herein are highly tolerable as demonstrated by having no increase in liver, spleen, or kidney weight over control animals.

Certain embodiments provide a composition comprising the compound of any of the aforementioned embodiments or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. In certain embodiments, the composition has a viscosity less than about 40 centipoise (cP), less than about 30 centipose (cP), less than about 20 centipose (cP), less than about 15 centipose (cP), or less than about 10 centipose (cP). In certain embodiments, the composition having any of the aforementioned viscosities comprises a compound provided herein at a concentration of about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, or about 300 mg/mL. In certain embodiments, the composition having any of the aforementioned viscosities and/or compound concentrations has a temperature of room temperature or about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C.

Non-limiting numbered embodiments include:

E1. A compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940.

E2. A compound comprising a modified oligonucleotide 9 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 9 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940.

E3. A compound comprising a modified oligonucleotide 10 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940.

E4. A compound comprising a modified oligonucleotide 11 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 11 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940.

E5. A compound comprising a modified oligonucleotide 12 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940.

E6. A compound comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940.

E7. A compound comprising a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940.

E8. A compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides complementary within nucleotides 2565-2580, 2566-2581, or 4600-4615 of SEQ ID NO: 1 or within nucleotides 123590-123605, 117330-117345, 117761-117776, 117757-117772, 117758-117773, 117330-117345, 119672-119687, 123591-123606, 125625-125640, or 117755-117770 of SEQ ID NO: 2.

E9. A compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E10. A compound comprising a modified oligonucleotide 9 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 9 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E11. A compound comprising a modified oligonucleotide 10 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E12. A compound comprising a modified oligonucleotide 11 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 11 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E13. A compound comprising a modified oligonucleotide 12 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E14. A compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides having a nucleobase sequence comprising any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E15. A compound comprising a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E16. A compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides having a nucleobase sequence comprising any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E17. A compound comprising a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863.

E18. The compound of any one of embodiments E1-E17, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.

E19. The compound of embodiment E18, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

E20. The compound of embodiment E18 or E19, wherein the modified sugar is a bicyclic sugar.

E21. The compound of embodiment E20, wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH₂)—O-2′ (LNA); 4′-(CH₂)₂—O-2′ (ENA); and 4′-CH(CH₃)—O-2′ (cEt).

E22. The compound of embodiment E18 or E19, wherein the modified sugar is 2′-O-methoxyethyl.

E23. The compound of any one of embodiments E18-E22, wherein the modified nucleobase is a 5-methylcytosine.

E24. The compound of any one of embodiments E1-E23, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked 2′-deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

E25. A compound comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides having a nucleobase sequence comprising any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863, wherein the modified oligonucleotide comprises:

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

E26. A compound comprising a modified oligonucleotide consisting of 16-80 linked nucleobases having a nucleobase sequence comprising the sequence recited in any one of SEQ ID NOs: 810 and 1404, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

E27. A compound comprising a modified oligonucleotide consisting of 16-80 linked nucleobases having a nucleobase sequence comprising the sequence recited in SEQ ID NOs: 2864, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

E28. A compound comprising a modified oligonucleotide consisting of 16-80 linked nucleobases having a nucleobase sequence comprising the sequence recited in SEQ ID NO: 2868, wherein the modified oligonucleotide comprises a gapmer consisting of a 5′-region, a 3′-region, and a central region positioned between the 5′-region and the 3′-region wherein:

- the 5′-region consists of 3 linked modified nucleosides, wherein each nucleoside of the 5′-region comprises a cEt nucleoside;

the 3′-region consists of 3 linked modified nucleosides, wherein each nucleoside of the 3′-region comprises a cEt nucleoside;

wherein each internucleoside linkage is a phosphorothioate linkage; and

wherein each cytosine is a 5-methylcytosine.

E29. A compound comprising a modified oligonucleotide consisting of 16-80 linked nucleobases having a nucleobase sequence comprising the sequence recited in SEQ ID NOs: 1200 or 2863, wherein the modified oligonucleotide comprises:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.

E30. A compound comprising or consisting of a modified oligonucleotide consisting of 16-80 linked nucleobases having a nucleobase sequence comprising the sequence recited in SEQ ID NO: 2865, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

E31. The compound of any one of embodiments E1-E30, wherein the oligonucleotide is at least 80%, 85%, 90%, 95% or 100% complementary to any of SEQ ID NOs: 1-10.

E32. The compound of any one of embodiments E1-E31, wherein the compound is single-stranded.

E33. The compound of any one of embodiments E1-E31, wherein the compound is double-stranded.

E34. The compound of any one of embodiments E1-E33, wherein the compound comprises ribonucleotides.

E35. The compound of any one of embodiments E1-E33, wherein the compound comprises deoxyribonucleotides.

E36. The compound of any one of embodiments E1-E35, wherein the modified oligonucleotide consists of 16 to 30 linked nucleosides.

E37. The compound of any preceding embodiment E1-E36, wherein the compound consists of the modified oligonucleotide.

E38. A compound consisting of a pharmaceutically acceptable salt of any of the compounds of embodiments E1-E36.

E39. The compound of embodiment E38, wherein the pharmaceutically acceptable salt is a sodium salt.

E40. The compound of embodiment E38, wherein the pharmaceutically acceptable salt is a potassium salt.

E41. A compound having the formula:

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or a salt thereof.

E42. A compound having the formula:

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E43. A composition comprising the compound of any one of embodiments E1-E42 and a pharmaceutically acceptable diluent or carrier.

E44. A composition comprising the compound of any one of embodiments E1-E42 and water.

E45. A composition comprising a compound or modified oligonucleotide of any preceding embodiment E1-E44, for use in therapy.

E46. A combination comprising the compound of any one of embodiments E1-E42 or the composition of any of embodiments E43-E45 and a secondary agent.

E47. The combination of embodiment E46, wherein the secondary agent is a CDK4/6 inhibitor.

E48. The combination of embodiment E47, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, or abemaciclib.

E49. The combination of embodiment E46, wherein the secondary agent is an EGFR inhibitor.

E50. The combination of embodiment E49, wherein the EGFR inhibitor is cetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib.

E51. The combination of embodiment E46, wherein the secondary agent is a kinase inhibitor.

E52. The combination of embodiment E51, wherein the kinase inhibitor is sorafenib, regorafenib, or carbozantinib.

E53. A method of treating or ameliorating cancer in an individual comprising administering to the individual a compound targeted to YAP1, thereby treating or ameliorating the cancer.

E54. The method of embodiment E53, wherein the compound is an antisense compound targeted to YAP1.

E55. The method of embodiment E53 or E54, further comprising administering a secondary agent.

E56. The method of embodiment E55, wherein the secondary agent is a CDK4/6 inhibitor.

E57. The method of embodiment E56, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, or abemaciclib.

E58. The method of embodiment E55, wherein the secondary agent is an EGFR inhibitor.

E59. The method of embodiment E58, wherein the EGFR inhibitor is cetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib.

E60. The method of embodiment E55, wherein the secondary agent is a kinase inhibitor.

E61. The method of embodiment E60, wherein the kinase inhibitor is sorafenib, regorafenib, or carbozantinib.

E62. The method of any of embodiments E53-E61, wherein the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, or a cancer having a heterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamous cell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutant FAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1 gene.

E63. The method of any of embodiments E53-E62, wherein administering the compound inhibits or reduces cancer cell proliferation, tumor growth, or metastasis.

E64. A method of inhibiting expression of YAP1 in a cell comprising contacting the cell with a compound targeted to YAP1, thereby inhibiting expression of YAP1 in the cell.

E65. The method of embodiment E64, wherein the cell a cancer cell.

E66. The method of embodiment E65, wherein the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, or a cancer having a heterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamous cell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutant FAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1 gene.

E67. A method of reducing or inhibiting cancer cell proliferation, tumor growth, or metastasis in an individual having cancer comprising administering a compound targeted to YAP1 to the individual, thereby reducing or inhibiting cancer cell proliferation, tumor growth, or metastasis in the individual.

E68. The method of embodiment E67, wherein the individual has hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, or a cancer having a heterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamous cell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutant FAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1 gene.

E69. The method of any one of embodiments E64-E68, wherein the compound is an antisense compound targeted to YAP1.

E70. The method of any one of embodiments E64-E69, wherein the compound is the compound of any one of embodiments 1-42 or composition of any one of embodiments 43-45.

E71. The method of any of embodiments E64-E70, wherein the compound is administered parenterally.

E72. Use of a compound targeted to YAP1 for treating, preventing, or ameliorating a cancer associated with YAP1.

E73. Use of a compound targeted to YAP1 and a secondary agent for treating, preventing, or ameliorating a cancer associated with YAP1.

E74. The use of embodiment E73, wherein the secondary agent is a CDK4/6 inhibitor.

E75. The use of embodiment E74, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, or abemaciclib.

E76. The use of embodiment E73, wherein the secondary agent is an EGFR inhibitor.

E77. The use of embodiment E76, wherein the EGFR inhibitor is cetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib.

E78. The use of embodiment E73, wherein the secondary agent is a kinase inhibitor.

E79. The use of embodiment E78, wherein the kinase inhibitor is sorafenib, regorafenib, or carbozantinib.

E80. The use of any of embodiments E72-E79, wherein the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, or a cancer having a heterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamous cell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutant FAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1 gene.

E81. The use of any of embodiments E72-E80, wherein the compound is an antisense compound targeted to YAP1.

E82. The use of any of embodiments E72-E81, wherein the compound is the compound of any one of embodiments E1-E42 or composition of any one of embodiments E43-E45.

E83. Use of a compound targeted to YAP1 in the manufacture of a medicament for treating or ameliorating a cancer associated with YAP1.

E84. The use of embodiment E83, wherein the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, or a cancer having a heterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamous cell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutant FAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1 gene.

E85. The use of embodiment E83 or E84, wherein the compound is an antisense compound targeted to YAP1.

E86. The use of any one of embodiments E83-E85, wherein the compound is the compound of any one of embodiments 1-42 or composition of any one of embodiments E43-E45.

E87. Use of a compound targeted to YAP1 in the preparation of a medicament for treating or ameliorating a cancer associated with YAP1.

E88. The use of embodiment E87, wherein the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL), a cancer having a mutant FAT1 gene, a cancer having a homozygous FAT1 gene mutation, or a cancer having a heterozygous FAT1 gene mutation, a squamous cell carcinoma (SCC) having a mutant FAT1 gene, a head and neck squamous cell carcinoma (HNSCC) having a mutant FAT1 gene, an oral tongue squamous cell carcinoma (OTSCC) having a mutant FAT1 gene, a pharynx carcinoma having a mutant FAT1 gene, or a laryngeal squamous cell carcinoma having a mutant FAT1 gene.

E89. The use of embodiment E87 or E88, wherein the compound is an antisense compound targeted to YAP1.

E90. The use of any one of embodiments E87-E89, wherein the compound is the compound of any one of embodiments 1-42 or composition of any one of embodiments E43-E45.

Certain Indications

Certain embodiments provided herein relate to methods of inhibiting YAP1 expression, which can be useful for treating, preventing, or ameliorating a cancer associated with YAP1 in an individual, by administration of a compound that targets YAP1. In certain embodiments, the compound can be a YAP1 specific inhibitor. In certain embodiments, the compound can be an antisense compound, oligomeric compound, or oligonucleotide targeted to YAP1.

Examples of cancers associated with YAP1 treatable, preventable, and/or ameliorable with the compounds and methods provided herein include hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma.

In certain embodiments, a method of treating, preventing, or ameliorating a cancer associated with YAP1 in an individual comprises administering to the individual a compound comprising a YAP1 specific inhibitor, thereby treating, preventing, or ameliorating the cancer. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, a compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, a compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, a compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound inhibits or reduces cancer cell proliferation, tumor growth, or metastasis.

In certain embodiments, a method of treating or ameliorating caner comprises administering to the individual a compound comprising a YAP1 specific inhibitor, thereby treating or ameliorating the cancer. In certain embodiments, the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound inhibits or reduces cancer cell proliferation, tumor growth, or metastasis. In certain embodiments, the individual is identified as having or at risk of having a cancer associated with YAP1.

In certain embodiments, a method of inhibiting expression of YAP1 in an individual having, or at risk of having, a cancer associated with YAP1 comprises administering to the individual a compound comprising a YAP1 specific inhibitor, thereby inhibiting expression of YAP1 in the individual. In certain embodiments, administering the compound inhibits expression of YAP1 in a cancer cell in the individual. In certain embodiments, the individual has, or is at risk of having hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound inhibits or reduces cancer cell proliferation, tumor growth, or metastasis. In certain embodiments, the individual is identified as having or at risk of having a cancer associated with YAP1.

In certain embodiments, a method of inhibiting expression of YAP1 in a cell comprises contacting the cell with a compound comprising a YAP1 specific inhibitor, thereby inhibiting expression of YAP1 in the cell. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a liver cancer cell or squamous cancer cell. In certain embodiments, the cancer cell is in the liver, head, or neck of an individual having cancer. In certain embodiments, the cell is in an individual who has, or is at risk of having cancer, such as hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In certain embodiments, a method of reducing or inhibiting cancer cell proliferation, tumor growth, or metastasis of an individual having, or at risk of having, a cancer associated with YAP1 comprises administering to the individual a compound comprising a YAP1 specific inhibitor, thereby reducing or inhibiting cancer cell proliferation, tumor growth, or metastasis in the individual. In certain embodiments, the individual has, or is at risk of having, hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the individual is identified as having or at risk of having a cancer associated with YAP1.

Certain embodiments are drawn to a compound comprising a YAP1 specific inhibitor for use in treating cancer. In certain embodiments, the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to a compound comprising a YAP1 specific inhibitor for use in reducing or inhibiting cancer cell proliferation, tumor growth, or metastasis in an individual having cancer. In certain embodiments, the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to use of a compound comprising a YAP1 specific inhibitor for the manufacture or preparation of a medicament for treating cancer. Certain embodiments are drawn to use of a compound comprising a YAP1 specific inhibitor for the preparation of a medicament for treating a cancer associated with YAP1. In certain embodiments, the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to use of a compound comprising a YAP1 specific inhibitor for the manufacture or preparation of a medicament for reducing or inhibiting cancer cell proliferation, tumor growth, or metastasis in an individual having cancer. In certain embodiments, the cancer is hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, the compound comprises an antisense compound targeted to YAP1. In certain embodiments, the compound comprises an oligonucleotide targeted to YAP1. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863. In any of the foregoing embodiments, the modified oligonucleotide can consist of 10 to 30 linked nucleosides. In certain embodiments, the compound is ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense compound or oligomeric compound.

In any of the foregoing methods or uses, the compound can be targeted to YAP1. In certain embodiments, the compound comprises or consists of a modified oligonucleotide, for example a modified oligonucleotide consisting of 8 to 80 linked nucleosides, 10 to 30 linked nucleosides, 12 to 30 linked nucleosides, or 20 linked nucleosides. In certain embodiments, the modified oligonucleotide is at least 80%, 85%, 90%, 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NOs: 1-10. In certain embodiments, at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage, at least one nucleoside of the modified oligonucleotide comprises a modified sugar and/or at least one nucleobase of the modified oligonucleotide is a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage, the modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl, and the modified nucleobase is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide has a gap segment consisting of linked 2′-deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; and a 3′ wing segment consisting of linked nucleosides, wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

In any of the foregoing embodiments, the modified oligonucleotide can consist of 12 to 30, 15 to 30, 15 to 25, 15 to 24, 16 to 24, 17 to 24, 18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to 22, 16 to 20, or 17 or 20 linked nucleosides. In certain embodiments, the modified oligonucleotide is at least 80%, 85%, 90%, 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NOs: 1-10. In certain embodiments, at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage, at least one nucleoside of the modified oligonucleotide comprises a modified sugar and/or at least one nucleobase of the modified oligonucleotide is a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage, the modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl, and the modified nucleobase is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide has a gap segment consisting of linked 2′-deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; and a 3′ wing segment consisting of linked nucleosides, wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

In any of the foregoing methods or uses, the compound can comprise or consist of a modified oligonucleotide consisting of 16 to 80 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940, wherein the modified oligonucleotide has:

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise or consist of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 810, 1404, 2868, 2864, 2865, 1404, 1101, 2812, 1200, or 2863, wherein the modified oligonucleotide has:

- a gap segment consisting of linked 2′-deoxynucleosides;
- a 5′ wing segment consisting of linked nucleosides; and
- a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise or consist of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in any one of SEQ ID NOs: 810 and 1404, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

In any of the foregoing methods or uses, the compound can comprise or consist of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the sequence recited in SEQ ID NO: 2864, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

In any of the foregoing methods or uses, the compound can comprise or consist of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in SEQ ID NOs: 1200 or 2863, wherein the modified oligonucleotide has:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of two linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of the 5′ wing segment comprises a cEt nucleoside; wherein the 3′ wing segment comprises a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, a cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and a cEt nucleoside in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise or consist of a modified oligonucleotide consisting of 16 to 80 linked nucleobases and having a nucleobase sequence comprising the nucleobase sequence recited in SEQ ID NO: 2865, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of one linked nucleoside; and

a 3′ wing segment consisting of five linked nucleosides;

In any of the foregoing methods or uses, the compound can be a modified oligonucleotide, wherein the anion form of the modified oligonucleotide has the following chemical structure:

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or a salt thereof.

In any of the foregoing methods or uses, the compound can be a modified oligonucleotide according to the following chemical structure:

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or a salt thereof.

In any of the foregoing methods or uses, the compound can be a modified oligonucleotide according to the following chemical structure:

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In any of the foregoing methods or uses, the compound can be administered parenterally. For example, in certain embodiments the compound can be administered through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

Certain Combinations and Combination Therapies

In certain embodiments, a first agent comprising a compound described herein is co-administered with one or more secondary agents. In certain embodiments, such second agents are designed to treat the same disease, disorder, or condition as the first agent described herein. In certain embodiments, such second agents are designed to treat a different disease, disorder, or condition as the first agent described herein. In certain embodiments, a first agent is designed to treat an undesired side effect of a second agent. In certain embodiments, second agents are co-administered with the first agent to treat an undesired effect of the first agent. In certain embodiments, such second agents are designed to treat an undesired side effect of one or more pharmaceutical compositions as described herein. In certain embodiments, second agents are co-administered with the first agent to produce a combinational effect. In certain embodiments, second agents are co-administered with the first agent to produce a synergistic effect. In certain embodiments, the co-administration of the first and second agents permits use of lower dosages than would be required to achieve a therapeutic or prophylactic effect if the agents were administered as independent therapy.

In certain embodiments, one or more compounds or compositions provided herein, such as ION 1198440, are co-administered with one or more secondary agents. In certain embodiments, one or more compounds or compositions provided herein and one or more secondary agents, are administered at different times. In certain embodiments, one or more compounds or compositions provided herein and one or more secondary agents, are prepared together in a single formulation. In certain embodiments, one or more compounds or compositions provided herein and one or more secondary agents, are prepared separately. In certain embodiments, a secondary agent is selected from: CDK4/6 inhibitors including but not limited to palbociclib, ribociclib, or abemaciclib; EGFR inhibitors including but not limited to cetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib; or kinase inhibitors including but not limited to sorafenib, regorafenib, or carbozantinib.

Certain embodiments are directed to the use of a compound targeted to YAP1 as described herein, such as ION 1198440, in combination with a secondary agent. In particular embodiments such use is in a method of treating a patient suffering from cancer including, but not limited to, hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), head and neck cancer, pharynx carcinoma, laryngeal squamous cell carcinoma, oral tongue squamous cell carcinoma (OTSCC), squamous cell carcinoma (SCC), sarcomas (e.g. epitheloid, rhabdoid and synovial), esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, tumors with mutations in SWI/SNF complex, lung cancer, non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), gastrointestinal cancer, large intestinal cancer, small intestinal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, liver cancer, biliary tract cancer, urothelial cancer, breast cancer, triple-negative breast cancer (TNBC), endometrial cancer, cervical cancer, prostate cancer, mesothelioma, chordoma, renal cancer, renal cell carcinoma (RCC), brain cancer, neuroblastoma, glioblastoma, skin cancer, melanoma, basal cell carcinoma, merkel cell carcinoma, blood cancer, hematopoetic cancer, myeloma, multiple myeloma (MM), B cell malignancies, lymphoma, B cell lymphoma, Hodgkin lymphoma, T cell lymphoma, leukemia, or acute lymphocytic leukemia (ALL). In certain embodiments, the cancer has a mutant FAT1 gene. In certain embodiments, the cancer has a homozygous or heterozygous FAT1 gene mutation. In certain embodiments, the cancer having a mutant FAT1 gene, a homozygous FAT1 gene mutation, or a heterozygous FAT gene mutation is squamous cell carcinoma (SCC), head and neck squamous cell carcinoma (HNSCC), oral tongue squamous cell carcinoma (OTSCC), pharynx carcinoma, or laryngeal squamous cell carcinoma. In certain embodiments, a secondary agent is selected from: CDK4/6 inhibitors including but not limited to palbociclib, ribociclib, or abemaciclib; EGFR inhibitors including but not limited to cetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib; or kinase inhibitors including but not limited to sorafenib, regorafenib, or carbozantinib.

Certain embodiments are drawn to a combination of a compound targeted to YAP1 as described herein, such as ION 1198440, and a secondary agent, such as CDK4/6 inhibitors including but not limited to palbociclib, ribociclib, or abemaciclib; EGFR inhibitors including but not limited to cetuximab, necitumumab, panitumumab, vandetanib, dacomitinib, neratinib, osimertinib, gefitinib, lapatinib, or erlotinib; or kinase inhibitors including but not limited to sorafenib, regorafenib, or carbozantinib.

In certain embodiments the compound targeted to YAP1 as described herein, such as ION 1198440, and the secondary agent are used in combination treatment by administering the two agents simultaneously, separately or sequentially. In certain embodiments the two agents are formulated as a fixed dose combination product. In other embodiments the two agents are provided to the patient as separate units which can then either be taken simultaneously or serially (sequentially).

In certain embodiments, a compound targeted to YAP1 as described herein, such as ION 1198440, is used in combination with an immunomodulatory agent such as an anti-PD-L1 antibody (or an antigen-binding fragment thereof), an anti-PD-1 antibody (or an antigen-binding fragment thereof), an anti-CTLA-4 antibody (or an antigen-binding fragment thereof) or an OX40 agonist ((e.g., an OX40 ligand fusion protein, or an OX40 agonist antibody or antigen-binding fragment thereof).

In certain embodiments, a compound targeted to YAP1 as described herein, such as ION 1198440, is used in combination with an immune checkpoint inhibitor such as an anti-PD-L1 antibody (or an antigen-binding fragment thereof), an anti-PD-1 antibody (or an antigen-binding fragment thereof), or an anti-CTLA-4 antibody (or an antigen-binding fragment thereof).

Anti-PD-L1 antibodies are known in the art. Exemplary anti-PD-L1 antibodies include: MEDI4736 (durvalumab), MPDL3280A, BMS936559, 2.7A4, AMP-714, MDX-1105 and MPDL3280A (atezolizumab).

Anti-PD-1 antibodies are known in the art. Exemplary anti-PD-1 antibodies include: nivolumab, pembrolizumab, pidilizumab, and AMP-514

Anti-CTLA-4 antibodies are known in the art. Exemplary anti-CTLA-4 antibodies include: tremelimumab and ipilimumab, also termed MDX-010 (or BMS-734016).

OX40 agonists and antibodies are known in the art. Exemplary OX40 agonists and/or antibodies include: MEDI6383, 9B12 and MEDI0562.

In one embodiment, the combination includes the antisense oligonucleotide Ionis 1198440 or a salt thereof, and at least one immunomodulator selected from the group consisting of: MEDI4736, MPDL3280A, BMS936559, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, MPDL3280A, tremelimumab, ipilimumab, MEDI0562 and MEDI0562.

In one embodiment, the combination includes the anti-PD-L1 antibody MEDI4736 (duvalumab) and ION 1198440.

In one embodiment, the combination includes ION 1198440, the anti-PD-L1 antibody MEDI4736 (durvalumab) and the anti-CTLA-4 antibody tremelimumab.

Certain Anti-PD-L1 Antibodies

Antibodies that specifically bind and inhibit PD-L1 are included in the present disclosure.

Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody that is selective for a PD-L1 polypeptide and blocks the binding of PD-L1 to the PD-1 and CD80 receptors. Durvalumab can relieve PD-L1-mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.

Information regarding durvalumab (or fragments thereof) for use in the methods provided herein can be found in U.S. Pat. No. 8,779,108, the disclosure of which is incorporated herein by reference in its entirety. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to the complement component C1q and the Fcγ receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).

Durvalumab and antigen-binding fragments thereof for use in the methods provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In certain embodiments, MEDI4736 or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H9OPT antibody as disclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, which is herein incorporated by reference in its entirety.

There are numerous anti-PD-L1 antibodies in the published literature that could feature in the present disclosure, including compounds in development and/or in clinical trials such as: durvalumab (MEDI4736), MPDL3280A, BMS936559, 2.7A4, AMP-714 and MDX-1105. Patent specifications disclosing anti-PD-L1 antibodies that may be useful in the present disclosure include: U.S. Pat. Nos. 7,943,743; 8,383,796; 9,102,725; 9,273,135 (BMS/Medarex), US2006/0153841 (Dana Farber), US2011/0271358 (Dana Farber), U.S. Pat. Nos. 8,552,154 and 9,102,727 (Dana Farber), U.S. Pat. No. 8,217,149 (Genentech), including issued U.S. Pat. No. 8,217,149, US2012/0039906 (INSERM), US2016/0031990 (Amplimmune), U.S. Pat. No. 8,779,108 (Medlmmune—for durvalumab/MEDI4726 and 2.7A4), US2014/0044738 (Amplimmune—for AMP-714) and US2010/0285039 (John's Hopkins University). Each of these disclosures is herein incorporated by reference in its entirety.

Certain Anti-CTLA-4 Antibodies

Antibodies that specifically bind CTLA-4 and inhibit CTLA-4 activity are useful for enhancing an anti-tumor immune response. Information regarding tremelimumab (or antigen-binding fragments thereof) for use in the methods provided herein can be found in U.S. Pat. No. 6,682,736 (where it is referred to as 11.2.1), the disclosure of which is incorporated herein by reference in its entirety. Tremelimumab (also known as CP-675,206, CP-675, CP-675206, and ticilimumab) is a human IgG2 monoclonal antibody that is highly selective for CTLA-4 and blocks binding of CTLA-4 to CD80 (B7.1) and CD86 (B7.2). It has been shown to result in immune activation in vitro and some patients treated with tremelimumab have shown tumor regression.

Tremelimumab for use in the methods provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a specific aspect, tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequences shown herein above and a heavy chain variable region comprising the amino acid sequence shown herein above. In a specific aspect, tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences shown herein above, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences shown herein above. Those of ordinary skill in the art would easily be able to identify Chothia-defined, Abm-defined or other CDR definitions known to those of ordinary skill in the art. In a specific aspect, tremelimumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 11.2.1 antibody as disclosed in U.S. Pat. No. 6,682,736, which is herein incorporated by reference in its entirety.

Other anti-CTLA-4 antibodies are described, for example, in US 20070243184. In one embodiment, the anti-CTLA-4 antibody is Ipilimumab, also termed MDX-010; BMS-734016.

Certain OX40 Agonists

OX40 agonists interact with the OX40 receptor on CD4+ T-cells during, or shortly after, priming by an antigen resulting in an increased response of the CD4+ T-cells to the antigen. An OX40 agonist interacting with the OX40 receptor on antigen specific CD4+ T-cells can increase T cell proliferation as compared to the response to antigen alone. The elevated response to the antigen can be maintained for a period of time substantially longer than in the absence of an OX40 agonist. Thus, stimulation via an OX40 agonist enhances the antigen specific immune response by boosting T-cell recognition of antigens, e.g., tumor cells. OX40 agonists are described, for example, in U.S. Pat. Nos. 6,312,700, 7,504,101, 7,622,444, and 7,959,925, which are incorporated herein by reference in their entireties. Methods of using such agonists in cancer treatment are described, for example, in US2015/0098942 and in US2015/0157710, each of which are incorporated herein by reference in its entirety.

OX40 agonists include, but are not limited to OX40 binding molecules, e.g., binding polypeptides, e.g., OX40 ligand (“OX40L”) or an OX40-binding fragment, variant, or derivative thereof, such as soluble extracellular ligand domains and OX40L fusion proteins, and anti-OX40 antibodies (for example, monoclonal antibodies such as humanized monoclonal antibodies), or an antigen-binding fragment, variant or derivative thereof. Examples of anti-OX40 monoclonal antibodies are described, for example, in U.S. Pat. Nos. 5,821,332 and 6,156,878, the disclosures of which are incorporated herein by reference in their entireties. In certain embodiments, the anti-OX40 monoclonal antibody is 9B12, or an antigen-binding fragment, variant, or derivative thereof, as described in Weinberg, A. D., et al. J Immunother 29, 575-585 (2006), which is incorporated herein by reference in its entirety. In another embodiment, an OX40 antibody is MEDI0562 as described in US 2016/0137740.

In certain embodiments, the antibody which specifically binds to OX40, or an antigen-binding fragment thereof binds to the same OX40 epitope as mAb 9B12. An example of a humanized OX40 antibody is described by Morris et al., Mol Immunol. May 2007; 44(12): 3112-3121. 9B12 is a murine IgG1, anti-OX40 mAb directed against the extracellular domain of human OX40 (CD134) (Weinberg, A. D., et al. J Immunother 29, 575-585 (2006)). It was selected from a panel of anti-OX40 monoclonal antibodies because of its ability to elicit an agonist response for OX40 signaling, stability, and for its high level of production by the hybridoma. For use in clinical applications, 9B12 mAb is equilibrated with phosphate buffered saline, pH 7.0, and its concentration is adjusted to 5.0 mg/ml by diafiltration.

“OX40 ligand” (“OX40L”) (also variously termed tumor necrosis factor ligand superfamily member 4, gp34, TAX transcriptionally-activated glycoprotein-1, and CD252) is found largely on antigen presenting cells (APCs), and can be induced on activated B cells, dendritic cells (DCs), Langerhans cells, plamacytoid DCs, and macrophages (Croft, M., (2010) Ann Rev Immunol 28:57-78). Other cells, including activated T cells, NK cells, mast cells, endothelial cells, and smooth muscle cells can express OX40L in response to inflammatory cytokines (Id.). OX40L specifically binds to the OX40 receptor. The human protein is described in U.S. Pat. No. 6,156,878. The mouse OX40L is described in U.S. Pat. No. 5,457,035. OX40L is expressed on the surface of cells and includes an intracellular, a transmembrane and an extracellular receptor-binding domain. A functionally active soluble form of OX40L can be produced by deleting the intracellular and transmembrane domains as described, e.g., in U.S. Pat. Nos. 5,457,035; 6,312,700; 6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184; and 7,125,670, the disclosures of which are incorporated herein for all purposes. A functionally active form of OX40L is a form that retains the capacity to bind specifically to OX40, that is, that possesses an OX40 “receptor binding domain.” An example is amino acids 51 to 183 of human OX40L. Methods of determining the ability of an OX40L molecule or derivative to bind specifically to OX40 are discussed below. Methods of making and using OX40L and its derivatives (such as derivatives that include an OX40 binding domain) are described in U.S. Pat. Nos. 6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184; and 7,125,670, which also describe proteins comprising the soluble form of OX40L linked to other peptides, such as human immunoglobulin (“Ig”) Fc regions, that can be produced to facilitate purification of OX40 ligand from cultured cells, or to enhance the stability of the molecule after in vivo administration to a mammal (see also, U.S. Pat. Nos. 5,457,035 and 7,959,925, both of which are incorporated by reference herein in their entireties).

Also included within the definition of OX40L are OX40 ligand variants which vary in amino acid sequence from naturally occurring OX40 ligand molecules but which retain the ability to specifically bind to an OX40 receptor. Such variants are described in U.S. Pat. Nos. 5,457,035; 6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184; and 7,125,670. In a related embodiment, a mutant of OX40L which has lost the ability to specifically bind to OX40, for example amino acids 51 to 183, in which the phenylalanine at position 180 of the receptor-binding domain of human OX40L has been replaced with alanine (F180A) is used.

OX40 agonists include a fusion protein in which one or more domains of OX40L is covalently linked to one or more additional protein domains. Exemplary OX40L fusion proteins that can be used as OX40 agonists are described in U.S. Pat. No. 6,312,700, the disclosure of which is incorporated herein by reference in its entirety. In one embodiment, an OX40 agonist includes an OX40L fusion polypeptide that self-assembles into a multimeric (e.g., trimeric or hexameric) OX40L fusion protein. Such fusion proteins are described, e.g., in U.S. Pat. No. 7,959,925, which is incorporated by reference herein in its entirety. The multimeric OX40L fusion protein exhibits increased efficacy in enhancing antigen specific immune response in a subject, particularly a human subject, due to its ability to spontaneously assemble into highly stable trimers and hexamers.

In another embodiment, an OX40 agonist capable of assembling into a multimeric form includes a fusion polypeptide comprising in an N-terminal to C-terminal direction: an immunoglobulin domain, wherein the immunoglobulin domain includes an Fc domain, a trimerization domain, wherein the trimerization domain includes a coiled coil trimerization domain, and a receptor binding domain, wherein the receptor binding domain is an OX40 receptor binding domain, e.g., an OX40L or an OX40-binding fragment, variant, or derivative thereof, where the fusion polypeptide can self-assemble into a trimeric fusion protein. In one aspect, an OX40 agonist capable of assembling into a multimeric form is capable of binding to the OX40 receptor and stimulating at least one OX40 mediated activity. In certain aspects, the OX40 agonist includes an extracellular domain of OX40 ligand.

The trimerization domain of an OX40 agonist capable of assembling into a multimeric form serves to promote self-assembly of individual OX40L fusion polypeptide molecules into a trimeric protein. Thus, an OX40L fusion polypeptide with a trimerization domain self-assembles into a trimeric OX40L fusion protein. In one aspect, the trimerization domain is an isoleucine zipper domain or other coiled coli polypeptide structure. Exemplary coiled coil trimerization domains include: TRAF2 (GENBANK® Accession No. Q12933, amino acids 299-348; Thrombospondin 1 (Accession No. PO7996, amino acids 291-314; Matrilin-4 (Accession No. O95460, amino acids 594-618; CMP (matrilin-1) (Accession No. NP-002370, amino acids 463-496; HSF1 (Accession No. AAX42211, amino acids 165-191; and Cubilin (Accession No. NP-001072, amino acids 104-138. In certain specific aspects, the trimerization domain includes a TRAF2 trimerization domain, a Matrilin-4 trimerization domain, or a combination thereof.

OX40L FP is a human OX40 ligand IgG4P fusion protein that specifically binds to, and triggers signaling by, the human OX40 receptor, a member of the TNFR superfamily. OX40L FP is also disclosed in US2016/0024176, incorporated herein by reference in its entirety. OX40L FP is composed of three distinct domains: (1) human OX40 ligand extracellular receptor binding domains (RBDs) that form homotrimers and bind the OX40 receptor; (2) isoleucine zipper trimerization domains derived from TNFR-associated factor 2 that stabilize the homotrimeric structure of the OX40 ligand RBDs; and (3) human IgG4 fragment crystallizable gamma (Fcγ) domains that facilitate Fcγ receptor clustering of the fusion protein when bound to OX40 receptors, and contain a serine to proline substitution at position 228 (according to EU numbering) in the hinge regions (IgG4P) to promote stability of two sets of OX40 ligand RBD homotrimers. The IgG4P Fc domain is fused directly to an isoleucine zipper trimerization domain derived from amino acid residues 310-349 of human tumor necrosis factor 2 (TRAF2). Fused to the c-terminus of the TRAF2 domain are amino acid residues 51-183 of the extracellular receptor binding domain (RBD) of human OX40L (gene name TNFSF4). The TRAF2 domain stabilizes the homotrimeric structure of OX40L RBDs to enable OX40 binding and activation, while the IgG4P Fc domain confers serum stability, dimerization of OX40L trimers, and facilitates Fcγ receptor clustering of the hexameric fusion protein. One OX40L FP variant possesses a phenylalanine (F) to alanine (A) mutation at the amino acid corresponding to position 180 in OX40L. Another OX40L FP variant has the IgG4P Fc domain replaced with a human IgG1 Fc domain. In particular embodiments, the OX40 agonist for use in the present disclosure is one of the OX40L FP variants.

In particular embodiments, the OX40 agonist for use in the present disclosure has been modified to increase its serum half-life. For example, the serum half-life of an OX40 agonist can be increased by conjugation to a heterologous molecule such as serum albumin, an antibody Fc region, or PEG. In certain embodiments, OX40 agonists can be conjugated to other therapeutic agents or toxins to form immunoconjugates and/or fusion proteins. In certain embodiments, the OX40 agonist can be formulated so as to facilitate administration and promote stability of the active agent.

Antibody Derivatives

Antibodies for use in the present disclosure (e.g., anti-CTLA-4, anti-PD-L1, anti-PD-1, anti-OX40) may include variants of these sequences that retain the ability to specifically bind their targets. Such variants may be derived from the sequence of these antibodies by a skilled artisan using techniques well known in the art. For example, amino acid substitutions, deletions, or additions, can be made in the FRs and/or in the CDRs. While changes in the FRs are usually designed to improve stability and immunogenicity of the antibody, changes in the CDRs are typically designed to increase affinity of the antibody for its target. Variants of FRs also include naturally occurring immunoglobulin allotypes. Such affinity-increasing changes may be determined empirically by routine techniques that involve altering the CDR and testing the affinity antibody for its target. For example, conservative amino acid substitutions can be made within any one of the disclosed CDRs. Various alterations can be made according to the methods described in Antibody Engineering, 2nd ed., Oxford University Press, ed. Borrebaeck, 1995. These include but are not limited to nucleotide sequences that are altered by the substitution of different codons that encode a functionally equivalent amino acid residue within the sequence, thus producing a “silent” change. For example, the nonpolar amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine. The polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. The positively charged (basic) amino acids include arginine, lysine, and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid.

Derivatives and analogs of antibodies of the present disclosure can be produced by various techniques well known in the art, including recombinant and synthetic methods (Maniatis (1990) Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., and Bodansky et al. (1995) The Practice of Peptide Synthesis, 2nd ed., Spring Verlag, Berlin, Germany). Analogous shuffling or combinatorial techniques are also disclosed by Stemmer (Nature (1994) 370: 389-391), who describes the technique in relation to a β-lactamase gene but observes that the approach may be used for the generation of antibodies.

One may generate novel VH or VL regions carrying one or more sequences derived from the sequences disclosed herein using random mutagenesis of one or more selected VH and/or VL genes. One such technique, error-prone PCR, is described by Gram et al. (Proc. Nat. Acad. Sci. U.S.A. (1992) 89: 3576-3580).

Another method that may be used is to direct mutagenesis to CDRs of VH or VL genes. Such techniques are disclosed by Barbas et al. (Proc. Nat. Acad. Sci. U.S.A. (1994) 91: 3809-3813) and Schier et al. (J. Mol. Biol. (1996) 263: 551-567).

Similarly, one or more, or all three CDRs may be grafted into a repertoire of VH or VL domains, which are then screened for an antigen-binding fragment specific for CTLA-4 or PD-L1.

A portion of an immunoglobulin variable domain will comprise at least one of the CDRs substantially as set out herein and, optionally, intervening framework regions from the scFv fragments as set out herein. The portion may include at least about 50% of either or both of FR1 and FR4, the 50% being the C-terminal 50% of FR1 and the N-terminal 50% of FR4. Additional residues at the N-terminal or C-terminal end of the substantial part of the variable domain may be those not normally associated with naturally occurring variable domain regions. For example, construction of antibodies by recombinant DNA techniques may result in the introduction of N- or C-terminal residues encoded by linkers introduced to facilitate cloning or other manipulation steps. Other manipulation steps include the introduction of linkers to join variable domains to further protein sequences including immunoglobulin heavy chain constant regions, other variable domains (for example, in the production of diabodies), or proteinaceous labels as discussed in further detail below.

A skilled artisan will recognize that antibodies for use in the present disclosure may comprise antigen-binding fragments containing only a single CDR from either VL or VH domain. Either one of the single chain specific binding domains can be used to screen for complementary domains capable of forming a two-domain specific antigen-binding fragment capable of, for example, binding to CTLA-4 and PD-L1.

Antibodies for use in the present disclosure described herein can be linked to another functional molecule, e.g., another peptide or protein (albumin, another antibody, etc.). For example, the antibodies can be linked by chemical cross-linking or by recombinant methods. The antibodies may also be linked to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; or 4,179,337. The antibodies can be chemically modified by covalent conjugation to a polymer, for example, to increase their circulating half-life. Exemplary polymers and methods to attach them are also shown in U.S. Pat. Nos. 4,766,106; 4,179,337; 4,495,285, and 4,609,546.

The antibodies may also be altered to have a glycosylation pattern that differs from the native pattern. For example, one or more carbohydrate moieties can be deleted and/or one or more glycosylation sites added to the original antibody. Addition of glycosylation sites to the presently disclosed antibodies may be accomplished by altering the amino acid sequence to contain glycosylation site consensus sequences known in the art. Another means of increasing the number of carbohydrate moieties on the antibodies is by chemical or enzymatic coupling of glycosides to the amino acid residues of the antibody. Such methods are described in WO 87/05330, and in Aplin et al. (1981) CRC Crit. Rev. Biochem., 22: 259-306. Removal of any carbohydrate moieties from the antibodies may be accomplished chemically or enzymatically, for example, as described by Hakimuddin et al. (1987) Arch. Biochem. Biophys., 259: 52; and Edge et al. (1981) Anal. Biochem., 118: 131 and by Thotakura et al. (1987) Meth. Enzymol., 138: 350. The antibodies may also be tagged with a detectable, or functional, label. Detectable labels include radiolabels such as 131I or 99Tc, which may also be attached to antibodies using conventional chemistry. Detectable labels also include enzyme labels such as horseradish peroxidase or alkaline phosphatase. Detectable labels further include chemical moieties such as biotin, which may be detected via binding to a specific cognate detectable moiety, e.g., labeled avidin.

Antibodies, in which CDR sequences differ only insubstantially from those set forth herein are encompassed within the scope of this present disclosure. Typically, an amino acid is substituted by a related amino acid having similar charge, hydrophobic, or stereochemical characteristics. Such substitutions would be within the ordinary skills of an artisan. Unlike in CDRs, more substantial changes can be made in FRs without adversely affecting the binding properties of an antibody. Changes to FRs include, but are not limited to, humanizing a non-human derived or engineering certain framework residues that are important for antigen contact or for stabilizing the binding site, e.g., changing the class or subclass of the constant region, changing specific amino acid residues which might alter the effector function such as Fc receptor binding, e.g., as described in U.S. Pat. Nos. 5,624,821 and 5,648,260 and Lund et al. (1991) J. Immun. 147: 2657-2662 and Morgan et al. (1995) Immunology 86: 319-324, or changing the species from which the constant region is derived.

One of skill in the art will appreciate that the modifications described above are not all-exhaustive, and that many other modifications would be obvious to a skilled artisan in light of the teachings of the present disclosure.

Certain Compounds

In certain embodiments, compounds described herein can be antisense compounds. In certain embodiments, the antisense compound comprises or consists of an oligomeric compound. In certain embodiments, the oligomeric compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

In certain embodiments, a compound described herein comprises or consists of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

In certain embodiments, a compound or antisense compound is single-stranded. Such a single-stranded compound or antisense compound comprises or consists of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises or consists of an oligonucleotide and optionally a conjugate group. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide is modified. In certain embodiments, the oligonucleotide of a single-stranded antisense compound or oligomeric compound comprises a self-complementary nucleobase sequence.

In certain embodiments, compounds are double-stranded. Such double-stranded compounds comprise a first modified oligonucleotide having a region complementary to a target nucleic acid and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the modified oligonucleotide is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase. In certain embodiments, compound comprises a conjugate group. In certain embodiments, one of the modified oligonucleotides is conjugated. In certain embodiments, both the modified oligonucleotides are conjugated. In certain embodiments, the first modified oligonucleotide is conjugated. In certain embodiments, the second modified oligonucleotide is conjugated. In certain embodiments, the first modified oligonucleotide consists of 12-30 linked nucleosides and the second modified oligonucleotide consists of 12-30 linked nucleosides. In certain embodiments, one of the modified oligonucleotides has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of SEQ ID NOs: 23-2940.

In certain embodiments, antisense compounds are double-stranded. Such double-stranded antisense compounds comprise a first oligomeric compound having a region complementary to a target nucleic acid and a second oligomeric compound having a region complementary to the first oligomeric compound. The first oligomeric compound of such double stranded antisense compounds typically comprises or consists of a modified oligonucleotide and optionally a conjugate group. The oligonucleotide of the second oligomeric compound of such double-stranded antisense compound may be modified or unmodified. Either or both oligomeric compounds of a double-stranded antisense compound may comprise a conjugate group. The oligomeric compounds of double-stranded antisense compounds may include non-complementary overhanging nucleosides.

Examples of single-stranded and double-stranded compounds include but are not limited to oligonucleotides, siRNAs, microRNA targeting oligonucleotides, and single-stranded RNAi compounds, such as small hairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNA mimics.

In certain embodiments, a compound described herein has a nucleobase sequence that, when written in the 5′ to 3′ direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted.

In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 10 to 30 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 12 to 30 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 12 to 22 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 14 to 30 linked subunits. In certain embodiments, compound described herein comprises an oligonucleotide consisting of 14 to 20 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 15 to 30 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 15 to 20 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 16 to 30 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 16 to 20 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 17 to 30 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 17 to 20 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 18 to 30 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 18 to 21 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 18 to 20 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 20 to 30 linked subunits. In other words, such oligonucleotides consist of 12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to 20 subunits, 18 to 21 subunits, 20 to 30 subunits, or 12 to 22 linked subunits, respectively. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 14 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 16 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 17 linked subunits. In certain embodiments, compound described herein comprises an oligonucleotide consisting of 18 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 19 linked subunits. In certain embodiments, a compound described herein comprises an oligonucleotide consisting of 20 linked subunits. In other embodiments, a compound described herein comprises an oligonucleotide consisting of 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. In certain such embodiments, the compound described herein comprises an oligonucleotide consisting of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 linked subunits, or a range defined by any two of the above values. In some embodiments the linked subunits are nucleotides, nucleosides, or nucleobases.

In certain embodiments, the compound may further comprise additional features or elements, such as a conjugate group, that are attached to the oligonucleotide. In certain embodiments, such compounds are antisense compounds. In certain embodiments, such compounds are oligomeric compounds. In embodiments where a conjugate group comprises a nucleoside (i.e. a nucleoside that links the conjugate group to the oligonucleotide), the nucleoside of the conjugate group is not counted in the length of the oligonucleotide.

In certain embodiments, compounds may be shortened or truncated. For example, a single subunit may be deleted from the 5′ end (5′ truncation), or alternatively from the 3′ end (3′ truncation). A shortened or truncated compound targeted to an YAP1 nucleic acid may have two subunits deleted from the 5′ end, or alternatively may have two subunits deleted from the 3′ end, of the compound. Alternatively, the deleted nucleosides may be dispersed throughout the compound.

When a single additional subunit is present in a lengthened compound, the additional subunit may be located at the 5′ or 3′ end of the compound. When two or more additional subunits are present, the added subunits may be adjacent to each other, for example, in a compound having two subunits added to the 5′ end (5′ addition), or alternatively to the 3′ end (3′ addition), of the compound. Alternatively, the added subunits may be dispersed throughout the compound.

It is possible to increase or decrease the length of a compound, such as an oligonucleotide, and/or introduce mismatch bases without eliminating activity (Woolf et al. Proc. Natl. Acad. Sci. USA 1992, 89:7305-7309; Gautschi et al. J. Natl. Cancer Inst. March 2001, 93:463-471; Maher and Dolnick Nuc. Acid. Res. 1998, 16:3341-3358). However, seemingly small changes in oligonucleotide sequence, chemistry and motif can make large differences in one or more of the many properties required for clinical development (Seth et al. J. Med. Chem. 2009, 52, 10; Egli et al. J. Am. Chem. Soc. 2011, 133, 16642).

In certain embodiments, compounds described herein are interfering RNA compounds (RNAi), which include double-stranded RNA compounds (also referred to as short-interfering RNA or siRNA) and single-stranded RNAi compounds (or ssRNA). Such compounds work at least in part through the RISC pathway to degrade and/or sequester a target nucleic acid (thus, include microRNA/microRNA-mimic compounds). As used herein, the term siRNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term “RNAi” is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics.

In certain embodiments, a compound described herein can comprise any of the oligonucleotide sequences targeted to YAP1 described herein. In certain embodiments, the compound can be double-stranded. In certain embodiments, the compound comprises a first strand comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobase portion of any one of SEQ ID NOs: 23-2940 and a second strand. In certain embodiments, the compound comprises a first strand comprising the nucleobase sequence of any one of SEQ ID NOs: 23-2940 and a second strand. In certain embodiments, the compound comprises ribonucleotides in which the first strand has uracil (U) in place of thymine (T) in any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises (i) a first strand comprising a nucleobase sequence complementary to the site on YAP1 to which any of SEQ ID NOs: 23-2940 is targeted, and (ii) a second strand. In certain embodiments, the compound comprises one or more modified nucleotides in which the 2′ position in the sugar contains a halogen (such as fluorine group; 2′-F) or contains an alkoxy group (such as a methoxy group; 2′-OMe). In certain embodiments, the compound comprises at least one 2′-F sugar modification and at least one 2′-OMe sugar modification. In certain embodiments, the at least one 2′-F sugar modification and at least one 2′-OMe sugar modification are arranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strand of the dsRNA compound. In certain embodiments, the compound comprises one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The compounds may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the compound contains one or two capped strands, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000.

In certain embodiments, the first strand of the compound is an siRNA guide strand and the second strand of the compound is an siRNA passenger strand. In certain embodiments, the second strand of the compound is complementary to the first strand. In certain embodiments, each strand of the compound consists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. In certain embodiments, the first or second strand of the compound can comprise a conjugate group.

In certain embodiments, a compound described herein can comprise any of the oligonucleotide sequences targeted to YAP1 described herein. In certain embodiments, the compound is single stranded. In certain embodiments, such a compound is a single-stranded RNAi (ssRNAi) compound. In certain embodiments, the compound comprises at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobase portion of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises the nucleobase sequence of any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises ribonucleotides in which uracil (U) is in place of thymine (T) in any one of SEQ ID NOs: 23-2940. In certain embodiments, the compound comprises a nucleobase sequence complementary to the site on YAP1 to which any of SEQ ID NOs: 23-2940 is targeted. In certain embodiments, the compound comprises one or more modified nucleotides in which the 2′ position in the sugar contains a halogen (such as fluorine group; 2′-F) or contains an alkoxy group (such as a methoxy group; 2′-OMe). In certain embodiments, the compound comprises at least one 2′-F sugar modification and at least one 2′-OMe sugar modification. In certain embodiments, the at least one 2′-F sugar modification and at least one 2′-OMe sugar modification are arranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strand of the compound. In certain embodiments, the compound comprises one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The compounds may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the compound contains a capped strand, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000. In certain embodiments, the compound consists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. In certain embodiments, the compound can comprise a conjugate group.

In certain embodiments, compounds described herein comprise modified oligonucleotides. Certain modified oligonucleotides have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as α or β such as for sugar anomers, or as (D) or (L) such as for amino acids etc. Included in the modified oligonucleotides provided herein are all such possible isomers, including their racemic and optically pure forms, unless specified otherwise. Likewise, all cis- and trans-isomers and tautomeric forms are also included.

The compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the ¹H hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to: ²H or ³H in place of ¹H, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certain embodiments, non-radioactive isotopic substitutions may impart new properties on the compound that are beneficial for use as a therapeutic or research tool. In certain embodiments, radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes, such as an imaging assay.

Certain Mechanisms

In certain embodiments, compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, compounds described herein are antisense compounds. In certain embodiments, compounds comprise oligomeric compounds. In certain embodiments, compounds described herein are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity. In certain embodiments, compounds described herein selectively affect one or more target nucleic acid. Such compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in a significant undesired antisense activity.

In certain antisense activities, hybridization of a compound described herein to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid. For example, certain compounds described herein result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, compounds described herein are sufficiently “DNA-like” to elicit RNase H activity. Further, in certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

In certain antisense activities, compounds described herein or a portion of the compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein result in cleavage of the target nucleic acid by Argonaute. Compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA).

In certain embodiments, hybridization of compounds described herein to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain such embodiments, hybridization of the compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of the compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain such embodiments, hybridization of the compound to a target nucleic acid results in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and/or a phenotypic change in a cell or animal.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

In certain embodiments, compounds described herein comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from: an mRNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target RNA is an mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron.

Nucleotide sequences that encode YAP1 include, without limitation, the following: GENBANK or RefSEQ No. NM_001282101.1 (SEQ ID NO: 1); NC_000011.10 truncated from nucleotides 102107001 to 102236000 (SEQ ID NO: 2); NM_006106.4 (SEQ ID NO: 3); NM_001130145.2 (SEQ ID NO: 4); NM_001195044.1 (SEQ ID NO: 5); NM_001195045.1 (SEQ ID NO: 6); NM_001282097.1 (SEQ ID NO: 7); NM_001282098.1 (SEQ ID NO: 8); NM_001282099.1 (SEQ ID NO: 9); and NM_001282100.1 (SEQ ID NO: 10), each of which is incorporated by reference in its entirety.

Hybridization

In some embodiments, hybridization occurs between a compound disclosed herein and a YAP1 nucleic acid. The most common mechanism of hybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules.

Hybridization can occur under varying conditions. Hybridization conditions are sequence-dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized.

Methods of determining whether a sequence is specifically hybridizable to a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein are specifically hybridizable with a YAP1 nucleic acid.

Complementarity

An oligonucleotide is said to be complementary to another nucleic acid when the nucleobase sequence of such oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Nucleobase matches or complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) and guanine (G) unless otherwise specified. Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches. An oligonucleotide is fully complementary or 100% complementary when such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

In certain embodiments, compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, compounds described herein are antisense compounds. In certain embodiments, compounds comprise oligomeric compounds. Non-complementary nucleobases between a compound and a YAP1 nucleic acid may be tolerated provided that the compound remains able to specifically hybridize to a target nucleic acid. Moreover, a compound may hybridize over one or more segments of a YAP1 nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).

In certain embodiments, the compounds provided herein, or a specified portion thereof, are, are at least, or are up to 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a YAP1 nucleic acid, a target region, target segment, or specified portion thereof. In certain embodiments, the compounds provided herein, or a specified portion thereof, are 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any number in between these ranges, complementary to a YAP1 nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of a compound with a target nucleic acid can be determined using routine methods.

For example, a compound in which 18 of 20 nucleobases of the compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining non-complementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, a compound which consists of 18 nucleobases having four non-complementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid. Percent complementarity of a compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489).

In certain embodiments, compounds described herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, or specified portion thereof. For example, a compound may be fully complementary to a YAP1 nucleic acid, or a target region, or a target segment or target sequence thereof. As used herein, “fully complementary” means each nucleobase of a compound is complementary to the corresponding nucleobase of a target nucleic acid. For example, a 20 nucleobase compound is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the compound. Fully complementary can also be used in reference to a specified portion of the first and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase compound can be “fully complementary” to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase compound is fully complementary to the target sequence if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the compound. At the same time, the entire 30 nucleobase compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the compound are also complementary to the target sequence.

In certain embodiments, compounds described herein comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain such embodiments, antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount. Thus, in certain such embodiments selectivity of the compound is improved. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5′-end of the gap region. In certain such embodiments, the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of the gap region. In certain such embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5′-end of the wing region. In certain such embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-end of the wing region. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide not having a gapmer motif. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. In certain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

The location of a non-complementary nucleobase may be at the 5′ end or 3′ end of the compound. Alternatively, the non-complementary nucleobase or nucleobases may be at an internal position of the compound. When two or more non-complementary nucleobases are present, they may be contiguous (i.e. linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer oligonucleotide.

In certain embodiments, compounds described herein that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a YAP1 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a YAP1 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein also include those which are complementary to a portion of a target nucleic acid. As used herein, “portion” refers to a defined number of contiguous (i.e. linked) nucleobases within a region or segment of a target nucleic acid. A “portion” can also refer to a defined number of contiguous nucleobases of a compound. In certain embodiments, the—compounds, are complementary to at least an 8 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 9 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 10 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least an 11 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 13 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 14 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 15 nucleobase portion of a target segment. In certain embodiments, the compounds are complementary to at least a 16 nucleobase portion of a target segment. Also contemplated are compounds that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values.

Identity

The compounds provided herein may also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific ION number, or portion thereof. In certain embodiments, compounds described herein are antisense compounds or oligomeric compounds. In certain embodiments, compounds described herein are modified oligonucleotides. As used herein, a compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the compounds described herein as well as compounds having non-identical bases relative to the compounds provided herein also are contemplated. The non-identical bases may be adjacent to each other or dispersed throughout the compound. Percent identity of an compound is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared.

In certain embodiments, compounds described herein, or portions thereof, are, or are at least, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the compounds or SEQ ID NOs, or a portion thereof, disclosed herein. In certain embodiments, compounds described herein are about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, or any percentage between such values, to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific ION number, or portion thereof, in which the compounds comprise an oligonucleotide having one or more mismatched nucleobases. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. In certain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

In certain embodiments, compounds described herein comprise or consist of antisense compounds. In certain embodiments, a portion of the antisense compound is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

In certain embodiments, compounds described herein comprise or consist of oligonucleotides. In certain embodiments, a portion of the oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid.

Certain Modified Compounds

In certain embodiments, compounds described herein comprise or consist of oligonucleotides consisting of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA (i.e., comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage).

A. Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modifed sugar moiety and a modified nucleobase.

1. Modified Sugar Moieties

In certain embodiments, sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more acyclic substituent, including but not limited to substituents at the 2′, 4′, and/or 5′ positions. In certain embodiments one or more acyclic substituent of non-bicyclic modified sugar moieties is branched. Examples of 2′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2′-F, 2′-OCH₃(“OMe” or “O-methyl”), and 2′-O(CH₂)₂OCH₃(“MOE”). In certain embodiments, 2′-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF₃, OCF₃, alkoxy, O—C₁-C₁₀substituted alkoxy, O—C₁-C₁₀alkyl, O—C₁-C₁₀substituted alkyl, S-alkyl, N(R_m)-alkyl, O-alkenyl, S-alkenyl, N(R_m)-alkenyl, O-alkynyl, S-alkynyl, N(R_m)-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_m)(R_n) or OCH₂C(═O)—N(R_m)(R_n), where each R_mand R_nis, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat. No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al., U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groups suitable for linearly non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. Examples of 5′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certain embodiments, non-bicyclic modified sugars comprise more than one non-bridging sugar substituent, for example, 2′-F-5′-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., US2010/190837 and Rajeev et al., US2013/0203836.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclic modified nucleoside comprises a sugar moiety comprising a linear 2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂, CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_m)(R_n), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substituted acetamide (OCH₂C(═O)—N(R_m)(R_n)), where each R_mand R_nis, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀alkyl.

Nucleosides comprising modified sugar moieties, such as non-bicyclic modified sugar moieties, are referred to by the position(s) of the substitution(s) on the sugar moiety of the nucleoside. For example, nucleosides comprising 2′-substituted or 2-modified sugar moieties are referred to as 2′-substituted nucleosides or 2-modified nucleosides.

Certain modifed sugar moieties comprise a bridging sugar substituent that forms a second ring resulting in a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4′ and the 2′ furanose ring atoms. Examples of such 4′ to 2′ bridging sugar substituents include but are not limited to: 4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, (“LNA”), 4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt” when in the S configuration), 4′-CH₂—O—CH₂-2′, 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426), 4′-C(R_aR_b)—N(R)—O-2′, 4′-C(R_aR_b)—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O-2′, wherein each R, R_a, and R_bis, independently, H, a protecting group, or C₁-C₁₂alkyl (see, e.g. Imanishi et al., U.S. Pat. No. 7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprise from 1 to 4 linked groups independently selected from: —[C(R_a)(R_b)]_n—, —[C(R_a)(R_b)]_n—O—, —C(R_a)═C(R_b)—, —C(R_a)═N—, —C(═NR_a)—, —C(═O)—, —C(═S)—, —O—, —Si(R_a)₂—, —S(═O)_x—, and —N(R_a)—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_aand R_bis, independently, H, a protecting group, hydroxyl, C₁-C₁₂alkyl, substituted C₁-C₁₂alkyl, C₂-C₁₂alkenyl, substituted C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, substituted C₂-C₁₂alkynyl, C₅-C₂₀aryl, substituted C₅-C₂₀aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C₅-C₇alicyclic radical, substituted C₅-C₇alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃, COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), or sulfoxyl (S(═O)-J₁); and each J₁and J₂is, independently, H, C₁-C₁₂alkyl, substituted C₁-C₁₂alkyl, C₂-C₁₂alkenyl, substituted C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, substituted C₂-C₁₂alkynyl, C₅-C₂₀aryl, substituted C₅-C₂₀aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C₁-C₁₂aminoalkyl, substituted C₁-C₁₂aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129, 8362-8379; Elayadi et al., Curr. Opinion Invens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel et al., U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490, Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133, Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No. 6,525,191, Torsten et al., WO 2004/106356, Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; and Migawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the α-L configuration or in the β-D configuration.

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α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. When the positions of specific bicyclic nucleosides (e.g., LNA or cEt) are identified in exemplified embodiments herein, they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. In certain such embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4′-sulfur atom and a substitution at the 2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“MNA”) (see e.g., Leumann, C J. Bioorg. & Med. Chem. 2002,10, 841-854), fluoro HNA:

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(“F-HNA”, see e.g., Swayze et al., U.S. Pat. No. 8,088,904; Swayze et al., U.S. Pat. No. 8,440,803; and Swayze et al., U.S. Pat. No. 9,005,906, F-HNA can also be referred to as a F-THP or 3′-fluoro tetrahydropyran), and nucleosides comprising additional modified THP compounds having the formula:

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wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃and T₄are each, independently, an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide or one of T₃and T₄is an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide and the other of T₃and T₄is H, a hydroxyl protecting group, a linked conjugate group, or a 5′ or 3′-terminal group; q₁, q₂, q₃, q₄, q₅, q₆and q₇are each, independently, H, C₁-C₆alkyl, substituted C₁-C₆alkyl, C₂-C₆alkenyl, substituted C₂-C₆alkenyl, C₂-C₆alkynyl, or substituted C₂-C₆alkynyl; and each of R₁and R₂is independently selected from among: hydrogen, halogen, substituted or unsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂, NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃is, independently, H or C₁-C₆alkyl.

In certain embodiments, modified THP nucleosides are provided wherein q₁, q₂, q₃, q₄, q₅, q₆and q₇are each H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆and q₇is other than H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆and q₇is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R₁and R₂is F. In certain embodiments, R₁is F and R₂is H, in certain embodiments, R₁is methoxy and R₂is H, and in certain embodiments, R₁is methoxyethoxy and R₂is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following structure:

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In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are refered to herein as “modifed morpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieites. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US2013/130378.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

2. Modified Nucleobases

Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Such nucleobase modifications can impart nuclease stability, binding affinity or some other beneficial biological property to antisense compounds.

In certain embodiments, compounds described herein comprise modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimi¬dines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C—CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include without limitation, Manoharan et al., US2003/0158403, Manoharan et al., US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540; Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook et al., U.S. Pat. No. 6,166,199; and Matteucci et al., U.S. Pat. No. 6,005,096.

In certain embodiments, compounds targeted to a YAP1 nucleic acid comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

3. Modified Internucleoside Linkages

The naturally occuring internucleoside linkage of RNA and DNA is a 3′ to 5′ phosphodiester linkageln certain embodiments, compounds described herein having one or more modified, i.e. non-naturally occurring, internucleoside linkages are often selected over compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.

Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:

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Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

In certain embodiments, compounds targeted to an YAP1 nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage.

In certain embodiments, compounds described herein comprise oligonucleotides. Oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known.

In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include but are not limited to phosphates, which contain a phosphodiester bond (“P═O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), and phosphorodithioates (“HS—P═S”). Representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino (—CH2-N(CH3)-O—CH2-), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH2-O—); and N,N′-dimethylhydrazine (—CH2-N(CH3)-N(CH3)-). Modified internucleoside linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Representative chiral internucleoside linkages include but are not limited to alkylphosphonates and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.

Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH2-N(CH3)-O-5′), amide-3 (3′-CH2-C(═O)—N(H)-5′), amide-4 (3′-CH2-N(H)—C(═O)-5′), formacetal (3′-O—CH2-O-5), methoxypropyl, and thioformacetal (3′-S—CH2-O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH2 component parts.

In certain embodiments, oligonucleotides comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, internucleoside linkages are arranged in a gapped motif. In such embodiments, the internucleoside linkages in each of two wing regions are different from the internucleoside linkages in the gap region. In certain embodiments the internucleoside linkages in the wings are phosphodiester and the internucleoside linkages in the gap are phosphorothioate. The nucleoside motif is independently selected, so such oligonucleotides having a gapped internucleoside linkage motif may or may not have a gapped nucleoside motif and if it does have a gapped nucleoside motif, the wing and gap lengths may or may not be the same.

In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate.

In certain embodiments, the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least block of at least one 12 consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3′ end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3′ end of the oligonucleotide.

In certain embodiments, oligonucleotides comprise one or more methylphosponate linkages. In certain embodiments, oligonucleotides having a gapmer nucleoside motif comprise a linkage motif comprising all phosphorothioate linkages except for one or two methylphosponate linkages. In certain embodiments, one methylphosponate linkage is in the central gap of an oligonucleotide having a gapmer nucleoside motif.

In certain embodiments, it is desirable to arrange the number of phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages to maintain nuclease resistance. In certain embodiments, it is desirable to arrange the number and position of phosphorothioate internucleoside linkages and the number and position of phosphodiester internucleoside linkages to maintain nuclease resistance. In certain embodiments, the number of phosphorothioate internucleoside linkages may be decreased and the number of phosphodiester internucleoside linkages may be increased. In certain embodiments, the number of phosphorothioate internucleoside linkages may be decreased and the number of phosphodiester internucleoside linkages may be increased while still maintaining nuclease resistance. In certain embodiments it is desirable to decrease the number of phosphorothioate internucleoside linkages while retaining nuclease resistance. In certain embodiments it is desirable to increase the number of phosphodiester internucleoside linkages while retaining nuclease resistance.

Certain Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. Oligonucleotides can have a motif, e.g. a pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages. In certain embodiments, modified oligonucleotides comprise one or more modified nucleoside comprising a modified sugar. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).

a. Certain Sugar Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include but are not limited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which comprises two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside of the 3′-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5′-wing differs from the sugar motif of the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides. In certain embodiments, the wings of a gapmer comprise 2-5 nucleosides. In certain embodiments, the wings of a gapmer comprise 3-5 nucleosides. In certain embodiments, the nucleosides of a gapmer are all modified nucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides. In certain embodiments, the gap of a gapmer comprises 7-10 nucleosides. In certain embodiments, the gap of a gapmer comprises 8-10 nucleosides. In certain embodiments, the gap of a gapmer comprises 10 nucleosides. In certain embodiment, each nucleoside of the gap of a gapmer is an unmodified 2′-deoxy nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In such embodiments, the nucleosides on the gap side of each wing/gap junction are unmodified 2′-deoxy nucleosides and the nucleosides on the wing sides of each wing/gap junction are modified nucleosides. In certain such embodiments, each nucleoside of the gap is an unmodified 2′-deoxy nucleoside. In certain such embodiments, each nucleoside of each wing is a modified nucleoside.

In certain embodiments, a modified oligonucleotide has a fully modified sugar motif wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif wherein each nucleoside of the region comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified comprises the same 2′-modification.

In certain embodiments, a modified oligonucleotide can comprise a sugar motif described in Swayze et al., US2010/0197762; Freier et al., US2014/0107330; Freier et al., US2015/0184153; and Seth et al., US2015/0267195, each of which is incorporated by reference in its entirety herein.

Certain embodiments provided herein are directed to modified oligomeric compounds useful for inhibiting target nucleic acid expression, which can be useful for treating, preventing, ameliorating, or slowing progression of a disease associated with such a target nucleic acid. In certain embodiments, the modified oligomeric compounds comprise antisense oligonucleotides that are gapmers having certain sugar motifs. In certain embodiments, the gapmer sugar motifs provided herein can be combined with any nucleobase sequence and any internucleoside linkage motif to form potent antisense oligonucleotides.

In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: ekk-d9-kkee, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: k-d9-kekeke, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: kkk-d8-kekek, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: kkk-d9-keke, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: kk-d9-kdkdk, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

In certain embodiments, a compound comprises a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: kk-d9-eeekk, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: kk-d9-eeekk, wherein ‘d’ represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell or administering to a subject a compound comprising a modified oligonucleotide consisting of 16 linked nucleosides and having the motif: kk-d9-ekeke, wherein represents a 2′-deoxyribose sugar, 1′ represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell is a cancer cell. In certain embodiments, the subject has cancer. In certain embodiments, administering the compound to the subject treats the subject's cancer.

b. Certain Nucleobase Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosines.

In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosyl moiety. In certain embodiments, the modified nucleobase is selected from: a 2-thiopyrimidine and a 5-propynepyrimidine.

c. Certain Internucleoside Linkage Motifs

In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and/or unmodified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, essentially each internucleoside linking group is a phosphate internucleoside linkage (P═O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate (P═S). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is independently selected from a phosphorothioate and phosphate internucleoside linkage. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified. In certain such embodiments, some or all of the internucleoside linkages in the wings are unmodified phosphate linkages. In certain embodiments, the terminal internucleoside linkages are modified.

4. Certain Modified Oligonucleotides

In certain embodiments, compounds described herein comprise modified oligonucleotides. In certain embodiments, the above modifications (sugar, nucleobase, internucleoside linkage) are incorporated into a modified oligonucleotide. In certain embodiments, modified oligonucleotides are characterized by their modification, motifs, and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region of the sugar motif. Likewise, such gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications. Furthermore, in certain instances, an oligonucleotide is described by an overall length or range and by lengths or length ranges of two or more regions (e.g., a regions of nucleosides having specified sugar modifications), in such circumstances it may be possible to select numbers for each range that result in an oligonucleotide having an overall length falling outside the specified range. In such circumstances, both elements must be satisfied. For example, in certain embodiments, a modified oligonucleotide consists of 15-20 linked nucleosides and has a sugar motif consisting of three regions, A, B, and C, wherein region A consists of 2-6 linked nucleosides having a specified sugar motif, region B consists of 6-10 linked nucleosides having a specified sugar motif, and region C consists of 2-6 linked nucleosides having a specified sugar motif. Such embodiments do not include modified oligonucleotides where A and C each consist of 6 linked nucleosides and B consists of 10 linked nucleosides (even though those numbers of nucleosides are permitted within the requirements for A, B, and C) because the overall length of such oligonucleotide is 22, which exceeds the upper limit of the overall length of the modified oligonucleotide (20). Herein, if a description of an oligonucleotide is silent with respect to one or more parameter, such parameter is not limited. Thus, a modified oligonucleotide described only as having a gapmer sugar motif without further description may have any length, internucleoside linkage motif, and nucleobase motif. Unless otherwise indicated, all modifications are independent of nucleobase sequence.

Certain Conjugated Compounds

In certain embodiments, the compounds described herein comprise or consist of an oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and/or terminal groups. Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2′-position of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3′ and/or 5′-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 3′-end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 5′-end of oligonucleotides.

In certain embodiments, the oligonucleotide is modified. In certain embodiments, the oligonucleotide of a compound has a nucleobase sequence that is complementary to a target nucleic acid. In certain embodiments, oligonucleotides are complementary to a messenger RNA (mRNA). In certain embodiments, oligonucleotides are complementary to a sense transcript.

Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearanceln certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide.

Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic, a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, i, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; doi:10.1038/mtna.2014.72 and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g., WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates (e.g., GalNAc), vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

In certain embodiments, a conjugate moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugate linkers. In certain compounds, a conjugate group is a single chemical bond (i.e. conjugate moiety is attached to an oligonucleotide via a conjugate linker through a single bond). In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugate linkers described above, are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate groups to parent compounds, such as the oligonucleotides provided herein. In general, a bifunctional linking moiety comprises at least two functional groups. One ofthe functional groups is selected to bind to a particular site on a compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstituted C₁-C₁₀alkyl, substituted or unsubstituted C₂-C₁₀alkenyl or substituted or unsubstituted C₂-C₁₀alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker-nucleosides comprise a modified sugar moiety. In certain embodiments, linker-nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the compound through cleavable bonds. In certain embodiments, such cleavable bonds are phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which a compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or a specified percent complementarity to a reference nucleic acid and the compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, a compound may comprise (1) a modified oligonucleotide consisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10 linker-nucleosides that are contiguous with the nucleosides of the modified oligonucleotide. The total number of contiguous linked nucleosides in such a compound is more than 30. Alternatively, an compound may comprise a modified oligonucleotide consisting of 8-30 nucleosides and no conjugate group. The total number of contiguous linked nucleosides in such a compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to be cleaved from the oligonucleotide. For example, in certain circumstances compounds comprising a particular conjugate moiety are better taken up by a particular cell type, but once the compound has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate may comprise one or more cleavable moieties, typically within the conjugate linker. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide and a conjugate moiety or conjugate group.

In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nucleosides. In certain such embodiments, one or more linker-nucleosides are linked to one another and/or to the remainder of the compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2′-deoxy nucleoside that is attached to either the 3′ or 5′-terminal nucleoside of an oligonucleotide by a phosphate internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage. In certain such embodiments, the cleavable moiety is 2′-deoxyadenosine.

Compositions and Methods for Formulating Pharmaceutical Compositions

Compounds described herein may be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

Certain embodiments provide pharmaceutical compositions comprising one or more compounds or a salt thereof. In certain embodiments, the compounds are antisense compounds or oligomeric compounds. In certain embodiments, the compounds comprise or consist of a modified oligonucleotide. In certain such embodiments, the pharmaceutical composition comprises a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises a sterile saline solution and one or more compound. In certain embodiments, such pharmaceutical composition consists of a sterile saline solution and one or more compound. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises one or more compound and sterile water. In certain embodiments, a pharmaceutical composition consists of one compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises one or more compound and phosphate-buffered saline (PBS). In certain embodiments, a pharmaceutical composition consists of one or more compound and sterile PBS. In certain embodiments, the sterile PBS is pharmaceutical grade PBS. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

A compound described herein targeted to YAP1 nucleic acid can be utilized in pharmaceutical compositions by combining the compound with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising a compound targeted to YAP1 nucleic acid and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of a modified oligonucleotide provided herein.

Pharmaceutical compositions comprising compounds provided herein encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. In certain embodiments, the compounds are antisense compounds or oligomeric compounds. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at one or both ends of a compound which are cleaved by endogenous nucleases within the body, to form the active compound. In certain embodiments, the compounds or compositions further comprise a pharmaceutically acceptable carrier or diluent.

EXAMPLES

The Examples below describe the screening process to identify lead compounds targeted to YAP1. Out of over 3,000 oligonucleotides that were screened, ION 958499, 1076453, 1197270, 1198439, 1198440, 1198605, 1198623, 1198728, 1198831, or 1198872 emerged as the top lead compounds. In particular, ION 1198440 exhibited the best combination of properties in terms of potency and tolerability out of over 3,000 oligonucleotides.

Non-Limiting Disclosure and Incorporation by Reference

Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH for the natural 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) for natural uracil of RNA).

Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligonucleotide having the nucleobase sequence “ATCGATCG” encompasses any oligonucleotides having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and compounds having other modified nucleobases, such as “AT^mCGAUCG,” wherein ^mC indicates a cytosine base comprising a methyl group at the 5-position.

While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety.

Example 1
Antisense Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acid and were tested for their effect on Yap1 mRNA level in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured A-431 cells at a density of 5,000 cells per well were treated using free uptake with 2,000 nM of modified oligonucleotide. After a treatment period of approximately 48 hours, RNA was isolated from the cells and Yap1 mRNA levels were measured by quantitative real-time RTPCR. Human primer probe set RTS4814 (forward sequence GGGAAGTGAGCCTGTTTGGA, designated herein as SEQ ID NO.: 11; reverse sequence ACTGTTGAACAAACTAAATGCTGTGA, designated herein as SEQ ID NO.: 12; probe sequence ATGGATGCCATTCCTTTTGCCCAGTT, designated herein as SEQ ID NO.: 13) was used to measure mRNA levels. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides targeting the amplicon region.

The newly designed modified oligonucleotides in the Tables below were designed as 3-10-3 cEt gapmers. The gapmers are 16 nucleosides in length, wherein the central gap segment comprises of ten 2′-deoxynucleosides and is flanked by wing segments on the 5′ direction and the 3′ direction comprising three nucleosides each. Each nucleoside in the 5′ wing segment and each nucleoside in the 3′ wing segment has a cEt sugar modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P═S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either SEQ ID NO.: 1 (GENBANK Accession No. NM_001282101.1), or SEQ ID NO.: 2 (GENBANK Accession No. NC_000011.10 truncated from nucleotides 102107001 to 102236000). ‘N/A’ indicates that the modified oligonucleotide does not target that particular gene sequence with 100% complementarity. ‘N.D.’ indicates that the % UTC is not defined for that particular modified oligonucleotide in that particular experiment. Activity of the modified oligonucleotide may be defined in a different experiment.

TABLE 1

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715400
559
574
4019
4034
CTCCGAGTCCCCGCGG
107
23

715403
658
673
4118
4133
GAAGGAGTCGGGCAGC
72
24

715406
664
679
4124
4139
CTTGAAGAAGGAGTCG
58
25

715409
704
719
N/A
N/A
CAGTACTGGCCTGTCG
76
26

715412
710
725
7144
7159
CTGCATCAGTACTGGC
66
27

715415
744
759
7178
7193
CGAACATGCTGTGGAG
24
28

715418
798
813
7232
7247
AGTGTCCCAGGAGAAA
126
29

715421
949
964
N/A
N/A
GTGATTTAAGAAGTAT
71
30

715424
972
987
55467
55482
TGCCATGTTGTTGTCT
58
31

715427
1081
1096
79022
79037
CCATCCATCAGGAAGA
90
32

715430
1102
1117
79043
79058
ATCCTGAGTCATGGCT
118
33

715433
1133
1148
79074
79089
TGTTCTTATGGTTTAT
36
34

715436
1178
1193
N/A
N/A
TGGCAAAACGAGGGTC
126
35

715439
1184
1199
N/A
N/A
GGTTCATGGCAAAACG
99
36

715442
1210
1225
98912
98927
CACTGGAGCACTCTGA
64
37

715445
1460
1475
116649
116664
CATCCTGCTCCAGTGT
87
38

715448
1509
1524
116698
116713
CTCAATTCCTGAGACA
97
39

715451
1516
1531
116705
116720
CATTGTTCTCAATTCC
75
40

715454
1558
1573
N/A
N/A
ATAGGTGCCACTGTTA
78
41

715457
1564
1579
120469
120484
AGAGTGATAGGTGCCA
47
42

715460
1570
1585
120475
120490
ATCTCGAGAGTGATAG
114
43

715463
1608
1623
120513
120528
CTGTAGCTGCTCATGC
73
44

715466
1751
1766
122776
122791
CAAGGTCCACATTTGT
83
45

715469
1870
1885
122895
122910
TAGCTTGGTGGCAGCC
94
46

715472
1876
1891
122901
122916
TTTATCTAGCTTGGTG
52
47

715475
1883
1898
122908
122923
AGCTTTCTTTATCTAG
103
48

715478
3560
3575
124585
124600
ACCATTATTACTCCTG
7
49

715481
3566
3581
124591
124606
TTGGAAACCATTATTA
66
50

715484
3572
3587
101152
101167
TACTCTTTGGAAACCA
123
51

124597
124612

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
22
52

715490
3636
3651
124661
124676
CCAACTATTACTTCAT
38
53

715493
3665
3680
124690
124705
GTGCTAGCTGGTGCCA
62
54

715496
3720
3735
124745
124760
CCCTTGAAAATAAGGG
124
55

715499
3726
3741
124751
124766
TATGAACCCTTGAAAA
126
56

715502
4011
4026
125036
125051
CCAGACTTAATTCAAG
91
57

715505
4684
4699
125709
125724
ATTGGTTTATTGTAAA
84
58

715508
1397
1412
102529
102544
CTGTGCTGGGATTGAT
24
59

715511
1419
1434
N/A
N/A
TCCTGACATTTTGGAG
107
60

715514
N/A
N/A
4573
4588
GAGCGAAGGTGCGGAG
121
61

715517
N/A
N/A
5151
5166
GGCCTATGAGTCAACC
109
62

715520
N/A
N/A
5544
5559
TTCTTTCCACTCAAGT
122
63

715523
N/A
N/A
7140
7155
ATCAGTACTGGCCTAT
32
64

715526
N/A
N/A
7385
7400
ACTTACTTTAAGAAGT
112
65

715529
N/A
N/A
8646
8661
TGAAACCTGATCCTTT
148
66

715532
N/A
N/A
8820
8835
TAACAACCTGGTTTGT
91
67

715535
N/A
N/A
8906
8921
CTATTAAGCTGTTTAA
91
68

715538
N/A
N/A
10383
10398
CTTTGTAACTTAAAAG
110
69

715541
N/A
N/A
10918
10933
CTTGAAGAACTATTTC
105
70

715544
N/A
N/A
10924
10939
CAACTACTTGAAGAAC
128
71

715547
N/A
N/A
10930
10945
GTTGACCAACTACTTG
98
72

715550
N/A
N/A
10938
10953
AGGAAGTTGTTGACCA
70
73

715553
N/A
N/A
10944
10959
AGAAATAGGAAGTTGT
90
74

715556
N/A
N/A
10965
10980
AAGTTATTCAGCAGCT
63
75

715559
N/A
N/A
28556
28571
CTGCCATTTAAGAAAT
114
76

715562
N/A
N/A
37601
37616
CACACAACTCAGACAG
77
77

715565
N/A
N/A
37826
37841
GGATAAATGAATTATA
115
78

715568
N/A
N/A
37832
37847
AAGGTAGGATAAATGA
116
79

715571
N/A
N/A
105518
105533
AAAATCCTGCCAACAT
127
80

715574
N/A
N/A
79119
79134
TACCAAAACGAGGGTC
118
81

715577
N/A
N/A
80085
80100
GCATTCACAGAGTTAA
21
82

715580
N/A
N/A
80919
80934
GCCTGTCTGGAATACA
101
83

715583
N/A
N/A
80954
80969
GGGCCACAAAATAAAA
164
84

715586
N/A
N/A
80980
80995
AAAAGGTCTGGAACAG
53
85

715589
N/A
N/A
81086
81101
CCAGCAGCTAACAGCT
107
86

715592
N/A
N/A
81151
81166
TTCTTTGGCAGAGATA
89
87

715595
N/A
N/A
98883
98898
TCATGGCTGAAATGAA
104
88

715598
N/A
N/A
102395
102410
CCCAAGCTACCCAAGA
103
89

715601
N/A
N/A
102401
102416
AGAATTCCCAAGCTAC
106
90

715604
N/A
N/A
102407
102422
TAGCACAGAATTCCCA
107
91

715607
N/A
N/A
102413
102428
TCACCATAGCACAGAA
116
92

715610
N/A
N/A
102451
102466
GGCTGTGTAGGCTGAC
87
93

715613
N/A
N/A
102473
102488
ATTACTTTAAGCCACA
85
94

715616
N/A
N/A
102484
102499
GACGGATAAAAATTAC
95
95

715619
N/A
N/A
102490
102505
AAATAAGACGGATAAA
114
96

715622
N/A
N/A
102496
102511
AGTAAAAAATAAGACG
137
97

715625
N/A
N/A
102506
102521
ATTGCCTAAGAGTAAA
99
98

715628
N/A
N/A
102555
102570
GCCTACCTGACATTTT
114
99

715631
N/A
N/A
102561
102576
ATAAGAGCCTACCTGA
134
100

TABLE 2

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715401
562
577
4022
4037
GGTCTCCGAGTCCCCG
84
101

715404
660
675
4120
4135
AAGAAGGAGTCGGGCA
64
102

715407
666
681
4126
4141
GGCTTGAAGAAGGAGT
53
103

715410
706
721
N/A
N/A
ATCAGTACTGGCCTGT
61
104

715413
740
755
7174
7189
CATGCTGTGGAGTCAG
96
105

715416
746
761
7180
7195
CTCGAACATGCTGTGG
53
106

715419
929
944
7363
7378
GACCAGAAGATGTCTT
107
107

715422
968
983
55463
55478
ATGTTGTTGTCTGATC
57
108

715425
976
991
55471
55486
GTCCTGCCATGTTGTT
98
109

715428
1083
1098
79024
79039
TCCCATCCATCAGGAA
106
110

715431
1104
1119
79045
79060
CCATCCTGAGTCATGG
99
111

715434
1136
1151
79077
79092
TCTTGTTCTTATGGTT
31
112

715437
1180
1195
N/A
N/A
CATGGCAAAACGAGGG
89
113

715440
1186
1201
N/A
N/A
CTGGTTCATGGCAAAA
85
114

715443
1212
1227
98914
98929
TTCACTGGAGCACTCT
40
115

715446
1505
1520
116694
116709
ATTCCTGAGACATCCC
81
116

715449
1511
1526
116700
116715
TTCTCAATTCCTGAGA
124
117

715452
1518
1533
116707
116722
GTCATTGTTCTCAATT
71
118

715455
1560
1575
N/A
N/A
TGATAGGTGCCACTGT
65
119

715458
1566
1581
120471
120486
CGAGAGTGATAGGTGC
58
120

715461
1572
1587
120477
120492
TCATCTCGAGAGTGAT
153
121

715464
1745
1760
122770
122785
CCACATTTGTCCCAGG
89
122

715467
1769
1784
122794
122809
CATCTCCTTCCAGTGT
77
123

715470
1872
1887
122897
122912
TCTAGCTTGGTGGCAG
83
124

715473
1878
1893
122903
122918
TCTTTATCTAGCTTGG
32
125

715476
1885
1900
122910
122925
AAAGCTTTCTTTATCT
84
126

715479
3562
3577
124587
124602
AAACCATTATTACTCC
38
127

715482
3568
3583
124593
124608
CTTTGGAAACCATTAT
58
128

715485
3574
3589
124599
124614
AATACTCTTTGGAAAC
72
129

715488
3632
3647
124657
124672
CTATTACTTCATAGCT
66
130

715491
3638
3653
124663
124678
AACCAACTATTACTTC
71
131

715494
3668
3683
124693
124708
GAGGTGCTAGCTGGTG
46
132

715497
3722
3737
124747
124762
AACCCTTGAAAATAAG
155
133

715500
3966
3981
11043
11058
AAGCCTTAGAGTCAAT
30
134

124991
125006

715503
4013
4028
125038
125053
CCCCAGACTTAATTCA
136
135

715506
4686
4701
125711
125726
AAATTGGTTTATTGTA
112
136

715509
1399
1414
102531
102546
TGCTGTGCTGGGATTG
42
137

715512
N/A
N/A
4550
4565
AGGCGCGCGCATTGTG
97
138

715515
N/A
N/A
5147
5162
TATGAGTCAACCTGCA
94
139

715518
N/A
N/A
5477
5492
TTTGGGCAAAGTTCCT
60
140

715521
N/A
N/A
5546
5561
TCTTCTTTCCACTCAA
72
141

715524
N/A
N/A
7381
7396
ACTTTAAGAAGTATCT
93
142

715527
N/A
N/A
7387
7402
TCACTTACTTTAAGAA
111
143

715530
N/A
N/A
8816
8831
AACCTGGTTTGTTTCC
61
144

715533
N/A
N/A
8822
8837
CCTAACAACCTGGTTT
97
145

715536
N/A
N/A
8908
8923
GGCTATTAAGCTGTTT
137
146

715539
N/A
N/A
10637
10652
AGATCTCACTGACCTA
102
147

715542
N/A
N/A
10920
10935
TACTTGAAGAACTATT
120
148

715545
N/A
N/A
10926
10941
ACCAACTACTTGAAGA
87
149

715548
N/A
N/A
10934
10949
AGTTGTTGACCAACTA
117
150

715551
N/A
N/A
10940
10955
ATAGGAAGTTGTTGAC
82
151

715554
N/A
N/A
10961
10976
TATTCAGCAGCTTATA
93
152

715557
N/A
N/A
10967
10982
GGAAGTTATTCAGCAG
46
153

715560
N/A
N/A
37563
37578
CCCTTTACAAAAATAG
98
154

715563
N/A
N/A
37603
37618
AGCACACAACTCAGAC
86
155

715566
N/A
N/A
37828
37843
TAGGATAAATGAATTA
94
156

715569
N/A
N/A
37834
37849
CAAAGGTAGGATAAAT
122
157

715572
N/A
N/A
78867
78882
TCAGAGAAGAAAGGTA
97
158

715575
N/A
N/A
79123
79138
CCTTTACCAAAACGAG
134
159

715578
N/A
N/A
80087
80102
TGGCATTCACAGAGTT
50
160

715581
N/A
N/A
80921
80936
AAGCCTGTCTGGAATA
106
161

715584
N/A
N/A
80976
80991
GGTCTGGAACAGATTA
96
162

715587
N/A
N/A
80982
80997
TGAAAAGGTCTGGAAC
79
163

715590
N/A
N/A
81147
81162
TTGGCAGAGATAAAAC
84
164

715593
N/A
N/A
81153
81168
ATTTCTTTGGCAGAGA
60
165

715596
N/A
N/A
98885
98900
GTTCATGGCTGAAATG
104
166

715599
N/A
N/A
102397
102412
TTCCCAAGCTACCCAA
82
167

715602
N/A
N/A
102403
102418
ACAGAATTCCCAAGCT
110
168

715605
N/A
N/A
102409
102424
CATAGCACAGAATTCC
112
169

715608
N/A
N/A
102430
102445
AATTGTATCCAGACAT
100
170

715611
N/A
N/A
102469
102484
CTTTAAGCCACATGGT
106
171

715614
N/A
N/A
102475
102490
AAATTACTTTAAGCCA
110
172

715617
N/A
N/A
102486
102501
AAGACGGATAAAAATT
98
173

715620
N/A
N/A
102492
102507
AAAAATAAGACGGATA
111
174

715623
N/A
N/A
102502
102517
CCTAAGAGTAAAAAAT
113
175

715626
N/A
N/A
102551
102566
ACCTGACATTTTGGAG
64
176

715629
N/A
N/A
102557
102572
GAGCCTACCTGACATT
112
177

715632
N/A
N/A
109609
109624
ATCCAATTATGTCCCA
109
178

TABLE 3

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715402
656
671
4116
4131
AGGAGTCGGGCAGCTT
59
179

715405
662
677
4122
4137
TGAAGAAGGAGTCGGG
60
180

715408
668
683
4128
4143
GCGGCTTGAAGAAGGA
60
181

715411
708
723
7142
7157
GCATCAGTACTGGCCT
94
182

715414
742
757
7176
7191
AACATGCTGTGGAGTC
31
183

715417
749
764
7183
7198
GAGCTCGAACATGCTG
104
184

715420
947
962
N/A
N/A
GATTTAAGAAGTATCT
107
185

715423
970
985
55465
55480
CCATGTTGTTGTCTGA
30
186

715426
1079
1094
79020
79035
ATCCATCAGGAAGAGG
80
187

715429
1100
1115
79041
79056
CCTGAGTCATGGCTTG
62
188

715432
1106
1121
79047
79062
CTCCATCCTGAGTCAT
65
189

715435
1138
1153
79079
79094
GGTCTTGTTCTTATGG
36
190

715438
1182
1197
N/A
N/A
TTCATGGCAAAACGAG
82
191

715441
1188
1203
N/A
N/A
CTCTGGTTCATGGCAA
57
192

715444
1249
1264
98951
98966
TCCCTGTGGGCTCTGG
84
193

715447
1507
1522
116696
116711
CAATTCCTGAGACATC
81
194

715450
1514
1529
116703
116718
TTGTTCTCAATTCCTG
53
195

715453
1556
1571
N/A
N/A
AGGTGCCACTGTTAAG
59
196

715456
1562
1577
120467
120482
AGTGATAGGTGCCACT
96
197

715459
1568
1583
120473
120488
CTCGAGAGTGATAGGT
93
198

715462
1574
1589
120479
120494
TCTCATCTCGAGAGTG
94
199

715465
1747
1762
122772
122787
GTCCACATTTGTCCCA
91
200

715468
1868
1883
122893
122908
GCTTGGTGGCAGCCAA
90
201

715471
1874
1889
122899
122914
TATCTAGCTTGGTGGC
36
202

715474
1881
1896
122906
122921
CTTTCTTTATCTAGCT
78
203

715477
3543
3558
124568
124583
AGACACATACTCTAGT
61
204

715480
3564
3579
124589
124604
GGAAACCATTATTACT
23
205

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
15
206

715486
3628
3643
124653
124668
TACTTCATAGCTTATA
27
207

715489
3634
3649
124659
124674
AACTATTACTTCATAG
90
208

715492
3663
3678
124688
124703
GCTAGCTGGTGCCACT
76
209

715495
3671
3686
124696
124711
ACAGAGGTGCTAGCTG
80
210

715498
3724
3739
124749
124764
TGAACCCTTGAAAATA
91
211

715501
3968
3983
64588
64603
AAAAGCCTTAGAGTCA
28
212

124993
125008

715504
4682
4697
125707
125722
TGGTTTATTGTAAAAG
70
213

715507
1391
1406
102523
102538
TGGGATTGATATTCCG
95
214

715510
1402
1417
102534
102549
ATTTGCTGTGCTGGGA
22
215

715513
N/A
N/A
4554
4569
GCGGAGGCGCGCGCAT
125
216

715516
N/A
N/A
5149
5164
CCTATGAGTCAACCTG
77
217

715519
N/A
N/A
5540
5555
TTCCACTCAAGTTACA
96
218

715522
N/A
N/A
5548
5563
ACTCTTCTTTCCACTC
87
219

715525
N/A
N/A
7383
7398
TTACTTTAAGAAGTAT
100
220

715528
N/A
N/A
8644
8659
AAACCTGATCCTTTGA
98
221

715531
N/A
N/A
8818
8833
ACAACCTGGTTTGTTT
94
222

715534
N/A
N/A
8885
8900
TCCCCAGGTCAGCATG
112
223

715537
N/A
N/A
10155
10170
ACTTGGCACCAAAAGC
122
224

715540
N/A
N/A
10916
10931
TGAAGAACTATTTCCT
82
225

715543
N/A
N/A
10922
10937
ACTACTTGAAGAACTA
72
226

715546
N/A
N/A
10928
10943
TGACCAACTACTTGAA
59
227

715549
N/A
N/A
10936
10951
GAAGTTGTTGACCAAC
66
228

715552
N/A
N/A
10942
10957
AAATAGGAAGTTGTTG
86
229

715555
N/A
N/A
10963
10978
GTTATTCAGCAGCTTA
21
230

715558
N/A
N/A
10969
10984
CAGGAAGTTATTCAGC
37
231

715561
N/A
N/A
37599
37614
CACAACTCAGACAGGG
69
232

715564
N/A
N/A
37605
37620
CAAGCACACAACTCAG
75
233

715567
N/A
N/A
37830
37845
GGTAGGATAAATGAAT
99
234

715570
N/A
N/A
37836
37851
GCCAAAGGTAGGATAA
79
235

715573
N/A
N/A
64347
64362
TATATATGGTAGTCTA
76
236

715576
N/A
N/A
79125
79140
AACCTTTACCAAAACG
80
237

715579
N/A
N/A
80917
80932
CTGTCTGGAATACACA
100
238

715582
N/A
N/A
80924
80939
GTCAAGCCTGTCTGGA
33
239

715585
N/A
N/A
80978
80993
AAGGTCTGGAACAGAT
73
240

715588
N/A
N/A
81084
81099
AGCAGCTAACAGCTTG
96
241

715591
N/A
N/A
81149
81164
CTTTGGCAGAGATAAA
41
242

715594
N/A
N/A
81155
81170
ATATTTCTTTGGCAGA
39
243

715597
N/A
N/A
98888
98903
CTGGTTCATGGCTGAA
89
244

715600
N/A
N/A
102399
102414
AATTCCCAAGCTACCC
82
245

715603
N/A
N/A
102405
102420
GCACAGAATTCCCAAG
106
246

715606
N/A
N/A
102411
102426
ACCATAGCACAGAATT
88
247

715609
N/A
N/A
102448
102463
TGTGTAGGCTGACTTA
56
248

715612
N/A
N/A
102471
102486
TACTTTAAGCCACATG
77
249

715615
N/A
N/A
102482
102497
CGGATAAAAATTACTT
94
250

715618
N/A
N/A
102488
102503
ATAAGACGGATAAAAA
101
251

715621
N/A
N/A
102494
102509
TAAAAAATAAGACGGA
106
252

715624
N/A
N/A
102504
102519
TGCCTAAGAGTAAAAA
123
253

715627
N/A
N/A
102553
102568
CTACCTGACATTTTGG
88
254

715630
N/A
N/A
102559
102574
AAGAGCCTACCTGACA
94
255

715633
N/A
N/A
120466
120481
GTGATAGGTGCCACTA
78
256

Example 2
Antisense Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acid and were tested for their effect on Yap1 mRNA level in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured A-431 cells at a density of 5,000 cells per well were treated using free uptake with 2,000 nM of modified oligonucleotide. After a treatment period of approximately 48 hours, RNA was isolated from the cells and Yap1 mRNA levels were measured by quantitative real-time RTPCR. Human primer probe set RTS4814 was used to measure mRNA levels. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides targeting the amplicon region.

“Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Gapmers listed in the Tables below are targeted to either SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 (GENBANK Accession No. NM_006106.4), or SEQ ID NO: 4 (GENBANK Accession No. NM_001130145.2). ‘N/A’ indicates that the modified oligonucleotide does not target that particular gene sequence with 100% complementarity. ‘N.D.’ indicates that the % UTC is not defined for that particular modified oligonucleotide in that particular experiment. Activity ofthe modified oligonucleotide may be defined in a different experiment.

TABLE 4

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

716346
1
16
3461
3476
TTTCCCTGGCGGCGGC
77
257

716349
107
122
3567
3582
ACTTTTTCCCTCCAAC
78
258

716352
184
199
3644
3659
CTGCGCCCCGGCTCCA
105
259

716355
279
294
3739
3754
GACGGCTGCGGGCCGG
96
260

716358
331
346
3791
3806
CGAGGGCTACGCCCGG
104
261

716361
405
420
3865
3880
GGTTGAGGCGGCGGCT
75
262

716364
493
508
3953
3968
CGCCGCGGGTGCCGGT
110
263

716367
631
646
4091
4106
CATGGGCACGGTCTGG
70
264

716370
716
731
7150
7165
CAGTGCCTGCATCAGT
25
265

716373
775
790
7209
7224
CAACTGCAGAGAAGCT
69
266

716376
855
870
7289
7304
CGAAGATGCTGAGCTG
35
267

716379
927
942
7361
7376
CCAGAAGATGTCTTTG
123
268

716382
993
1008
55488
55503
AGCATGGCCTTCCTGG
73
269

716385
1084
1099
79025
79040
TTCCCATCCATCAGGA
87
270

716388
1144
1159
79085
79100
AGAGGTGGTCTTGTTC
55
271

716391
1206
1221
98908
98923
GGAGCACTCTGACTGA
44
272

716394
1304
1319
99006
99021
GTTGCTGCAGTCGCAT
120
273

716397
1365
1380
99067
99082
GGCCTCACCTGCCGAA
88
274

716400
1423
1438
N/A
N/A
TAACTCCTGACATTTT
106
275

716403
1491
1506
116680
116695
CCGGGAGAAGACACTG
110
276

716406
1576
1591
120481
120496
ACTCTCATCTCGAGAG
117
277

716409
1636
1651
120541
120556
CAGGAAGTCATCTGGG
99
278

716412
1717
1732
122742
122757
GTAGTCTGGGAAACGG
41
279

716415
1794
1809
122819
122834
AGCTCCTCTCCTTCTA
90
280

716418
1910
1925
122935
122950
CCTGAGGGCTCTATAA
75
281

716421
1996
2011
123021
123036
TATTAGCCTGAAAACT
86
282

716424
2064
2079
123089
123104
GCAATGGACAAGGAAG
25
283

716427
2170
2185
123195
123210
AGCCCCCAAAATGAAC
86
284

716430*
2221
2236
123246
123261
TAACTGGGCAAAAGGA
28
285

716433*
2272
2287
123297
123312
AGCATCTGACTTCTAA
20
286

716436
2329
2344
123354
123369
ACTGGACAAAGGAAGC
59
287

716439
2387
2402
123412
123427
GTATTTAATATCAGAT
77
288

716442
2466
2481
123491
123506
GCACTAGGAGGAAAAG
63
289

716445
2559
2574
123584
123599
GTATGTGGCAATAATT
28
290

716448
2683
2698
123708
123723
CCGACAAAACCAACCA
62
291

716451
2734
2749
123759
123774
CCCAAGCTACAACTAT
67
292

716454
2803
2818
123828
123843
CGAGATTTAAATAAGG
27
293

716457
2883
2898
123908
123923
AAAGGATACATTCCAC
61
294

716460
2946
2961
123971
123986
TATTCTAAATGCATAC
86
295

716463
2998
3013
124023
124038
GACTGCCCCAACCAGA
64
296

716466
3071
3086
124096
124111
GTGGAGCACTCCCCTA
58
297

716469
3122
3137
124147
124162
GTTTGCTCCTTTCCAA
25
298

716472
3204
3219
124229
124244
GTCATGCACATTATGA
78
299

716475
3272
3287
124297
124312
CTTCCAAAACTAAGGC
63
300

716478
3330
3345
124355
124370
TATTTTAATCTAGTCG
46
301

716481
3382
3397
121835
121850
TCAGCATAGAAGTAGG
23
302

124407
124422

716484
3433
3448
124458
124473
CACTTTTCCAGCTAAC
35
303

716487
3541
3556
42912
42927
ACACATACTCTAGTTA
64
304

124566
124581

716490
3640
3655
124665
124680
ACAACCAACTATTACT
63
305

716493
3692
3707
124717
124732
ACATTGAAAGACCCTT
30
306

716496
3745
3760
124770
124785
GAAGAGATTTTATGCC
19
307

716499
3852
3867
124877
124892
TTTTGCCCTCCTCCAA
102
308

716502
3913
3928
124938
124953
CACAGTGATTGCATTT
11
309

716505
3996
4011
125021
125036
GATTTAATCTTTCTGC
35
310

716508
4065
4080
125090
125105
CTAGGTAGAATTTCAT
67
311

716511
4131
4146
125156
125171
GATCTTCTGCACATTA
51
312

716514
4201
4216
125226
125241
GCTGATATATAAGATA
68
313

716517
4255
4270
125280
125295
TTCACAACCCCCCCCC
53
314

716520
4312
4327
125337
125352
AGTCTTTATTAAAGAG
96
315

716523
4426
4441
125451
125466
CAAATTAAAGTTGAGG
37
316

716526
4481
4496
125506
125521
TCAAAGCACTGTGCCA
88
317

716529
4544
4559
125569
125584
CAAACTCAAAAAGGGA
61
318

716532
4615
4630
125640
125655
CAAGAAGCAGTTAAGC
70
319

716535
4737
4752
125762
125777
CCTGACTGAAAATAAC
86
320

716538
4789
4804
125814
125829
TCTGAAACTCCAAATC
77
321

716541
4840
4855
125865
125880
TAAAGGCACTACATTT
92
322

716544
4898
4913
125923
125938
TACTTAACACAGCAAC
71
323

716547
4986
5001
44309
44324
GGTATGAATTCTGAAT
44
324

126011
126026

716550
5037
5052
126062
126077
GCACTGAATATTGCCA
77
325

716553
5088
5103
126113
126128
ATCCACCTGAGCACTC
54
326

716556
5211
5226
126236
126251
GCATTAAAGAATTCTC
39
327

716559
5294
5309
126319
126334
CCTAACATATGAGCAT
62
328

716565
N/A
N/A
5516
5531
GGGCTAACTACATTGC
129
329

716568
N/A
N/A
5640
5655
GATTTTTTCTGAGTTC
72
330

716574
N/A
N/A
11831
11846
TACACTGTATATGTTC
91
331

11769
11784

716577
N/A
N/A
58766
58781
TCTGTCAGTTATCCTA
21
332

58782
58797

TABLE 5

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

716347
64
79
3524
3539
TGCCTTTCCCCGCCTC
85
333

716350
129
144
3589
3604
CTCGGACCTGCGGCGC
99
334

716353
216
231
3676
3691
GCATCCCCCGCCCCGG
98
335

716356
296
311
3756
3771
CGAGGTGGAGAAGCGG
112
336

716359
348
363
3808
3823
CCCCTGACCCAGGCGA
101
337

716362
433
448
3893
3908
AGGCGGCTGCCCTTGG
94
338

716365
533
548
3993
4008
TCTGATGCCCGGCGGG
83
339

716368
652
667
4112
4127
GTCGGGCAGCTTCCGG
86
340

716371
733
748
7167
7182
TGGAGTCAGGGCTCCT
115
341

716374
802
817
7236
7251
GGTCAGTGTCCCAGGA
54
342

716377
876
891
7310
7325
GGTATCTCAAAAGAAG
76
343

716380
944
959
7378
7393
TTAAGAAGTATCTCTG
54
344

716383
1049
1064
55544
55559
TCATCATATTCTGCTG
98
345

716386
1110
1125
79051
79066
ATTTCTCCATCCTGAG
60
346

716389
1161
1176
79102
79117
AGCCTTGGGTCTAGCC
93
347

716392
1266
1281
98968
98983
CTGCCACCCATGACGC
95
348

716395
1331
1346
99033
99048
GCCGCAGCCTCTCCTT
92
349

716398
1382
1397
N/A
N/A
TATTCCGCATTGCCTG
70
350

716401
1440
1455
116629
116644
AACTGGCTACGCAGGG
92
351

716404
1519
1534
116708
116723
CGTCATTGTTCTCAAT
63
352

716407
1593
1608
120498
120513
CTTAGTCCACTGTCTG
35
353

716410
1668
1683
N/A
N/A
GTATCACCTGTATCCA
52
354

716413
1753
1768
122778
122793
TCCAAGGTCCACATTT
79
355

716416
1834
1849
122859
122874
AAGGATGTCAGAACTC
45
356

716419
1962
1977
122987
123002
TTTCCGGTGCATGTGT
36
357

716422
2030
2045
123055
123070
AGTATCTTGCTGGACG
39
358

716425
2081
2096
123106
123121
GCAATACATTAACAGC
71
359

716428*
2187
2202
123212
123227
ACAGGCTCACTTCCCC
10
360

716431*
2238
2253
123263
123278
AATGATTGGTGAACAT
55
361

716434*
2289
2304
123314
123329
TAAATGCTGTGACATG
44
362

716437
2349
2364
123374
123389
CCAGTAAATCATGTTT
41
363

716440
2406
2421
123431
123446
CTCTTCAAATCAGCAT
45
364

716443
2483
2498
123508
123523
TTATGTGACTAATGAT
73
365

716446
2597
2612
123622
123637
GCACACCCACAAAATT
83
366

716449
2700
2715
123725
123740
GGTCATTTGCCTAGGT
49
367

716452
2759
2774
123784
123799
TTACCAAAACAACTAC
98
368

716455
2849
2864
123874
123889
GTTATGTTTGGGTGTG
17
369

716458
2900
2915
123925
123940
AAGCAGGGAAACCTAA
94
370

716461
2963
2978
123988
124003
ATAAACTACTAGTCAT
123
371

716464
3015
3030
124040
124055
TACTTCAAACATCTGC
62
372

716467
3088
3103
124113
124128
CCGTATGCCCAGAGGG
99
373

716470
3170
3185
124195
124210
AATCGAGACTTAAAAA
104
374

716473
3221
3236
124246
124261
CTATAAAGCTTATTTC
104
375

716476
3292
3307
124317
124332
GAACTACAAACTAGAA
91
376

716479
3348
3363
124373
124388
GAACAATCTTGAAGGC
32
377

716482
3399
3414
124424
124439
CTATCCAGGGTCAATT
83
378

716485
3461
3476
124486
124501
ACTACCAATATACATT
84
379

716488
3558
3573
38751
38766
CATTATTACTCCTGTA
67
380

124583
124598

716491
3658
3673
124683
124698
CTGGTGCCACTTTAAT
54
381

716494
3709
3724
124734
124749
AAGGGCTTATTCTAGA
112
382

716497
3762
3777
124787
124802
AGCAGCTTTTGCCAGG
65
383

716500
3869
3884
124894
124909
AACTTCTTACTTCCAA
18
384

716503
3951
3966
124976
124991
TTATTATGAGTGATCA
33
385

716506
4031
4046
125056
125071
TCTGCAGTGGCCATTT
62
386

716509
4083
4098
125108
125123
TATACCCAATTTTGCA
70
387

716512
4150
4165
125175
125190
ACTCCTTCCAAGTAGC
99
388

716515
4218
4233
125243
125258
TAAGCTAAAGCTAATC
123
389

716518
4272
4287
125297
125312
CAAGGTCCCCCTAAAT
88
390

716521
4329
4344
125354
125369
CAGCACGGTGTAAGAC
79
391

716524
4443
4458
125468
125483
ACTGAGGTATAACTGG
35
392

716527
4502
4517
125527
125542
AGTACAGAGGGCATCG
64
393

716530
4561
4576
125586
125601
ACATCAAGGCTATGAT
83
394

716533
4666
4681
125691
125706
CAATTCAAGAATACCC
64
395

716536
4754
4769
125779
125794
AAGTAGATCTAAGAAG
94
396

716539
4806
4821
125831
125846
AATAGTGCTTTGGAAG
59
397

716542
4863
4878
125888
125903
CTTCCCTGTGTTCATT
45
398

716545
4916
4931
125941
125956
GCATGTATTTAATATG
91
399

716548
5003
5018
126028
126043
GAGTTTCAACACTGAT
31
400

716551
5054
5069
126079
126094
CGCTAGAAAAGTGTTA
76
401

716554
5105
5120
126130
126145
ATGCTTGCGAGGATAA
30
402

716557
5243
5258
126268
126283
ATTGGTACTATATATA
80
403

716560
5312
5327
126337
126352
TAACAATTTATGTAAG
107
404

716563
N/A
N/A
5445
5460
TGAAGCAAGTTCTCAA
126
405

716566
N/A
N/A
5552
5567
GGTAACTCTTCTTTCC
102
406

716569
N/A
N/A
5674
5689
CTCCTTAACCCGGGTT
115
407

716572
N/A
N/A
126465
126480
CAGTAAGAAGCCAAAA
122
408

716575
N/A
N/A
30867
30882
AAAGAACTTAGTTCCC
84
409

31189
31204

716578
N/A
N/A
70445
70460
AACTTTCACATAAACT
102
410

70695
70710

TABLE 6

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

716348
84
99
3544
3559
ACGGAGGCCGGACAGC
107
411

716351
166
181
3626
3641
GGTCTGGCGGCTGCGC
112
412

716354
251
266
3711
3726
TCGCTCTCAGGGCCGG
114
413

716357
314
329
3774
3789
CGCCCCGGCTCCACGG
127
414

716360
388
403
3848
3863
CTGCCCGGGATCCATG
118
415

716363
467
482
3927
3942
CGGACGGCGGGCCCTG
103
416

716366
568
583
4028
4043
CAGGTCGGTCTCCGAG
95
417

716369
670
685
4130
4145
CGGCGGCTTGAAGAAG
94
418

716372
751
766
7185
7200
ATGAGCTCGAACATGC
61
419

716375
819
834
7253
7268
GAGACTACTCCAGTGG
63
420

716378
893
908
7327
7342
GCAGAGGTACATCATC
44
421

716381
961
976
55456
55471
TGTCTGATCGATGTGA
35
422

716384
1066
1081
N/A
N/A
AGGACCTGAAGCCGAG
71
423

716387
1127
1142
79068
79083
TATGGTTTATATAGTA
33
424

716390
1189
1204
N/A
N/A
TCTCTGGTTCATGGCA
66
425

716393
1285
1300
98987
99002
TTGCTGCTGGTTGGAG
46
426

716396
1348
1363
99050
99065
CAGTTCTTGCTGTTTC
123
427

716399
1403
1418
102535
102550
AATTTGCTGTGCTGGG
40
428

716402
1474
1489
116663
116678
ATTTTGAGTCCCACCA
85
429

716405
1547
1562
116736
116751
TGTTAAGGAAAGGATC
149
430

716408
1610
1625
120515
120530
CACTGTAGCTGCTCAT
54
431

716411
1700
1715
122725
122740
TCTGCTGTGAGGGCAG
102
432

716414
1777
1792
122802
122817
GTTCATTCCATCTCCT
59
433

716417
1891
1906
122916
122931
TGTAAGAAAGCTTTCT
78
434

716420
1979
1994
24076
24091
CAACTGGCTTATGGAA
50
435

123004
123019

716423
2047
2062
71297
71312
GCAAAATAGAGGATTA
43
436

123072
123087

716426
2115
2130
123140
123155
TTTGATTCTTTAGAGC
45
437

716429*
2204
2219
123229
123244
TGGCATCCATCATCCA
28
438

716432*
2255
2270
123280
123295
TCTGAGTATTTAGTTA
30
439

716435*
2306
2321
123331
123346
ACAACTGTTGAACAAA
45
440

716438
2366
2381
123391
123406
ATTTTTGGCTTGTCAG
32
441

716441
2423
2438
123448
123463
GCCTTGGTTTCAGCTA
57
442

716444
2528
2543
123553
123568
AAATTGTCTCATGCCT
40
443

716447
2666
2681
123691
123706
CCAACCAACCCCCCCA
97
444

716450
2717
2732
123742
123757
AACAGATTCACTAATA
83
445

716453
2786
2801
123811
123826
GGTAAAAAAAACCAGG
87
446

716456
2866
2881
123891
123906
ACCACACTATTATAAA
96
447

716459
2926
2941
123951
123966
CGCTACCATTTTAAAA
121
448

716462
2981
2996
124006
124021
TTAAACTACCAGTGAA
86
449

716465
3036
3051
124061
124076
GCTCTTTCTAGAACAC
82
450

716468
3105
3120
124130
124145
TCATCAGATAATATCT
118
451

716471
3187
3202
124212
124227
CCTACTCACTGAATTC
48
452

716474
3238
3253
124263
124278
TAAATGAAGGTAAACC
120
453

716477
3309
3324
124334
124349
GTGTTCATTACAAATG
42
454

716480
3365
3380
124390
124405
GCAAGTCTTGTAAGTA
18
455

716483
3416
3431
15582
15597
CAAAACCTTATAGTAT
159
456

82739
82754

124441
124456

716486
3494
3509
124519
124534
ATCATGATTATCTCTA
68
457

716489
3606
3621
124631
124646
AGTTAATTCATGCTCG
23
458

716492
3675
3690
124700
124715
AAACACAGAGGTGCTA
72
459

716495
3728
3743
124753
124768
GTTATGAACCCTTGAA
58
460

716498
3833
3848
124858
124873
GAAGGGCCAAAATACT
92
461

716501
3891
3906
124916
124931
GCACTGAAAGTACTTA
32
462

716504
3970
3985
6107
6122
ATAAAAGCCTTAGAGT
112
463

62583
62598

124995
125010

716507
4048
4063
125073
125088
ACTACTCTAAAACTCC
53
464

716510
4102
4117
125127
125142
CAACATGCTATGTAAT
122
465

716513
4184
4199
125209
125224
AATCTTAATCTGTGGC
30
466

716516
4237
4252
125262
125277
AACTTTCCCACCCTCC
84
467

716519
4290
4305
125315
125330
GTTTATAAAGTTCTCT
57
468

716522
4363
4378
125388
125403
GTGACTGAAACTCTAG
47
469

716525
4460
4475
125485
125500
CACAGTACTGCTACAA
64
470

716528
4520
4535
125545
125560
TTAGGTCTCCTTCAGG
70
471

716531
4580
4595
125605
125620
GGACATAAAACAAGAG
65
472

716534
4693
4708
125718
125733
GATTATAAAATTGGTT
90
473

716537
4772
4787
125797
125812
ATGTGCTCCATCAACC
36
474

716540
4823
4838
125848
125863
GAAAAGTTATTACAAC
120
475

716543
4880
4895
125905
125920
TATTTGTAGCAAAGTC
35
476

716546
4968
4983
125993
126008
CACAATTAATTACTGT
103
477

716549
5020
5035
126045
126060
CCACTTTTGCAATGTT
44
478

716552
5071
5086
126096
126111
TTTCTCAGATGTACCA
53
479

716555
5167
5182
126192
126207
TACTTTTTCAAGATAC
99
480

716558
5277
5292
126302
126317
CTCTTACATCTAAAAC
81
481

716561
5338
5353
126363
126378
AAGGTATTACATAAGA
58
482

716564
N/A
N/A
5479
5494
CTTTTGGGCAAAGTTC
103
483

716567
N/A
N/A
5599
5614
GACTATACAACAGGCC
134
484

716570
N/A
N/A
5717
5732
AAGTGTTTAGGCAAGC
56
485

716573
N/A
N/A
126516
126531
AGTTACTACTGTAATC
116
486

716576
N/A
N/A
58764
58779
TGTCAGTTATCCTATC
52
487

58780
58795

716579
N/A
N/A
94212
94227
ATAGAGATTTTCCCTC
84
488

103505
103520

TABLE 7

Inhibition of Yap1 nRNA by 3-10-3 cEt gapmers targeting

SEQ ID NO: 3, and 4

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 3
NO: 3
NO: 4
NO: 4

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ ID

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
NO

716562
N/A
N/A
1359
1374
GCCTGCCGAAGCAGTT
103
489

716571
1062
1077
N/A
N/A
GCTGAAGCCGAGTTCA
91
490

Example 3
Antisense Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acid and were tested for their effect on Yap1 mRNA level in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured A-431 cells at a density of 5,000 cells per well were treated using free uptake with 2,000 nM of modified oligonucleotide. After a treatment period of approximately 48 hours, RNA was isolated from the cells and Yap1 mRNA levels were measured by quantitative real-time RTPCR. Human primer probe set RTS36584 (forward sequence ACGACCAATAGCTCAGATCCT, designated herein as SEQ ID NO.: 14; reverse sequence CACCTGTATCCATCTCATCCAC, designated herein as SEQ ID NO.: 15; probe sequence TGTAGCTGCTCATGCTTAGTCCACTG, designated herein as SEQ ID NO.: 16) was used to measure mRNA levels. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides targeting the amplicon region.

“Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either SEQ ID NO.: 1 or SEQ ID NO.: 2. ‘N/A’ indicates that the modified oligonucleotide does not target that particular gene sequence with 100% complementarity. ‘N.D.’ indicates that the % UTC is not defined for that particular modified oligonucleotide in that particular experiment. Activity of the modified oligonucleotide may be defined in a different experiment.

TABLE 8

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
2
206

715491
3638
3653
124663
124678
AACCAACTATTACTTC
8
131

958348
556
571
4016
4031
CGAGTCCCCGCGGACG
122
491

958349
557
572
4017
4032
CCGAGTCCCCGCGGAC
81
492

958350
558
573
4018
4033
TCCGAGTCCCCGCGGA
106
493

958351
560
575
4020
4035
TCTCCGAGTCCCCGCG
67
494

958352
563
578
4023
4038
CGGTCTCCGAGTCCCC
110
495

958353
564
579
4024
4039
TCGGTCTCCGAGTCCC
43
496

958354
565
580
4025
4040
GTCGGTCTCCGAGTCC
31
497

958355
611
626
4071
4086
CGTTGGCCGTCTTGGG
51
498

958356
663
678
4123
4138
TTGAAGAAGGAGTCGG
9
499

958357
667
682
4127
4142
CGGCTTGAAGAAGGAG
12
500

958358
669
684
4129
4144
GGCGGCTTGAAGAAGG
34
501

958359
709
724
7143
7158
TGCATCAGTACTGGCC
117
502

958360
745
760
7179
7194
TCGAACATGCTGTGGA
12
503

958361
747
762
7181
7196
GCTCGAACATGCTGTG
8
504

958362
748
763
7182
7197
AGCTCGAACATGCTGT
58
505

958363
750
765
7184
7199
TGAGCTCGAACATGCT
70
506

958364
969
984
55464
55479
CATGTTGTTGTCTGAT
19
507

958365
971
986
55466
55481
GCCATGTTGTTGTCTG
34
508

958366
1607
1622
120512
120527
TGTAGCTGCTCATGCT
16*
509

958367
1871
1886
122896
122911
CTAGCTTGGTGGCAGC
105
510

958368
1873
1888
122898
122913
ATCTAGCTTGGTGGCA
11
511

958369
1875
1890
122900
122915
TTATCTAGCTTGGTGG
4
512

958370
1877
1892
122902
122917
CTTTATCTAGCTTGGT
7
513

958371
3637
3652
124662
124677
ACCAACTATTACTTCA
2
514

958372
3666
3681
124691
124706
GGTGCTAGCTGGTGCC
49
515

958373
3667
3682
124692
124707
AGGTGCTAGCTGGTGC
8
516

958374
3670
3685
124695
124710
CAGAGGTGCTAGCTGG
38
517

958375
3967
3982
11044
11059
AAAGCCTTAGAGTCAA
2
518

124992
125007

958376
1392
1407
102524
102539
CTGGGATTGATATTCC
31
519

958377
1393
1408
102525
102540
GCTGGGATTGATATTC
9
520

958378
N/A
N/A
7141
7156
CATCAGTACTGGCCTA
25
521

958379
N/A
N/A
3336
3351
GCGCCCGCCCGCACCG
124
522

958380
N/A
N/A
3337
3352
CGCGCCCGCCCGCACC
106
523

958381
N/A
N/A
3344
3359
TCCTCTGCGCGCCCGC
146
524

958382
N/A
N/A
3345
3360
TTCCTCTGCGCGCCCG
111
525

958383
N/A
N/A
3346
3361
CTTCCTCTGCGCGCCC
96
526

958384
N/A
N/A
3347
3362
CCTTCCTCTGCGCGCC
131
527

958385
N/A
N/A
4548
4563
GCGCGCGCATTGTGCA
115
528

958386
N/A
N/A
4549
4564
GGCGCGCGCATTGTGC
111
529

958387
N/A
N/A
4551
4566
GAGGCGCGCGCATTGT
131
530

958388
N/A
N/A
4552
4567
GGAGGCGCGCGCATTG
112
531

958389
N/A
N/A
4553
4568
CGGAGGCGCGCGCATT
126
532

958390
N/A
N/A
4571
4586
GCGAAGGTGCGGAGCG
145
533

958391
N/A
N/A
4572
4587
AGCGAAGGTGCGGAGC
102
534

958392
N/A
N/A
5148
5163
CTATGAGTCAACCTGC
50
535

958393
N/A
N/A
5150
5165
GCCTATGAGTCAACCT
89
536

958394
N/A
N/A
8647
8662
TTGAAACCTGATCCTT
54
537

958395
N/A
N/A
8821
8836
CTAACAACCTGGTTTG
114
538

958396
N/A
N/A
8909
8924
AGGCTATTAAGCTGTT
131
539

958397
N/A
N/A
8910
8925
CAGGCTATTAAGCTGT
127
540

958398
N/A
N/A
8911
8926
GCAGGCTATTAAGCTG
76
541

958399
N/A
N/A
10927
10942
GACCAACTACTTGAAG
45
542

958400
N/A
N/A
10929
10944
TTGACCAACTACTTGA
26
543

958401
N/A
N/A
10964
10979
AGTTATTCAGCAGCTT
19
544

958402
N/A
N/A
29057
29072
CTCTTACACAGCCTAG
28
545

958403
N/A
N/A
36596
36611
CAGTTTATGTAGTAGT
5
546

958404
N/A
N/A
37602
37617
GCACACAACTCAGACA
52
547

958405
N/A
N/A
44925
44940
TTATGGGATGAGTGCT
24
548

958406
N/A
N/A
55773
55788
TTTCAGTTATCGGCCC
29
549

958407
N/A
N/A
63319
63334
AATACTGATCTGCAGC
35
550

958408
N/A
N/A
64348
64363
CTATATATGGTAGTCT
20
551

958409
N/A
N/A
79120
79135
TTACCAAAACGAGGGT
99
552

958410
N/A
N/A
79121
79136
TTTACCAAAACGAGGG
70
553

958411
N/A
N/A
79122
79137
CTTTACCAAAACGAGG
90
554

958412
N/A
N/A
79124
79139
ACCTTTACCAAAACGA
49
555

958413
N/A
N/A
90343
90358
CTAGTAATCTTACTGG
80
556

958414
N/A
N/A
102402
102417
CAGAATTCCCAAGCTA
73
557

958415
N/A
N/A
102449
102464
CTGTGTAGGCTGACTT
16
558

958416
N/A
N/A
102450
102465
GCTGTGTAGGCTGACT
36
559

958417
N/A
N/A
102483
102498
ACGGATAAAAATTACT
85
560

958418
N/A
N/A
102558
102573
AGAGCCTACCTGACAT
47
561

958419
N/A
N/A
102560
102575
TAAGAGCCTACCTGAC
68
562

958420
N/A
N/A
109095
109110
TTCATAATCTGACTAG
66
563

958421
N/A
N/A
112417
112432
CTCCGTGGTGATCCCA
13
564

958422
N/A
N/A
115003
115018
TTTCTTAACCAGCGGA
15
565

958423
N/A
N/A
121122
121137
GATCAACATGCTAACA
51
566

TABLE 9

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers

targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
1
206

958436
91
106
3551
3566
TCCCTTGACGGAGGCC
124
567

958441
281
296
3741
3756
GCGACGGCTGCGGGCC
72
568

958446
346
361
3806
3821
CCTGACCCAGGCGAGC
70
569

958451
538
553
3998
4013
CACGATCTGATGCCCG
10
570

958456
824
839
7258
7273
GGCCAGAGACTACTCC
90
571

958461
1355
1370
99057
99072
GCCGAAGCAGTTCTTG
79
572

958466
1840
1855
122865
122880
GTCATTAAGGATGTCA
9
573

958471
1943
1958
122968
122983
CTTAGATCCTTCACAG
14
574

958476
1961
1976
122986
123001
TTCCGGTGCATGTGTC
2
575

958481
1980
1995
123005
123020
GCAACTGGCTTATGGA
6
576

958486
2106
2121
123131
123146
TTAGAGCCAACTGTGA
9
577

958491
2291
2306
123316
123331
ACTAAATGCTGTGACA
4
578

958496
2515
2530
123540
123555
CCTTATAAGCTCCTAA
3
579

958501
2693
2708
123718
123733
TGCCTAGGTTCCGACA
41
580

958506
2812
2827
123837
123852
GCAGATAATCGAGATT
6
581

958511
2870
2885
123895
123910
CACTACCACACTATTA
31
582

958516
3003
3018
124028
124043
CTGCAGACTGCCCCAA
38
583

958521
3112
3127
124137
124152
TTCCAATTCATCAGAT
14
584

958526
3353
3368
124378
124393
AGTAAGAACAATCTTG
6
585

958531
3371
3386
124396
124411
GTAGGAGCAAGTCTTG
5
586

958536
3393
3408
124418
124433
AGGGTCAATTTTCAGC
3
587

958541
3404
3419
124429
124444
GTATTCTATCCAGGGT
4
588

958546
3538
3553
124563
124578
CATACTCTAGTTACAT
6
589

958551
3550
3565
124575
124590
CTCCTGTAGACACATA
5
590

958556
3639
3654
124664
124679
CAACCAACTATTACTT
10
591

958561
3673
3688
124698
124713
ACACAGAGGTGCTAGC
48
592

958566
3935
3950
124960
124975
ACCTATGAACTATTAT
18
593

958571
4105
4120
125130
125145
CAACAACATGCTATGT
43
594

958576
4173
4188
125198
125213
GTGGCTACTGGCAAAT
53
595

958581
4203
4218
125228
125243
CTGCTGATATATAAGA
26
596

958586
4331
4346
125356
125371
GGCAGCACGGTGTAAG
78
597

958591
4461
4476
125486
125501
TCACAGTACTGCTACA
38
598

958596
4610
4625
125635
125650
AGCAGTTAAGCACTTT
3
599

958601
4844
4859
125869
125884
CCTTTAAAGGCACTAC
17
600

958606
5087
5102
126112
126127
TCCACCTGAGCACTCA
31
601

958611
5284
5299
126309
126324
GAGCATGCTCTTACAT
92
602

958616
1141
1156
79082
79097
GGTGGTCTTGTTCTTA
10
603

958621
1172
1187
79113
79128
AACGAGGGTCAAGCCT
29
604

958626
N/A
N/A
5475
5490
TGGGCAAAGTTCCTAT
158
605

958631
N/A
N/A
5583
5598
TGCAAATAGGAGAGGG
122
606

958636
N/A
N/A
3328
3343
CCGCACCGCGGCCCGG
126
607

958641
N/A
N/A
7512
7527
AGCTACAGAGCTTAAC
102
608

958646
N/A
N/A
10769
10784
TATTATATGGCTAAGC
26
609

958651
N/A
N/A
12678
12693
AACTAAAGAGGACTTA
62
610

958656
N/A
N/A
17870
17885
ACGCAATCTGTGATCC
48
611

958661
N/A
N/A
21191
21206
TGCCGTTGGCCCCTCC
120
612

958666
N/A
N/A
24643
24658
GAAAAGGGCAATCATA
52
613

958671
N/A
N/A
30409
30424
CATTATATGGCACCCA
19
614

958676
N/A
N/A
31186
31201
GAACTTAGTTCCCTAT
34
615

958681
N/A
N/A
34104
34119
AATTAACACCTGAGCT
84
616

958686
N/A
N/A
36190
36205
CGCAATATAGTCTATA
4
617

958691
N/A
N/A
38179
38194
TCAGTTGGCAACAGTC
20
618

958696
N/A
N/A
40280
40295
GCATACTACACTATAA
56
619

958701
N/A
N/A
41534
41549
TTAAACTAGGCACATT
98
620

958706
N/A
N/A
45392
45407
TCGCATGGCCACTGCC
112
621

958711
N/A
N/A
48862
48877
CCAAATAAGGATCTGT
34
622

958716
N/A
N/A
54493
54508
ATGGACTGTATGCAGC
84
623

958721
N/A
N/A
56973
56988
GTAGTATAATGAGTTA
1
624

105504
105519

958726
N/A
N/A
58765
58780
CTGTCAGTTATCCTAT
3
625

58781
58796

958731
N/A
N/A
58768
58783
GCTCTGTCAGTTATCC
7
626

58784
58799

59523
59538

958736
N/A
N/A
62193
62208
GTGATATGGATTCTGT
3
627

958741
N/A
N/A
66072
66087
GTTACTGCAACTGCCC
14
628

958746
N/A
N/A
70253
70268
GTTATCCTCTATAGTC
22
629

958751
N/A
N/A
75535
75550
TCAATGCAGGATTCCA
30
630

958756
N/A
N/A
79463
79478
GTGTTGCATGACAGCC
15
631

958761
N/A
N/A
82824
82839
AGTCTCAACAACCTTC
7
632

958766
N/A
N/A
86559
86574
TAACATATGTCTACTC
23
633

958771
N/A
N/A
92071
92086
CTACAGACGAATTCCA
18
634

958776
N/A
N/A
94770
94785
GGTACTCTCCTTCAGA
94
635

958781
N/A
N/A
97391
97406
GTCATCTATGTGTCCT
6
636

958786
N/A
N/A
99922
99937
TATGTCCTACTTTCCC
10
637

958791
N/A
N/A
102044
102059
CATAAGAAAAGACGAC
123
638

958796
N/A
N/A
103309
103324
ATTATATGGTTGCTTC
3
639

958801
N/A
N/A
108999
109014
CGCTAGCACGCGCGCT
131
640

958806
N/A
N/A
112159
112174
TGCCTAGGGTTCTGTG
30
641

958811
N/A
N/A
115185
115200
CACTGAGGCACGGCCC
92
642

958816
N/A
N/A
120622
120637
GTGATAACATATCCCA
71
643

TABLE 10

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
2
206

958437
134
149
3594
3609
AGGCACTCGGACCTGC
84
644

958442
290
305
3750
3765
GGAGAAGCGGCGACGG
21
645

958447
404
419
3864
3879
GTTGAGGCGGCGGCTG
48
646

958452
571
586
4031
4046
CTCCAGGTCGGTCTCC
26
647

958457
857
872
7291
7306
GTCGAAGATGCTGAGC
5
648

958462
1439
1454
116628
116643
ACTGGCTACGCAGGGC
46
649

958467
1864
1879
122889
122904
GGTGGCAGCCAAAACA
32
650

958472
1945
1960
122970
122985
TCCTTAGATCCTTCAC
5
651

958477
1963
1978
122988
123003
ATTTCCGGTGCATGTG
2
652

958482
2000
2015
123025
123040
TCTGTATTAGCCTGAA
10
653

958487
2192
2207
123217
123232
TCCAAACAGGCTCACT
10
654

958492
2356
2371
123381
123396
TGTCAGACCAGTAAAT
12
655

958497
2534
2549
123559
123574
ATATGGAAATTGTCTC
1
656

958502
2722
2737
123747
123762
CTATTAACAGATTCAC
13
657

958507
2814
2829
123839
123854
GAGCAGATAATCGAGA
6
658

958512
2875
2890
123900
123915
CATTCCACTACCACAC
14
659

958517
3030
3045
124055
124070
TCTAGAACACTAAACT
88
660

958522
3156
3171
124181
124196
AATTAGTCCAAGGGAG
32
661

958527
3356
3371
124381
124396
GTAAGTAAGAACAATC
4
662

958532
3374
3389
124399
124414
GAAGTAGGAGCAAGTC
2
663

958537
3394
3409
124419
124434
CAGGGTCAATTTTCAG
3
664

79237
79252

958542
3408
3423
124433
124448
TATAGTATTCTATCCA
4
665

96503
96518

102951
102966

958547
3540
3555
124565
124580
CACATACTCTAGTTAC
4
666

56579
56594

958552
3555
3570
124580
124595
TATTACTCCTGTAGAC
16
667

958557
3641
3656
124666
124681
CACAACCAACTATTAC
10
668

958562
3691
3706
124716
124731
CATTGAAAGACCCTTA
6
669

958567
3938
3953
124963
124978
TCAACCTATGAACTAT
3
670

958572
4159
4174
125184
125199
ATTATAGGCACTCCTT
5
671

958577
4176
4191
125201
125216
TCTGTGGCTACTGGCA
4
672

958582
4206
4221
125231
125246
AATCTGCTGATATATA
21
673

958587
4364
4379
125389
125404
GGTGACTGAAACTCTA
2
674

958592
4488
4503
125513
125528
CGTAAGATCAAAGCAC
12
675

958597
4626
4641
125651
125666
CCCAATACAACCAAGA
6
676

958602
4936
4951
125961
125976
TGCCATGTTCCATATA
16
677

958607
5109
5124
126134
126149
CAACATGCTTGCGAGG
11
678

958612
5295
5310
126320
126335
ACCTAACATATGAGCA
18
679

958617
1143
1158
79084
79099
GAGGTGGTCTTGTTCT
40
680

958622
1384
1399
102516
102531
GATATTCCGCATTGCC
3
681

958627
N/A
N/A
5476
5491
TTGGGCAAAGTTCCTA
61
682

958632
N/A
N/A
5610
5625
CTCCGACAGGAGACTA
55
683

958637
N/A
N/A
4394
4409
CCGCAGAGAGAAACTC
101
684

958642
N/A
N/A
8249
8264
GACATCAATTTCAGTC
91
685

958647
N/A
N/A
10939
10954
TAGGAAGTTGTTGACC
11
686

958652
N/A
N/A
14156
14171
GCTACGACGGCTGGCC
136
687

958657
N/A
N/A
18786
18801
CAGTATAATATCCTAA
37
688

958662
N/A
N/A
21800
21815
GAACAGATAGGACTAC
51
689

958667
N/A
N/A
25870
25885
TGCCGGGCCCCTATGC
80
690

958672
N/A
N/A
30864
30879
GAACTTAGTTCCCTTC
67
691

958677
N/A
N/A
31187
31202
AGAACTTAGTTCCCTA
51
692

958682
N/A
N/A
34164
34179
CCATGAGGGACTCCCA
123
693

958687
N/A
N/A
36660
36675
ACACTATGTGTTCTGC
57
694

958692
N/A
N/A
39314
39329
GGCTAGAGGCCGGGTG
105
695

958697
N/A
N/A
40306
40321
CTAAAGATGACTACTG
39
696

958702
N/A
N/A
41672
41687
TGATGTCTTGTCCAGA
16
697

958707
N/A
N/A
46503
46518
TCAATGCTGTATCAGA
23
698

958712
N/A
N/A
49103
49118
TTATATAGGTTACAGA
52
699

958717
N/A
N/A
55730
55745
AATAATATAGCTTACG
11
700

958722
N/A
N/A
57612
57627
CATAATAGGACACAAC
59
701

958727
N/A
N/A
58767
58782
ATCTGTCAGTTATCCT
2
702

958732
N/A
N/A
59675
59690
AGCACGGTGTAGCTTT
60
703

958737
N/A
N/A
62586
62601
GGAATACAAGCCCGAG
8
704

958742
N/A
N/A
66232
66247
AGCAATATGGTATTAG
4
705

958747
N/A
N/A
72144
72159
GTAAAGAGGGTGACAT
106
706

958752
N/A
N/A
75582
75597
GAATTTTTAGTCCAGT
2
707

958757
N/A
N/A
79978
79993
GTGATCTGCACATTGT
5
708

958762
N/A
N/A
84225
84240
GATTAGAGGACTCATT
16
709

958767
N/A
N/A
86751
86766
ACGAATAAGGCATTAG
6
710

958772
N/A
N/A
92334
92349
CAACAAACATAGTTAC
61
711

958777
N/A
N/A
94786
94801
GTAACTGTTTCTAGGT
10
712

958782
N/A
N/A
97670
97685
ATGGTCTCCCAGTCAC
20
713

958787
N/A
N/A
101109
101124
TGGGCAAAGTTCCTCT
67
714

958792
N/A
N/A
102355
102370
GCCAATGGAGTCACCA
46
715

958797
N/A
N/A
105351
105366
ACGAGCACAGCACCCT
13
716

958802
N/A
N/A
110683
110698
AGATAATCATCCTCAA
25
717

958807
N/A
N/A
112517
112532
TCATTGTAGTCTGTCT
3
718

958812
N/A
N/A
115821
115836
TACTATAAGACACCAA
31
719

958817
N/A
N/A
121734
121749
TGCCAGGTAAGCCACA
30
720

TABLE 11

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
1
206

958438
181
196
3641
3656
CGCCCCGGCTCCACTG
61
721

958443
306
321
3766
3781
CTCCACGGGCCGAGGT
90
722

958448
437
452
3897
3912
GCGAAGGCGGCTGCCC
86
723

958453
635
650
4095
4110
GCCTCATGGGCACGGT
70
724

958458
1006
1021
55501
55516
GTTCATCTGGGACAGC
12
725

958463
1502
1517
116691
116706
CCTGAGACATCCCGGG
63
726

958468
1866
1881
122891
122906
TTGGTGGCAGCCAAAA
86
727

958473
1948
1963
122973
122988
GTCTCCTTAGATCCTT
5
728

958478
1967
1982
122992
123007
GGAAATTTCCGGTGCA
14
729

958483
2039
2054
123064
123079
GAGGATTAAAGTATCT
17
730

958488
2209
2224
123234
123249
AGGAATGGCATCCATC
41
731

958493
2435
2450
123460
123475
AAACAGTCTTCAGCCT
16
732

958498
2561
2576
74512
74527
GAGTATGTGGCAATAA
1
733

123586
123601

958503
2740
2755
123765
123780
AACCATCCCAAGCTAC
15
734

958508
2816
2831
123841
123856
GAGAGCAGATAATCGA
7
735

958513
2927
2942
123952
123967
GCGCTACCATTTTAAA
104
736

958518
3047
3062
124072
124087
CCACAGTAATAGCTCT
1
737

958523
3174
3189
124199
124214
TTCCAATCGAGACTTA
3
738

958528
3362
3377
124387
124402
AGTCTTGTAAGTAAGA
18
739

958533
3379
3394
124404
124419
GCATAGAAGTAGGAGC
3
740

958538
3397
3412
31598
31613
ATCCAGGGTCAATTTT
10
741

124422
124437

958543
3412
3427
124437
124452
ACCTTATAGTATTCTA
4
742

958548
3542
3557
124567
124582
GACACATACTCTAGTT
21
743

958553
3559
3574
38752
38767
CCATTATTACTCCTGT
1
744

121706
121721

124584
124599

958558
3643
3658
124668
124683
TTCACAACCAACTATT
9
745

958563
3759
3774
124784
124799
AGCTTTTGCCAGGAGA
3
746

958568
3947
3962
124972
124987
TATGAGTGATCAACCT
5
747

958573
4164
4179
125189
125204
GGCAAATTATAGGCAC
2
748

958578
4181
4196
125206
125221
CTTAATCTGTGGCTAC
4
749

958583
4210
4225
125235
125250
AGCTAATCTGCTGATA
89
750

958588
4373
4388
125398
125413
GTGTACTTAGGTGACT
10
751

958593
4506
4521
125531
125546
GGTCAGTACAGAGGGC
7
752

958598
4636
4651
125661
125676
CCCAATGCTACCCAAT
4
753

958603
4987
5002
44310
44325
TGGTATGAATTCTGAA
3
754

75463
75478

126012
126027

958608
5136
5151
126161
126176
TGATAGGCACACCCAC
11
755

958613
1062
1077
55557
55572
CCTGAAGCCGAGTTCA
15
756

958618
1149
1164
79090
79105
AGCCAAGAGGTGGTCT
36
757

958623
1386
1401
102518
102533
TTGATATTCCGCATTG
3
758

958628
N/A
N/A
5514
5529
GCTAACTACATTGCAG
81
759

958633
N/A
N/A
5656
5671
TGTCATCAGGTTAAGT
76
760

958638
N/A
N/A
4565
4580
GTGCGGAGCGCGCGGA
127
761

958643
N/A
N/A
8457
8472
TAGCAACCCACCCTGG
59
762

958648
N/A
N/A
10980
10995
GAATACTGAGTCAGGA
7
763

958653
N/A
N/A
15503
15518
TTACACACAGGCTATG
17
764

958658
N/A
N/A
18787
18802
ACAGTATAATATCCTA
6
765

958663
N/A
N/A
22200
22215
CTATTAGGGACTGAAC
32
766

958668
N/A
N/A
27649
27664
GTGATCTGTGAGAGGT
2
767

958673
N/A
N/A
30865
30880
AGAACTTAGTTCCCTT
30
768

958678
N/A
N/A
32244
32259
GGAGGAGTCACCATGG
74
769

958683
N/A
N/A
34256
34271
TATTGTGCTGCATCTC
16
770

958688
N/A
N/A
36686
36701
GGCTATGTAGCCTTCC
82
771

958693
N/A
N/A
39371
39386
GTGGTGTCTCACAGGC
99
772

958698
N/A
N/A
40400
40415
CTTATTAGCCCTCAAA
30
773

958703
N/A
N/A
43429
43444
GATAACTAAGCACTAC
49
774

958708
N/A
N/A
46790
46805
ATGTCAGATGTCAATT
19
775

958713
N/A
N/A
50391
50406
TGCTAGAGGCTGTTCC
55
776

958718
N/A
N/A
55941
55956
GAACACTATAGCTTGG
4
777

958723
N/A
N/A
58021
58036
AACCCACTAAAACCGG
63
778

958728
N/A
N/A
45026
45041
TATCTGTCAGTTATCC
10
779

58768
58783

58784
58799

958733
N/A
N/A
60397
60412
TAATAGACTAGACTTA
67
780

958738
N/A
N/A
63528
63543
TCTATATGTTTCCCCC
11
781

958743
N/A
N/A
66740
66755
GACTATAAAGGGTTTA
30
782

958748
N/A
N/A
72564
72579
ACATGTGACATTCCGG
83
783

958753
N/A
N/A
76248
76263
TGTATATGCCGTTCCC
4
784

958758
N/A
N/A
79985
80000
CTATTCAGTGATCTGC
2
785

958763
N/A
N/A
84603
84618
CACAATACAAGATGCA
3
786

958768
N/A
N/A
87653
87668
GTGCAAGCAGGTTCCC
17
787

958773
N/A
N/A
93005
93020
AGCTGGTAGGGCAAGA
43
788

958778
N/A
N/A
95129
95144
GCTACCTGGAGCGAAG
75
789

958783
N/A
N/A
98257
98272
TGATCTGATGCTTGCT
35
790

958788
N/A
N/A
101110
101125
CTGGGCAAAGTTCCTC
54
791

958793
N/A
N/A
102510
102525
CCGCATTGCCTAAGAG
9
792

958798
N/A
N/A
107371
107386
TGCAGTATAATATCCT
3
793

958803
N/A
N/A
110998
111013
GATAATCATCCTCAGC
24
794

958808
N/A
N/A
113126
113141
AGCGATTGGCCTCCCA
59
795

958813
N/A
N/A
116872
116887
TTACAGAGAGATTCAT
8
796

958818
N/A
N/A
121757
121772
GTTGTCAACTCTAGGG
23
797

TABLE 12

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
1
206

958439
182
197
3642
3657
GCGCCCCGGCTCCACT
77
798

958444
315
330
3775
3790
ACGCCCCGGCTCCACG
97
799

958449
468
483
3928
3943
CCGGACGGCGGGCCCT
84
800

958454
754
769
7188
7203
GGAATGAGCTCGAACA
3
801

958459
1061
1076
55556
55571
CTGAAGCCGAGTTCAT
28
802

958464
1600
1615
120505
120520
GCTCATGCTTAGTCCA
3*
803

958469
1904
1919
122929
122944
GGCTCTATAACCATGT
17
804

958474
1950
1965
122975
122990
GTGTCTCCTTAGATCC
3
805

958479
1969
1984
122994
123009
ATGGAAATTTCCGGTG
15
806

958484
2067
2082
123092
123107
GCAGCAATGGACAAGG
2
807

958489
2262
2277
123287
123302
TTCTAAGTCTGAGTAT
14
808

958494
2468
2483
123493
123508
TAGCACTAGGAGGAAA
28
809

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

958504
2805
2820
123830
123845
ATCGAGATTTAAATAA
63
811

958509
2851
2866
123876
123891
ATGTTATGTTTGGGTG
4
812

958514
2957
2972
123982
123997
TACTAGTCATGTATTC
20
813

958519
3061
3076
124086
124101
CCCCTAGGCACTATCC
20
814

958524
3199
3214
124224
124239
GCACATTATGAACCTA
13
815

958529
3364
3379
124389
124404
CAAGTCTTGTAAGTAA
3
816

958534
3383
3398
121836
121851
TTCAGCATAGAAGTAG
3
817

124408
124423

958539
3400
3415
124425
124440
TCTATCCAGGGTCAAT
11
818

958544
3471
3486
124496
124511
GCTAAATTCAACTACC
8
819

958549
3546
3561
100828
100843
TGTAGACACATACTCT
8
820

110388
110403

124571
124586

958554
3561
3576
38754
38769
AACCATTATTACTCCT
1
821

120229
120244

124586
124601

958559
3645
3660
124670
124685
AATTCACAACCAACTA
17
822

958564
3841
3856
124866
124881
TCCAAATTGAAGGGCC
62
823

958569
3965
3980
124990
125005
AGCCTTAGAGTCAATT
3
824

958574
4166
4181
125191
125206
CTGGCAAATTATAGGC
13
825

958579
4183
4198
125208
125223
ATCTTAATCTGTGGCT
4
826

958584
4221
4236
125246
125261
CCCTAAGCTAAAGCTA
74
827

958589
4409
4424
125434
125449
GTAAAGGAAGATCTCC
4
828

958594
4523
4538
125548
125563
CTCTTAGGTCTCCTTC
8
829

958599
4663
4678
125688
125703
TTCAAGAATACCCAGT
5
830

958604
5055
5070
126080
126095
ACGCTAGAAAAGTGTT
94
831

958609
5221
5236
126246
126261
TGACAAGTGTGCATTA
16
832

958614
1137
1152
79078
79093
GTCTTGTTCTTATGGT
6
833

958619
1156
1171
79097
79112
TGGGTCTAGCCAAGAG
71
834

958624
1390
1405
102522
102537
GGGATTGATATTCCGC
74
835

958629
N/A
N/A
5523
5538
CCCGAGTGGGCTAACT
128
836

958634
N/A
N/A
5673
5688
TCCTTAACCCGGGTTT
61
837

958639
N/A
N/A
6783
6798
GTTATGGGTGCTTTTC
18
838

958644
N/A
N/A
8524
8539
ATGATCAAACCTTTTC
5
839

958649
N/A
N/A
12237
12252
TGCCACTGGTGAATAC
36
840

958654
N/A
N/A
16919
16934
AATGGAGTGGCCGGGC
110
841

958659
N/A
N/A
18852
18867
GTTGTATTACTCTCCA
2
842

958664
N/A
N/A
23239
23254
ACGAACTAAGGTGTAC
40
843

958669
N/A
N/A
28420
28435
GCTATCTTTGGATCCA
76
844

958674
N/A
N/A
30866
30881
AAGAACTTAGTTCCCT
25
845

31188
31203

958679
N/A
N/A
33917
33932
GTAACTGCCACAGTTA
77
846

958684
N/A
N/A
35513
35528
GCTGAAGACGGCCCTT
70
847

958689
N/A
N/A
36864
36879
CATTAAGGAGGTTATG
87
848

958694
N/A
N/A
39375
39390
ATTGGTGGTGTCTCAC
41
849

958699
N/A
N/A
40415
40430
GACTAGAAAGATCATC
20
850

958704
N/A
N/A
43572
43587
CCCTACACTCGAGGAT
122
851

958709
N/A
N/A
46944
46959
TCAATCTATGAGACCC
57
852

958714
N/A
N/A
52275
52290
GAGCACTGCGCCCTGG
82
853

958719
N/A
N/A
56409
56424
GTACATAATGGGCTAA
49
854

958724
N/A
N/A
58762
58777
TCAGTTATCCTATCCC
2
855

958729
N/A
N/A
58763
58778
GTCAGTTATCCTATCT
4
856

58779
58794

958734
N/A
N/A
61207
61222
ACACATAGAGCTAAGG
7
857

958739
N/A
N/A
64256
64271
AGCAATAGAGTAACCA
4
858

958744
N/A
N/A
67858
67873
GCATACTGGTGCCCCA
45
859

958749
N/A
N/A
74623
74638
CCACAAGGGCAGTACG
51
860

958754
N/A
N/A
77489
77504
CCTTAGGAAGGCTCCC
31
861

958759
N/A
N/A
81664
81679
GCCTATCGCCCCAAGC
61
862

958764
N/A
N/A
85543
85558
TGGGTCTCTTGATTTC
34
863

958769
N/A
N/A
89667
89682
CATTGCCACGATCTAA
36
864

958774
N/A
N/A
94013
94028
TGCTAGATATCGCCAA
33
865

958779
N/A
N/A
95898
95913
TCGAATATAGAGGCCT
80
866

958784
N/A
N/A
99202
99217
GGCTGGATAGAATGCT
79
867

958789
N/A
N/A
101277
101292
TACTATATAATACCCT
17
868

958794
N/A
N/A
102512
102527
TTCCGCATTGCCTAAG
14
869

958799
N/A
N/A
107814
107829
ATTACTCAATCATGGT
2
870

958804
N/A
N/A
110999
111014
AGATAATCATCCTCAG
17
871

958809
N/A
N/A
113144
113159
TCTTAACACCTGAGCT
66
872

958814
N/A
N/A
117837
117852
GGCTATGCCTCTCTTA
214
873

958819
N/A
N/A
122502
122517
TGCTTCAACATTGTTC
9
874

TABLE 13

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

715483
3570
3585
124595
124610
CTCTTTGGAAACCATT
1
206

958440
183
198
3643
3658
TGCGCCCCGGCTCCAC
54
875

958445
327
342
3787
3802
GGCTACGCCCGGACGC
63
876

958450
496
511
3956
3971
GGTCGCCGCGGGTGCC
59
877

958455
757
772
7191
7206
AGAGGAATGAGCTCGA
43
878

958460
1294
1309
98996
99011
TCGCATCTGTTGCTGC
52
879

958465
1726
1741
122751
122766
GGCTTCAAGGTAGTCT
84
880

958470
1941
1956
8781
8796
TAGATCCTTCACAGAT
18
881

45134
45149

122966
122981

958475
1959
1974
122984
122999
CCGGTGCATGTGTCTC
37
882

958480
1978
1993
24075
24090
AACTGGCTTATGGAAA
24
883

123003
123018

958485
2089
2104
56507
56522
AGAGGTCAGCAATACA
3
884

122015
122030

123114
123129

958490
2281
2296
123306
123321
GTGACATGAAGCATCT
5
885

958495
2488
2503
123513
123528
GGTCATTATGTGACTA
56
886

958500
2570
2585
123595
123610
TCTATATTAGAGTATG
5
887

958505
2809
2824
123834
123849
GATAATCGAGATTTAA
6
888

958510
2867
2882
123892
123907
TACCACACTATTATAA
43
889

958515
2993
3008
124018
124033
CCCCAACCAGATTTAA
28
890

958520
3091
3106
124116
124131
CTACCGTATGCCCAGA
27
891

958525
3235
3250
124260
124275
ATGAAGGTAAACCACT
3
892

958530
3367
3382
124392
124407
GAGCAAGTCTTGTAAG
20
893

958535
3392
3407
124417
124432
GGGTCAATTTTCAGCA
10
894

958540
3402
3417
124427
124442
ATTCTATCCAGGGTCA
8
895

958545
3535
3550
5536
5551
ACTCTAGTTACATCAT
3
896

124560
124575

958550
3548
3563
124573
124588
CCTGTAGACACATACT
4
897

958555
3619
3634
124644
124659
GCTTATATTGAAGAGT
4
898

958560
3656
3671
124681
124696
GGTGCCACTTTAATTC
22
899

958565
3895
3910
124920
124935
TTGAGCACTGAAAGTA
4
900

958570
4092
4107
125117
125132
TGTAATTCATATACCC
5
901

958575
4171
4186
125196
125211
GGCTACTGGCAAATTA
9
902

958580
4186
4201
125211
125226
ATAATCTTAATCTGTG
4
903

958585
4278
4293
125303
125318
CTCTATCAAGGTCCCC
5
904

958590
4439
4454
125464
125479
AGGTATAACTGGGCAA
2
905

958595
4563
4578
125588
125603
CCACATCAAGGCTATG
8
906

958600
4752
4767
125777
125792
GTAGATCTAAGAAGCC
8
907

958605
5068
5083
126093
126108
CTCAGATGTACCAACG
7
908

958610
5250
5265
126275
126290
AGGTAACATTGGTACT
34
909

958615
1139
1154
79080
79095
TGGTCTTGTTCTTATG
3
910

958620
1162
1177
79103
79118
AAGCCTTGGGTCTAGC
57
911

958625
1394
1409
102526
102541
TGCTGGGATTGATATT
6
912

958630
N/A
N/A
5554
5569
GCGGTAACTCTTCTTT
52
913

958635
N/A
N/A
5713
5728
GTTTAGGCAAGCAGCT
43
914

958640
N/A
N/A
7413
7428
TAGATAACTGTCTCCC
13
915

958645
N/A
N/A
9559
9574
GCCCATAGTTGACAGG
54
916

958650
N/A
N/A
12498
12513
TCAATTGAGTCTGCTA
3
917

958655
N/A
N/A
17868
17883
GCAATCTGTGATCCCA
12
918

958660
N/A
N/A
19378
19393
CCCACTGGGTTTGTCC
106
919

958665
N/A
N/A
23878
23893
CTGCATACCCTCCAGC
84
920

958670
N/A
N/A
28665
28680
GGTCTTGGTGATTGGC
20
921

958675
N/A
N/A
31177
31192
TCCCTATCAGCTGGGC
112
922

958680
N/A
N/A
34103
34118
ATTAACACCTGAGCTG
50
923

958685
N/A
N/A
35577
35592
AGCTATGGAAAGTGTC
24
924

958690
N/A
N/A
37103
37118
TGGACTCTTGATCACA
26
925

958695
N/A
N/A
39759
39774
TCAATTCTCCACCAGA
45
926

958700
N/A
N/A
41085
41100
CTAATATAGACTACTC
55
927

958705
N/A
N/A
45162
45177
GGCCATCAATAAAGAC
112
928

958710
N/A
N/A
47735
47750
AGGGAACCCTTGGCTA
77
929

958715
N/A
N/A
53767
53782
GTAATAGGAGGTAAGA
48
930

958720
N/A
N/A
56594
56609
GTCTACTAGAGCTGCC
12
931

958725
N/A
N/A
58763
58778
GTCAGTTATCCTATCC
1
932

958730
N/A
N/A
58783
58798
CTCTGTCAGTTATCCT
4
933

958735
N/A
N/A
61265
61280
AGCAATCTTGTGGATC
7
934

958740
N/A
N/A
65047
65062
CGGCACCAAACACCCA
57
935

958745
N/A
N/A
69906
69921
TCCCAGCCGCATGGCT
78
936

958750
N/A
N/A
75333
75348
TGTAAGAGGAGACCAC
28
937

958755
N/A
N/A
78709
78724
TAACATAAGACACGGA
12
938

958760
N/A
N/A
82249
82264
AGTAATAGATCTACAA
76
939

958765
N/A
N/A
86532
86547
GTACAGGAGAGATTGC
37
940

958770
N/A
N/A
90915
90930
ACAGAGCGGTGCACCC
64
941

958775
N/A
N/A
94061
94076
GTCTATACGGGAGATT
29
942

958780
N/A
N/A
96542
96557
TCAACTACTTTTCAGC
24
943

958785
N/A
N/A
99371
99386
GCAATCCACAATTCCA
2
944

958790
N/A
N/A
102039
102054
GAAAAGACGACACAGT
68
945

958795
N/A
N/A
102514
102529
TATTCCGCATTGCCTA
8
946

958800
N/A
N/A
108359
108374
TCGATAATATATGGCA
22
947

958805
N/A
N/A
111001
111016
CAAGATAATCATCCTC
6
948

958810
N/A
N/A
114182
114197
TTATATACGGGAAAAT
47
949

958815
N/A
N/A
120003
120018
GGGCGAGGAGACAGGT
16
950

958820
N/A
N/A
126468
126483
GACCAGTAAGAAGCCA
49
951

Example 4
Antisense Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides were designed to target a Yap1 nucleic acid and were tested for their effect on Yap1 mRNA level in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured A-431 cells at a density of 5,000 cells per well were treated using free uptake with 2,000 nM of modified oligonucleotide. After a treatment period of approximately 48 hours, RNA was isolated from the cells and Yap1 mRNA levels were measured by quantitative real-time RTPCR. Human primer probe set RTS4814 was used to measure mRNA levels. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides targeting the amplicon region.

“Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either SEQ ID NO.: 1, SEQ ID NO.: 2, SEQ ID NO.: 3 (GENBANK Accession No. NM_006106.4), or SEQ ID NO.: 4 (GENBANK Accession No. NM_001130145.2). ‘N/A’ indicates that the modified oligonucleotide does not target that particular gene sequence with 100% complementarity. ‘N.D.’ indicates that the % UTC is not defined for that particular modified oligonucleotide in that particular experiment. Activity of the modified oligonucleotide may be defined in a different experiment.

TABLE 14

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074112
97
112
3557
3572
TCCAACTCCCTTGACG
83
952

1074144
285
300
3745
3760
AGCGGCGACGGCTGCG
92
953

1074176
364
379
3824
3839
CTCCCCCGACGCGCAC
84
954

1074208
541
556
4001
4016
GTGCACGATCTGATGC
96
955

1074240
896
911
7330
7345
CTGGCAGAGGTACATC
29
956

1074272
1118
1133
79059
79074
TATAGTAAATTTCTCC
16
957

1074304
1357
1372
99059
99074
CTGCCGAAGCAGTTCT
109
958

1074336
1451
1466
116640
116655
CCAGTGTTGGTAACTG
97
959

1074368
1672
1687
N/A
N/A
GATAGTATCACCTGTA
8
960

1074400
1928
1943
122953
122968
GATTTAGAATTCAGTC
42
961

1074432
2243
2258
123268
123283
GTTAAAATGATTGGTG
3*
962

1074464
2564
2579
123589
123604
TTAGAGTATGTGGCAA
2
963

1074496
2743
2758
123768
123783
AATAACCATCCCAAGC
69
964

1074528
2996
3011
124021
124036
CTGCCCCAACCAGATT
25
965

1074560
3172
3187
124197
124212
CCAATCGAGACTTAAA
3
966

1074592
3368
3383
124393
124408
GGAGCAAGTCTTGTAA
23
967

1074624
3706
3721
124731
124746
GGCTTATTCTAGAAAC
65
968

1074656
4008
4023
125033
125048
GACTTAATTCAAGATT
31
969

1074688
4224
4239
125249
125264
TCCCCCTAAGCTAAAG
83
970

1074720
4403
4418
125428
125443
GAAGATCTCCATATTC
58
971

1074752
4592
4607
125617
125632
CATTAGGAACAAGGAC
10
972

1074784
4758
4773
125783
125798
CCATAAGTAGATCTAA
25
973

1074816
5032
5047
126057
126072
GAATATTGCCACCCAC
15
974

1074848
5140
5155
126165
126180
GTTATGATAGGCACAC
11
975

1074912
N/A
N/A
5525
5540
ATCCCGAGTGGGCTAA
85
976

1074944
N/A
N/A
5623
5638
AAAACCCTTTGGTCTC
89
977

1074976
N/A
N/A
126479
126494
TTCTATTGGAAGACCA
35
978

1075008
N/A
N/A
5286
5301
TAATCGAACATTGTGT
61
979

1075040
N/A
N/A
7618
7633
TTATAAAGAGGCTCAG
10
980

1075072
N/A
N/A
9650
9665
TCCGGGTAAATATCTC
37
981

1075104
N/A
N/A
11109
11124
ATTATAAGGTCCTACA
67
982

1075136
N/A
N/A
13294
13309
CTAGAATATTAAAGGG
87
983

1075168
N/A
N/A
16596
16611
CATCAAAATTTCACGA
49
984

1075200
N/A
N/A
21836
21851
CATATTAACTAGATGA
120
985

1075232
N/A
N/A
24676
24691
ATTTATCAGCCATTGT
13
986

1075264
N/A
N/A
27401
27416
GAATAATATGCAGAAC
53
987

1075296
N/A
N/A
30827
30842
ATTATAAGCTGTGTTG
18
988

1075328
N/A
N/A
32291
32306
CTCGCAAAGCCTCTTC
21
989

1075360
N/A
N/A
34021
34036
AGGCAACAACATCTAA
50
990

1075392
N/A
N/A
36045
36060
GACGGGTGAACCTGTT
95
991

1075424
N/A
N/A
38749
38764
TTATTAATCCTGTCCA
18
992

1075456
N/A
N/A
40812
40827
TTACGAAATGTTTAGT
61
993

1075488
N/A
N/A
42808
42823
CAGAATAAGGGAGATC
56
994

1075520
N/A
N/A
45363
45378
CCCCAACAACTGCTAA
77
995

1075552
N/A
N/A
47526
47541
GATTATAACATGCTGT
74
996

1075584
N/A
N/A
49326
49341
AATAATTGACCTAGCA
57
997

1075616
N/A
N/A
51128
51143
GTAAAACCGATTTTTC
46
998

1075648
N/A
N/A
52713
52728
TCAATAAAGTGGGACT
67
999

1075680
N/A
N/A
55168
55183
ATTATTACCCCTTCTA
73
1000

1075712
N/A
N/A
57557
57572
GACGCGAAATACTTAC
7
1001

1075744
N/A
N/A
59642
59657
TTCGGGTTAGCAGACT
6
1002

1075776
N/A
N/A
62195
62210
ATGTGATATGGATTCT
10
1003

1075808
N/A
N/A
64255
64270
GCAATAGAGTAACCAG
3
1004

1075840
N/A
N/A
67174
67189
CCTAAAATAGGAATGC
89
1005

1075872
N/A
N/A
70920
70935
CAATTATGACAAACAG
21
1006

1075904
N/A
N/A
73288
73303
GTATAGGATCTACTAA
51
1007

1075936
N/A
N/A
76577
76592
CTTATATTCTCTCCGA
49
1008

1075968
N/A
N/A
80319
80334
TATTTAAGCCAAACCG
5
1009

1076000
N/A
N/A
82082
82097
CCTAATATGACTCCTT
4
1010

1076032
N/A
N/A
84424
84439
TATAATTTCCCTGATC
105
1011

1076064
N/A
N/A
86676
86691
TATGAACAATGTACTC
5
1012

1076096
N/A
N/A
90315
90330
AATAATAAACGATTCT
71
1013

1076128
N/A
N/A
92094
92109
TCTAAACCTAAAGACT
118
1014

1076160
N/A
N/A
93143
93158
TTATACTAGTACGGCA
20
1015

1076192
N/A
N/A
95979
95994
CTACAACCTGGACTTT
34
1016

1076224
N/A
N/A
97726
97741
TATAAACCTTGCTACA
67
1017

1076256
N/A
N/A
100250
100265
TTATTTAGGCCCCATA
4
1018

1076288
N/A
N/A
103352
103367
CTTATTTAGCATAGTG
3
1019

1076320
N/A
N/A
105383
105398
CATTAACCTCACCCAT
52
1020

1076352
N/A
N/A
109308
109323
GATAACCCTGAAACAA
37
1021

1076384
N/A
N/A
111269
111284
TATAAGGGACTTGCTG
25
1022

1076416
N/A
N/A
113834
113849
ACCGAAATGATACTGA
8
1023

1076448
N/A
N/A
117100
117115
CTTATAATGCAATCCT
2
1024

1076480
N/A
N/A
119636
119651
GTAAATATCCATTACC
72
1025

1076512
N/A
N/A
122045
122060
CATAAACCATTAAGTG
65
1026

1076544
N/A
N/A
71389
71404
GACCAACCTCCCCTTG
89
1027

TABLE 15

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ
SEQ
SEQ
SEQ

ID
ID
ID
ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1
SEQ

Compound
Start
Stop
Start
Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074113
98
113
3558
3573
CTCCAACTCCCTTGAC
61
1028

1074145
286
301
3746
3761
AAGCGGCGACGGCTGC
73
1029

1074177
365
380
3825
3840
CCTCCCCCGACGCGCA
69
1030

1074209
640
655
4100
4115
CCGGAGCCTCATGGGC
72
1031

1074241
921
936
7355
7370
GATGTCTTTGCCATCT
72
1032

1074273
1129
1144
79070
79085
CTTATGGTTTATATAG
34
1033

1074305
1360
1375
99062
99077
CACCTGCCGAAGCAGT
64
1034

1074337
1469
1484
116658
116673
GAGTCCCACCATCCTG
10
1035

1074369
1673
1688
N/A
N/A
TGATAGTATCACCTGT
19
1036

1074401
1960
1975
122985
123000
TCCGGTGCATGTGTCT
18
1037

1074433
2258
2273
123283
123298
AAGTCTGAGTATTTAG
5*
1038

1074465
2572
2587
123597
123612
AATCTATATTAGAGTA
44
1039

1074497
2744
2759
123769
123784
CAATAACCATCCCAAG
26
1040

1074529
3001
3016
124026
124041
GCAGACTGCCCCAACC
50
1041

1074561
3176
3191
124201
124216
AATTCCAATCGAGACT
10
1042

1074593
3369
3384
124394
124409
AGGAGCAAGTCTTGTA
6
1043

1074625
3711
3726
124736
124751
ATAAGGGCTTATTCTA
42
1044

1074657
4016
4031
125041
125056
TCCCCCCAGACTTAAT
59
1045

1074689
4225
4240
125250
125265
CTCCCCCTAAGCTAAA
70
1046

1074721
4404
4419
125429
125444
GGAAGATCTCCATATT
43
1047

1074753
4594
4609
125619
125634
TACATTAGGAACAAGG
4
1048

1074785
4759
4774
125784
125799
ACCATAAGTAGATCTA
10
1049

1074817
5034
5049
126059
126074
CTGAATATTGCCACCC
8
1050

1074849
5141
5156
126166
126181
TGTTATGATAGGCACA
18
1051

1074913
N/A
N/A
5526
5541
CATCCCGAGTGGGCTA
99
1052

1074945
N/A
N/A
5624
5639
CAAAACCCTTTGGTCT
74
1053

1074977
N/A
N/A
126483
126498
CTTGTTCTATTGGAAG
94
1054

1075009
N/A
N/A
5287
5302
ATAATCGAACATTGTG
43
1055

1075041
N/A
N/A
7620
7635
GATTATAAAGAGGCTC
5
1056

1075073
N/A
N/A
9719
9734
CATAAAAGTTCCCCAG
51
1057

1075105
N/A
N/A
11110
11125
AATTATAAGGTCCTAC
42
1058

1075137
N/A
N/A
13320
13335
GATTAAATACTGACCA
3
1059

1075169
N/A
N/A
16611
16626
AAAACGGAGTAATGCC
39
1060

1075201
N/A
N/A
21864
21879
CTTTAAAGCCCTAATT
114
1061

1075233
N/A
N/A
24679
24694
GTAATTTATCAGCCAT
2
1062

1075265
N/A
N/A
27404
27419
TCTGAATAATATGCAG
44
1063

1075297
N/A
N/A
30831
30846
GTTAATTATAAGCTGT
10
1064

1075329
N/A
N/A
32457
32472
AGGGAAAACTTTGCAC
26
1065

1075361
N/A
N/A
34085
34100
TCTTAAGGGAATGTAT
69
1066

1075393
N/A
N/A
36169
36184
CTTAACCTATGCCAAA
37
1067

1075425
N/A
N/A
38750
38765
ATTATTAATCCTGTCC
26
1068

1075457
N/A
N/A
40828
40843
AGTAATATGTACATGG
5
1069

1075489
N/A
N/A
42854
42869
GAGCAACAACTATGAG
51
1070

1075521
N/A
N/A
45427
45442
AAATCGAGGCGAATCT
65
1071

1075553
N/A
N/A
47527
47542
TGATTATAACATGCTG
77
1072

1075585
N/A
N/A
49327
49342
AAATAATTGACCTAGC
52
1073

1075617
N/A
N/A
51372
51387
TAAGAACGACATATGC
27
1074

1075649
N/A
N/A
52715
52730
CTTCAATAAAGTGGGA
56
1075

1075681
N/A
N/A
55170
55185
TAATTATTACCCCTTC
37
1076

1075713
N/A
N/A
57571
57586
AATCAACCTTGTTAGA
58
1077

1075745
N/A
N/A
59682
59697
CTTCAAAAGCACGGTG
58
1078

1075777
N/A
N/A
62196
62211
TATGTGATATGGATTC
12
1079

1075809
N/A
N/A
64257
64272
TAGCAATAGAGTAACC
13
1080

1075841
N/A
N/A
67205
67220
ATTTAGGTACTCAGTA
27
1081

1075873
N/A
N/A
70936
70951
CTTGAATACTACACCA
16
1082

1075905
N/A
N/A
73332
73347
CCTGAACACAGGAGTA
43
1083

1075937
N/A
N/A
76578
76593
ACTTATATTCTCTCCG
36
1084

1075969
N/A
N/A
80320
80335
GTATTTAAGCCAAACC
11
1085

1076001
N/A
N/A
82122
82137
ACTCAAGGAACCATTT
24
1086

1076033
N/A
N/A
84540
84555
CATTAGTAGGTATTTC
8
1087

1076065
N/A
N/A
86761
86776
CTTTAGTAACACGAAT
36
1088

1076097
N/A
N/A
90316
90331
CAATAATAAACGATTC
70
1089

1076129
N/A
N/A
92131
92146
CATAAACCTTAGTCCT
26
1090

1076161
N/A
N/A
93145
93160
TCTTATACTAGTACGG
14
1091

1076193
N/A
N/A
96059
96074
TTAATACACAGGTTCC
29
1092

1076225
N/A
N/A
97727
97742
ATATAAACCTTGCTAC
66
1093

1076257
N/A
N/A
100265
100280
CTAAGAAACTCATAGT
54
1094

1076289
N/A
N/A
103430
103445
AACGGACAACTTAACA
21
1095

1076321
N/A
N/A
105417
105432
CAATATCACTTGGGCC
63
1096

1076353
N/A
N/A
109381
109396
ATTAAACATTCGGATT
30
1097

1076385
N/A
N/A
111270
111285
ATATAAGGGACTTGCT
32
1098

1076417
N/A
N/A
113840
113855
CTTTACACCGAAATGA
42
1099

1076449
N/A
N/A
117101
117116
CCTTATAATGCAATCC
2
1100

1076481
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC
1
1101

1076513
N/A
N/A
122094
122109
CATTAACACTCCTCAG
36
1102

1076545
N/A
N/A
76624
76639
AACCAACCTTCCCTAC
68
1103

TABLE 16

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074114
109
124
3569
3584
GAACTTTTTCCCTCCA
30
1104

1074146
287
302
3747
3762
GAAGCGGCGACGGCTG
91
1105

1074178
366
381
3826
3841
GCCTCCCCCGACGCGC
95
1106

1074210
641
656
4101
4116
TCCGGAGCCTCATGGG
113
1107

1074242
925
940
7359
7374
AGAAGATGTCTTTGCC
56
1108

1074274
1132
1147
79073
79088
GTTCTTATGGTTTATA
4
1109

1074306
1363
1378
99065
99080
CCTCACCTGCCGAAGC
107
1110

1074338
1476
1491
116665
116680
GGATTTTGAGTCCCAC
77
1111

1074370
1674
1689
N/A
N/A
TTGATAGTATCACCTG
8
1112

1074402
1971
1986
122996
123011
TTATGGAAATTTCCGG
25
1113

1074434
2264
2279
123289
123304
ACTTCTAAGTCTGAGT
51*
1114

1074466
2651
2666
123676
123691
ACCGACCCTGCCAAAA
32
1115

1074498
2745
2760
123770
123785
ACAATAACCATCCCAA
17
1116

1074530
3021
3036
124046
124061
CTAAACTACTTCAAAC
88
1117

1074562
3177
3192
124202
124217
GAATTCCAATCGAGAC
30
1118

1074594
3370
3385
124395
124410
TAGGAGCAAGTCTTGT
6
1119

1074626
3730
3745
124755
124770
CTGTTATGAACCCTTG
5
1120

1074658
4023
4038
125048
125063
GGCCATTTCCCCCCAG
89
1121

1074690
4226
4241
125251
125266
CCTCCCCCTAAGCTAA
81
1122

1074722
4405
4420
125430
125445
AGGAAGATCTCCATAT
57
1123

1074754
4598
4613
125623
125638
CTTTTACATTAGGAAC
11
1124

1074786
4760
4775
125785
125800
AACCATAAGTAGATCT
28
1125

1074818
5035
5050
126060
126075
ACTGAATATTGCCACC
12
1126

1074850
5142
5157
126167
126182
TTGTTATGATAGGCAC
5
1127

1074914
N/A
N/A
5529
5544
TTACATCCCGAGTGGG
97
1128

1074946
N/A
N/A
5625
5640
CCAAAACCCTTTGGTC
109
1129

1074978
N/A
N/A
126492
126507
TTGCCAGTTCTTGTTC
38
1130

1075010
N/A
N/A
5288
5303
AATAATCGAACATTGT
88
1131

1075042
N/A
N/A
7676
7691
TTAAAAGGTTTGGCAC
17
1132

1075074
N/A
N/A
9744
9759
TATAGTAAGACTAATC
105
1133

1075106
N/A
N/A
11112
11127
CAAATTATAAGGTCCT
10
1134

1075138
N/A
N/A
13444
13459
AATAATAGATACTGCC
4
1135

1075170
N/A
N/A
17299
17314
ACTAAAATCCCCAAGG
94
1136

1075202
N/A
N/A
21884
21899
AATTATATAAGGCTGT
26
1137

1075234
N/A
N/A
24701
24716
GTAAATACTCTAGTTC
22
1138

1075266
N/A
N/A
27425
27440
TATTAGGACAAAGTAC
57
1139

1075298
N/A
N/A
30895
30910
ATCTCGGAAATTTAAA
128
1140

1075330
N/A
N/A
32458
32473
GAGGGAAAACTTTGCA
63
1141

1075362
N/A
N/A
34134
34149
CAGGAAAAATCTAGGT
50
1142

1075394
N/A
N/A
36170
36185
TCTTAACCTATGCCAA
27
1143

1075426
N/A
N/A
38752
38767
GTATTATTAATCCTGT
49
1144

1075458
N/A
N/A
40971
40986
CCACAATATACTCCAA
7
1145

1075490
N/A
N/A
42884
42899
CATATACGCAATTAGT
27
1146

1075522
N/A
N/A
45428
45443
CAAATCGAGGCGAATC
82
1147

1075554
N/A
N/A
47574
47589
TTGCAATAGTCACCCA
56
1148

1075586
N/A
N/A
49373
49388
TATTAGCACCTGGGTA
64
1149

1075618
N/A
N/A
51375
51390
TTTTAAGAACGACATA
69
1150

1075650
N/A
N/A
52783
52798
ATATTACAATCCCAGC
48
1151

1075682
N/A
N/A
55172
55187
GATAATTATTACCCCT
35
1152

1075714
N/A
N/A
57577
57592
AATTACAATCAACCTT
42
1153

1075746
N/A
N/A
59700
59715
GATTAACCCAGTAGAG
28
1154

1075778
N/A
N/A
62239
62254
CATTTATACCAGGCAC
3
1155

1075810
N/A
N/A
64258
64273
GTAGCAATAGAGTAAC
7
1156

1075842
N/A
N/A
67207
67222
GTATTTAGGTACTCAG
2
1157

1075874
N/A
N/A
71096
71111
CTTAACAACCCTACGA
113
1158

1075906
N/A
N/A
73792
73807
CCTCAATACAGATGAA
39
1159

1075938
N/A
N/A
76754
76769
GAATATATGGGTTTCA
55
1160

1075970
N/A
N/A
80333
80348
GCTTAAAAGGACAGTA
34
1161

1076002
N/A
N/A
82141
82156
ATTTAATGGCTTGCAT
21
1162

1076034
N/A
N/A
84970
84985
AATTAGAAACTTGGCC
74
1163

1076066
N/A
N/A
87168
87183
CATATAAGATGTTTGC
8
1164

1076098
N/A
N/A
90319
90334
TTACAATAATAAACGA
94
1165

1076130
N/A
N/A
92149
92164
CTGGAATAGTGGGTGC
34
1166

1076162
N/A
N/A
93320
93335
ATTTACTTGGCAACTC
9
1167

1076194
N/A
N/A
96060
96075
TTTAATACACAGGTTC
22
1168

1076226
N/A
N/A
97728
97743
CATATAAACCTTGCTA
36
1169

1076258
N/A
N/A
100563
100578
CTTTAGGTGCCTCCTT
10
1170

1076290
N/A
N/A
103434
103449
CTCCAACGGACAACTT
28
1171

1076322
N/A
N/A
106041
106056
ATTTACAAGTGAGCAC
21
1172

1076354
N/A
N/A
109382
109397
GATTAAACATTCGGAT
13
1173

1076386
N/A
N/A
111389
111404
AGTTATAACAGTGTAA
7
1174

1076418
N/A
N/A
113873
113888
TATAATAACCCATTGT
63
1175

1076450
N/A
N/A
117136
117151
CTTGAATAGCTATGTG
13
1176

1076482
N/A
N/A
119679
119694
CTTTAGACTAAGTAAG
107
1177

1076514
N/A
N/A
122224
122239
CCTTAGGAGATGCACC
18
1178

1076546
N/A
N/A
79333
79348
CCCCAACCTGAGGAGC
94
1179

TABLE 17

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1
SEQ

Compound
Start
Stop
Start
Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
3
810

1074115
110
125
3570
3585
AGAACTTTTTCCCTCC
33
1180

1074147
288
303
3748
3763
AGAAGCGGCGACGGCT
23
1181

1074179
383
398
3843
3858
CGGGATCCATGGCTTC
49
1182

1074211
643
658
4103
4118
CTTCCGGAGCCTCATG
67
1183

1074243
932
947
7366
7381
TCTGACCAGAAGATGT
60
1184

1074275
1146
1161
79087
79102
CAAGAGGTGGTCTTGT
73
1185

1074307
1367
1382
99069
99084
GTGGCCTCACCTGCCG
105
1186

1074339
1479
1494
116668
116683
ACTGGATTTTGAGTCC
31
1187

1074371
1675
1690
122700
122715
GTTGATAGTATCACCT
31
1188

1074403
1973
1988
122998
123013
GCTTATGGAAATTTCC
9
1189

1074435
2265
2280
123290
123305
GACTTCTAAGTCTGAG
19*
1190

1074467
2652
2667
123677
123692
CACCGACCCTGCCAAA
31
1191

1074499
2746
2761
123771
123786
TACAATAACCATCCCA
10
1192

1074531
3023
3038
124048
124063
CACTAAACTACTTCAA
73
1193

1074563
3178
3193
124203
124218
TGAATTCCAATCGAGA
4
1194

1074595
3376
3391
124401
124416
TAGAAGTAGGAGCAAG
4
1195

1074627
3731
3746
124756
124771
CCTGTTATGAACCCTT
3
1196

1074659
4042
4057
125067
125082
CTAAAACTCCATCTGC
12
1197

1074691
4227
4242
125252
125267
CCCTCCCCCTAAGCTA
76
1198

1074723
4410
4425
125435
125450
GGTAAAGGAAGATCTC
6
1199

1074755
4600
4615
125625
125640
CACTTTTACATTAGGA
3
1200

1074787
4761
4776
125786
125801
CAACCATAAGTAGATC
13
1201

1074819
5039
5054
126064
126079
AAGCACTGAATATTGC
33
1202

1074851
5143
5158
126168
126183
ATTGTTATGATAGGCA
6
1203

1074915
N/A
N/A
5531
5546
AGTTACATCCCGAGTG
65
1204

1074947
N/A
N/A
5626
5641
TCCAAAACCCTTTGGT
99
1205

1074979
N/A
N/A
126493
126508
ATTGCCAGTTCTTGTT
32
1206

1075011
N/A
N/A
5292
5307
GCACAATAATCGAACA
44
1207

1075043
N/A
N/A
7834
7849
CCCCAAAAGCCCTACT
73
1208

1075075
N/A
N/A
9942
9957
AATTTTATAAGCCCAC
9
1209

1075107
N/A
N/A
11251
11266
TAAAAACATTGTGGCC
114
1210

1075139
N/A
N/A
13448
13463
CCCAAATAATAGATAC
65
1211

1075171
N/A
N/A
17320
17335
CCCCAATATAAAGAAC
88
1212

1075203
N/A
N/A
21885
21900
TAATTATATAAGGCTG
68
1213

1075235
N/A
N/A
24702
24717
AGTAAATACTCTAGTT
38
1214

1075267
N/A
N/A
27547
27562
CTATTTAGAATAAGTG
83
1215

1075299
N/A
N/A
31204
31219
GATAACCAATGCACCA
21
1216

1075331
N/A
N/A
32471
32486
GATAAACACTGCAGAG
33
1217

1075363
N/A
N/A
34223
34238
ACACAATATCAAGTCC
25
1218

1075395
N/A
N/A
36225
36240
ATGAATAAGTATGCCA
4
1219

1075427
N/A
N/A
38797
38812
TATAAGGCATCTTGGA
60
1220

1075459
N/A
N/A
41050
41065
AACCAAGGATAGTCAT
37
1221

1075491
N/A
N/A
43058
43073
GACGGAAGTTGCAAGG
93
1222

1075523
N/A
N/A
45517
45532
AATTAAGGGCCCACAA
78
1223

1075555
N/A
N/A
47585
47600
GCCAAAAATTCTTGCA
92
1224

1075587
N/A
N/A
49375
49390
CTTATTAGCACCTGGG
50
1225

1075619
N/A
N/A
51414
51429
CTTAGATACTACTTTG
54
1226

1075651
N/A
N/A
52784
52799
TATATTACAATCCCAG
57
1227

1075683
N/A
N/A
55227
55242
CTGAAAAAGTTATGCC
56
1228

1075715
N/A
N/A
57578
57593
GAATTACAATCAACCT
12
1229

1075747
N/A
N/A
59709
59724
ATTTAGCATGATTAAC
43
1230

1075779
N/A
N/A
62290
62305
GTATTACAAACTGATT
28
1231

1075811
N/A
N/A
64261
64276
ATTGTAGCAATAGAGT
10
1232

1075843
N/A
N/A
67232
67247
CATGAAATGATGGAAC
47
1233

1075875
N/A
N/A
71097
71112
ACTTAACAACCCTACG
72
1234

1075907
N/A
N/A
73846
73861
AATTACTACTGGCCAT
55
1235

1075939
N/A
N/A
76757
76772
CTTGAATATATGGGTT
6
1236

1075971
N/A
N/A
80380
80395
TATTAACATACCTCAT
28
1237

1076003
N/A
N/A
82142
82157
AATTTAATGGCTTGCA
8
1238

1076035
N/A
N/A
84972
84987
GTAATTAGAAACTTGG
9
1239

1076067
N/A
N/A
87169
87184
GCATATAAGATGTTTG
4
1240

1076099
N/A
N/A
90414
90429
CCTCAAAACTTGGATT
41
1241

1076131
N/A
N/A
92180
92195
TATTATGAGGACTGAT
23
1242

1076163
N/A
N/A
93798
93813
GATATAAGTTACCAAT
16
1243

1076195
N/A
N/A
96248
96263
AATAACATGGTTCTGT
20
1244

1076227
N/A
N/A
97800
97815
ACTTATAAGGCCAGCA
16
1245

1076259
N/A
N/A
100700
100715
ATTTAACTCCTGAAGT
61
1246

1076291
N/A
N/A
103541
103556
GATTAATGGTGGCATT
4
1247

1076323
N/A
N/A
106043
106058
CAATTTACAAGTGAGC
5
1248

1076355
N/A
N/A
109562
109577
CTACAAAAGAGCTATG
92
1249

1076387
N/A
N/A
111398
111413
TGACAACACAGTTATA
13
1250

1076419
N/A
N/A
113874
113889
ATATAATAACCCATTG
47
1251

1076451
N/A
N/A
117183
117198
CCTTAAGAACATGAGG
77
1252

1076483
N/A
N/A
119774
119789
ACGGGAAATCATATAG
5
1253

1076515
N/A
N/A
122246
122261
CTGCAAGAATACTTTA
30
1254

1076547
N/A
N/A
97024
97039
GACCAACCTCCCTCAG
89
1255

TABLE 18

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074116
111
126
3571
3586
GAGAACTTTTTCCCTC
112
1256

1074148
292
307
3752
3767
GTGGAGAAGCGGCGAC
66
1257

1074180
384
399
3844
3859
CCGGGATCCATGGCTT
86
1258

1074212
644
659
4104
4119
GCTTCCGGAGCCTCAT
53
1259

1074244
933
948
7367
7382
CTCTGACCAGAAGATG
95
1260

1074276
1147
1162
79088
79103
CCAAGAGGTGGTCTTG
87
1261

1074308
1376
1391
N/A
N/A
GCATTGCCTGTGGCCT
132
1262

1074340
1493
1508
116682
116697
TCCCGGGAGAAGACAC
120
1263

1074372
1680
1695
122705
122720
CTTTGGTTGATAGTAT
10
1264

1074404
1974
1989
122999
123014
GGCTTATGGAAATTTC
16
1265

1074436
2277
2292
123302
123317
CATGAAGCATCTGACT
31*
1266

1074468
2653
2668
123678
123693
CCACCGACCCTGCCAA
34
1267

1074500
2747
2762
123772
123787
CTACAATAACCATCCC
10
1268

1074532
3026
3041
124051
124066
GAACACTAAACTACTT
59
1269

1074564
3179
3194
124204
124219
CTGAATTCCAATCGAG
4
1270

1074596
3401
3416
124426
124441
TTCTATCCAGGGTCAA
12
1271

1074628
3732
3747
124757
124772
GCCTGTTATGAACCCT
5
1272

1074660
4057
4072
125082
125097
AATTTCATTACTACTC
48
1273

1074692
4245
4260
125270
125285
CCCCCCCAAACTTTCC
101
1274

1074724
4411
4426
125436
125451
GGGTAAAGGAAGATCT
22
1275

1074756
4601
4616
125626
125641
GCACTTTTACATTAGG
3
1276

1074788
4762
4777
125787
125802
TCAACCATAAGTAGAT
25
1277

1074820
5046
5061
126071
126086
AAGTGTTAAGCACTGA
85
1278

1074852
5144
5159
126169
126184
AATTGTTATGATAGGC
4
1279

1074916
N/A
N/A
5532
5547
AAGTTACATCCCGAGT
75
1280

1074948
N/A
N/A
5630
5645
GAGTTCCAAAACCCTT
61
1281

1074980
N/A
N/A
126494
126509
TATTGCCAGTTCTTGT
26
1282

1075012
N/A
N/A
5349
5364
CTATTGGAATGTTAAC
119
1283

1075044
N/A
N/A
7844
7859
AATTAGACTCCCCCAA
58
1284

1075076
N/A
N/A
10048
10063
CATAACATCATGGAAG
25
1285

1075108
N/A
N/A
11252
11267
CTAAAAACATTGTGGC
67
1286

1075140
N/A
N/A
13661
13676
CTTTAGGTTAAGCAAT
86
1287

1075172
N/A
N/A
17404
17419
CTTTACATGAACTGAT
14
1288

1075204
N/A
N/A
22115
22130
GTTAAACACATCTCAG
43
1289

1075236
N/A
N/A
24827
24842
TATAATACCACAAAGT
81
1290

1075268
N/A
N/A
27596
27611
TATTAACCTGGAGAGT
47
1291

1075300
N/A
N/A
31414
31429
CGTGAAAAGAAAGGCC
98
1292

1075332
N/A
N/A
32520
32535
AGCGGGTTTAGAATGC
66
1293

1075364
N/A
N/A
34293
34308
CGAAAATAGTTCTCAA
59
1294

1075396
N/A
N/A
36570
36585
ATTATCGCACATACAT
89
1295

1075428
N/A
N/A
38799
38814
TATATAAGGCATCTTG
53
1296

1075460
N/A
N/A
41053
41068
AATAACCAAGGATAGT
30
1297

1075492
N/A
N/A
43309
43324
GCTAAAATGATACTTC
29
1298

1075524
N/A
N/A
45518
45533
TAATTAAGGGCCCACA
71
1299

1075556
N/A
N/A
47618
47633
TGGCAAAAGAGTGGTG
68
1300

1075588
N/A
N/A
49376
49391
ACTTATTAGCACCTGG
27
1301

1075620
N/A
N/A
51476
51491
GATGAAGAATCTATAG
88
1302

1075652
N/A
N/A
52785
52800
GTATATTACAATCCCA
40
1303

1075684
N/A
N/A
55228
55243
TCTGAAAAAGTTATGC
78
1304

1075716
N/A
N/A
57654
57669
GCCGAAATACTCTCAT
19
1305

1075748
N/A
N/A
59723
59738
GTAAATCAAGTTGCAT
7
1306

1075780
N/A
N/A
62440
62455
TATAATAATCCAGAAC
98
1307

1075812
N/A
N/A
64470
64485
CATTAAGATTTTAACC
103
1308

1075844
N/A
N/A
67247
67262
TATTAAATAAGAGCTC
84
1309

1075876
N/A
N/A
71176
71191
GTATTTATGATGATTC
6
1310

1075908
N/A
N/A
74518
74533
AATAAGGAGTAGGTGG
50
1311

1075940
N/A
N/A
77113
77128
ACTCAACAACCCCAAG
54
1312

1075972
N/A
N/A
80426
80441
TCACAAGGGCTAATTC
22
1313

1076004
N/A
N/A
82143
82158
TAATTTAATGGCTTGC
2
1314

1076036
N/A
N/A
84973
84988
CGTAATTAGAAACTTG
19
1315

1076068
N/A
N/A
87383
87398
CTAAAATGACCTTAGC
73
1316

1076100
N/A
N/A
90552
90567
AATAAGGGACTACTTT
65
1317

1076132
N/A
N/A
92207
92222
CATCAATACTGACATC
28
1318

1076164
N/A
N/A
93799
93814
TGATATAAGTTACCAA
50
1319

1076196
N/A
N/A
96347
96362
TATCAAGGGAATTATT
113
1320

1076228
N/A
N/A
98039
98054
ATTAACCTCAGTGAGC
69
1321

1076260
N/A
N/A
100704
100719
CTTAATTTAACTCCTG
3
1322

1076292
N/A
N/A
103572
103587
TATTATTGAGTTATCC
27
1323

1076324
N/A
N/A
106059
106074
GCTCAAAAGGTCTCTC
13
1324

1076356
N/A
N/A
109576
109591
CATAATTGGACTGTCT
99
1325

1076388
N/A
N/A
111483
111498
GAAATATTCGAGAAGA
6
1326

1076420
N/A
N/A
113876
113891
CCATATAATAACCCAT
26
1327

1076452
N/A
N/A
117193
117208
GGACTATAGCCCTTAA
16
1328

1076484
N/A
N/A
119777
119792
GAAACGGGAAATCATA
10
1329

1076516
N/A
N/A
122314
122329
CATAAACATGAGTGGT
8
1330

1076548
N/A
N/A
116744
116759
CACCAACCTGTTAAGG
106
1331

TABLE 19

Inhibition of Yap 1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ
SEQ
SEQ
SEQ

ID
ID
ID
ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1
SEQ

Compound
Start
Stop
Start
Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074117
117
132
3577
3592
GCGCCTGAGAACTTTT
87
1332

1074149
298
313
3758
3773
GCCGAGGTGGAGAAGC
58
1333

1074181
385
400
3845
3860
CCCGGGATCCATGGCT
107
1334

1074213
654
669
4114
4129
GAGTCGGGCAGCTTCC
55
1335

1074245
941
956
7375
7390
AGAAGTATCTCTGACC
5
1336

1074277
1153
1168
79094
79109
GTCTAGCCAAGAGGTG
18
1337

1074309
1378
1393
N/A
N/A
CCGCATTGCCTGTGGC
80
1338

1074341
1494
1509
116683
116698
ATCCCGGGAGAAGACA
106
1339

1074373
1681
1696
122706
122721
GCTTTGGTTGATAGTA
26
1340

1074405
1991
2006
123016
123031
GCCTGAAAACTGCAAC
27
1341

1074437
2278
2293
123303
123318
ACATGAAGCATCTGAC
4*
1342

1074469
2654
2669
123679
123694
CCCACCGACCCTGCCA
77
1343

1074501
2748
2763
123773
123788
ACTACAATAACCATCC
9
1344

1074533
3028
3043
124053
124068
TAGAACACTAAACTAC
80
1345

1074565
3180
3195
124205
124220
ACTGAATTCCAATCGA
5
1346

1074597
3405
3420
124430
124445
AGTATTCTATCCAGGG
5
1347

1074629
3742
3757
124767
124782
GAGATTTTATGCCTGT
3
1348

1074661
4058
4073
125083
125098
GAATTTCATTACTACT
36
1349

1074693
4246
4261
125271
125286
CCCCCCCCAAACTTTC
92
1350

1074725
4437
4452
125462
125477
GTATAACTGGGCAAAT
17
1351

1074757
4607
4622
125632
125647
AGTTAAGCACTTTTAC
21
1352

1074789
4763
4778
125788
125803
ATCAACCATAAGTAGA
17
1353

1074821
5049
5064
126074
126089
GAAAAGTGTTAAGCAC
18
1354

1074853
5145
5160
126170
126185
CAATTGTTATGATAGG
15
1355

1074917
N/A
N/A
5533
5548
CAAGTTACATCCCGAG
80
1356

1074949
N/A
N/A
5642
5657
GTGATTTTTTCTGAGT
31
1357

1074981
N/A
N/A
126495
126510
TTATTGCCAGTTCTTG
9
1358

1075013
N/A
N/A
5768
5783
CATAAACCCACTTCGA
102
1359

1075045
N/A
N/A
7845
7860
AAATTAGACTCCCCCA
18
1360

1075077
N/A
N/A
10057
10072
TATACGGTCCATAACA
35
1361

1075109
N/A
N/A
11253
11268
ACTAAAAACATTGTGG
71
1362

1075141
N/A
N/A
13863
13878
TATACGAGAAGTTGAA
54
1363

1075173
N/A
N/A
17464
17479
CTTTAGGGCAACTGTA
22
1364

1075205
N/A
N/A
22160
22175
ATTAAATGAGCACCAC
29
1365

1075237
N/A
N/A
25230
25245
GCTGAAAATGCTAACT
105
1366

1075269
N/A
N/A
27597
27612
TTATTAACCTGGAGAG
13
1367

1075301
N/A
N/A
31460
31475
CAGCAACACCTAAGGA
92
1368

1075333
N/A
N/A
32529
32544
AGTTAACAAAGCGGGT
14
1369

1075365
N/A
N/A
34295
34310
CACGAAAATAGTTCTC
11
1370

1075397
N/A
N/A
36571
36586
CATTATCGCACATACA
79
1371

1075429
N/A
N/A
38974
38989
CTTTACTATCTGGGTC
23
1372

1075461
N/A
N/A
41056
41071
CTAAATAACCAAGGAT
64
1373

1075493
N/A
N/A
43320
43335
AGACAAGGGATGCTAA
67
1374

1075525
N/A
N/A
45519
45534
TTAATTAAGGGCCCAC
130
1375

1075557
N/A
N/A
47655
47670
TATTAAGGTGGCTTAC
57
1376

1075589
N/A
N/A
49390
49405
AATTAGCAGGGCAGAC
84
1377

1075621
N/A
N/A
51645
51660
GATTAACATTGATACT
61
1378

1075653
N/A
N/A
53476
53491
CATAAACTCTGCTGTC
58
1379

1075685
N/A
N/A
55369
55384
CATAATCAAAGGGTGC
60
1380

1075717
N/A
N/A
57665
57680
CATAAATTTCAGCCGA
10
1381

1075749
N/A
N/A
59800
59815
AATTATGAATGATGGG
4
1382

1075781
N/A
N/A
62475
62490
CATATATTGTGACTTC
2
1383

1075813
N/A
N/A
64652
64667
ACTAATATGCAACTCT
4
1384

1075845
N/A
N/A
67654
67669
GTGGAAAAGTATGATC
19
1385

1075877
N/A
N/A
71248
71263
CTGGAAAAGTACATTC
28
1386

1075909
N/A
N/A
74519
74534
AAATAAGGAGTAGGTG
93
1387

1075941
N/A
N/A
77150
77165
AGTCAATAGCAATCAC
11
1388

1075973
N/A
N/A
80581
80596
CCGCAACACCATTCTT
8
1389

1076005
N/A
N/A
82193
82208
GTACAAAATCTCCAGG
69
1390

1076037
N/A
N/A
84987
85002
CTTAAATTCTCTTACG
21
1391

1076069
N/A
N/A
87384
87399
TCTAAAATGACCTTAG
118
1392

1076101
N/A
N/A
90553
90568
AAATAAGGGACTACTT
71
1393

1076133
N/A
N/A
92254
92269
CATACTAATTTGGTAA
60
1394

1076165
N/A
N/A
93923
93938
CCCCAAGGACTTGCCA
79
1395

1076197
N/A
N/A
96350
96365
TATTATCAAGGGAATT
94
1396

1076229
N/A
N/A
98040
98055
AATTAACCTCAGTGAG
91
1397

1076261
N/A
N/A
100852
100867
CCCCAACAAGTTCCTG
39
1398

1076293
N/A
N/A
103575
103590
GCTTATTATTGAGTTA
3
1399

1076325
N/A
N/A
106620
106635
CTAATAATGGAAGAGT
16
1400

1076357
N/A
N/A
109680
109695
TCCAAAAACTTCTTAG
22
1401

1076389
N/A
N/A
111486
111501
ATCGAAATATTCGAGA
76
1402

1076421
N/A
N/A
113900
113915
AATTATGACCTCCATG
65
1403

1076453
N/A
N/A
117330
117345
GTAATATTGCAATCTG
1
1404

1076485
N/A
N/A
119781
119796
AAACGAAACGGGAAAT
55
1405

1076517
N/A
N/A
122329
122344
CATAATAAGACTAAAC
102
1406

1076549
N/A
N/A
117537
117552
GTGCAAAATACCTTTG
8
1407

TABLE 20

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ ID

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074118
131
146
3591
3606
CACTCGGACCTGCGGC
66
1408

1074150
299
314
3759
3774
GGCCGAGGTGGAGAAG
85
1409

1074182
386
401
3846
3861
GCCCGGGATCCATGGC
82
1410

1074214
672
687
4132
4147
TCCGGCGGCTTGAAGA
89
1411

1074246
942
957
7376
7391
AAGAAGTATCTCTGAC
11
1412

1074278
1158
1173
79099
79114
CTTGGGTCTAGCCAAG
31
1413

1074310
1379
1394
N/A
N/A
TCCGCATTGCCTGTGG
100
1414

1074342
1495
1510
116684
116699
CATCCCGGGAGAAGAC
56
1415

1074374
1682
1697
122707
122722
TGCTTTGGTTGATAGT
13
1416

1074406
2032
2047
123057
123072
AAAGTATCTTGCTGGA
16
1417

1074438
2279
2294
123304
123319
GACATGAAGCATCTGA
1*
1418

1074470
2657
2672
123682
123697
CCCCCCACCGACCCTG
69
1419

1074502
2749
2764
123774
123789
AACTACAATAACCATC
31
1420

1074534
3041
3056
124066
124081
TAATAGCTCTTTCTAG
88
1421

1074566
3181
3196
124206
124221
CACTGAATTCCAATCG
3
1422

1074598
3410
3425
124435
124450
CTTATAGTATTCTATC
46
1423

1074630
3743
3758
124768
124783
AGAGATTTTATGCCTG
5
1424

1074662
4062
4077
125087
125102
GGTAGAATTTCATTAC
30
1425

1074694
4247
4262
125272
125287
CCCCCCCCCAAACTTT
79
1426

1074726
4438
4453
125463
125478
GGTATAACTGGGCAAA
2
1427

1074758
4608
4623
125633
125648
CAGTTAAGCACTTTTA
4
1428

1074790
4764
4779
125789
125804
CATCAACCATAAGTAG
28
1429

1074822
5051
5066
126076
126091
TAGAAAAGTGTTAAGC
25
1430

1074854
5146
5161
126171
126186
ACAATTGTTATGATAG
23
1431

1074918
N/A
N/A
5534
5549
TCAAGTTACATCCCGA
60
1432

1074950
N/A
N/A
5652
5667
ATCAGGTTAAGTGATT
120
1433

1074982
N/A
N/A
126500
126515
ACCTTTTATTGCCAGT
13
1434

1075014
N/A
N/A
6038
6053
GGAGAAATAAAAGTCG
46
1435

1075046
N/A
N/A
7846
7861
AAAATTAGACTCCCCC
12
1436

1075078
N/A
N/A
10061
10076
CAACTATACGGTCCAT
3
1437

1075110
N/A
N/A
11254
11269
GACTAAAAACATTGTG
120
1438

1075142
N/A
N/A
13865
13880
GATATACGAGAAGTTG
16
1439

1075174
N/A
N/A
17491
17506
CCTGAAAAGACAGTCC
74
1440

1075206
N/A
N/A
22161
22176
TATTAAATGAGCACCA
36
1441

1075238
N/A
N/A
25596
25611
CTTAAACAGGTGCCAA
24
1442

1075270
N/A
N/A
27599
27614
CTTTATTAACCTGGAG
18
1443

1075302
N/A
N/A
31497
31512
CCTTAAAGCTTCCACC
75
1444

1075334
N/A
N/A
32542
32557
TTAATAATCTACCAGT
60
1445

1075366
N/A
N/A
34296
34311
ACACGAAAATAGTTCT
27
1446

1075398
N/A
N/A
36612
36627
TATATATGGCCCTTTA
49
1447

1075430
N/A
N/A
39017
39032
CTTAACTAACTTGACC
96
1448

1075462
N/A
N/A
41259
41274
GTTTATAGACAAGTCA
15
1449

1075494
N/A
N/A
43450
43465
TCTCAACAATTTGCTA
47
1450

1075526
N/A
N/A
45520
45535
TTTAATTAAGGGCCCA
110
1451

1075558
N/A
N/A
47656
47671
ATATTAAGGTGGCTTA
51
1452

1075590
N/A
N/A
49396
49411
CATCAAAATTAGCAGG
50
1453

1075622
N/A
N/A
51771
51786
TCTTATACCTATCTTC
56
1454

1075654
N/A
N/A
53501
53516
TATTAAGACGAATCCA
76
1455

1075686
N/A
N/A
55578
55593
GTAATTACAGTGTCTC
10
1456

1075718
N/A
N/A
57703
57718
CCACTAAAACCAAGTT
48
1457

1075750
N/A
N/A
59801
59816
CAATTATGAATGATGG
10
1458

1075782
N/A
N/A
62506
62521
TATTAGGTTTCCCGTT
10
1459

1075814
N/A
N/A
64821
64836
TATAAAGCAGGGCATT
47
1460

1075846
N/A
N/A
67670
67685
GATTAAGAGCCTATCT
96
1461

1075878
N/A
N/A
71286
71301
GATTATCAAGTAGTTT
35
1462

1075910
N/A
N/A
74520
74535
GAAATAAGGAGTAGGT
93
1463

1075942
N/A
N/A
77172
77187
TGACTATACATGGTGA
46
1464

1075974
N/A
N/A
80589
80604
AAAAAATTCCGCAACA
39
1465

1076006
N/A
N/A
82219
82234
TTTAAACCTGAGACTC
41
1466

1076038
N/A
N/A
85047
85062
AGGCAAGAATTGGGTA
11
1467

1076070
N/A
N/A
87434
87449
ATTAGTAATGCACAGG
6
1468

1076102
N/A
N/A
90613
90628
CTTAACAAATCAGCCC
32
1469

1076134
N/A
N/A
92267
92282
GATTAGAGTTGGGCAT
10
1470

1076166
N/A
N/A
93997
94012
ATTTACACCACCGCCC
77
1471

1076198
N/A
N/A
96351
96366
CTATTATCAAGGGAAT
81
1472

1076230
N/A
N/A
98041
98056
GAATTAACCTCAGTGA
50
1473

1076262
N/A
N/A
101120
101135
AGACAATAGTCTGGGC
41
1474

1076294
N/A
N/A
103629
103644
TATATTAGTGCCCCCT
6
1475

1076326
N/A
N/A
106621
106636
GCTAATAATGGAAGAG
4
1476

1076358
N/A
N/A
109745
109760
GTTTAACAAACTTGTA
43
1477

1076390
N/A
N/A
111487
111502
GATCGAAATATTCGAG
54
1478

1076422
N/A
N/A
113901
113916
GAATTATGACCTCCAT
13
1479

1076454
N/A
N/A
117469
117484
TAAACTAATCCCATAT
35
1480

1076486
N/A
N/A
119782
119797
GAAACGAAACGGGAAA
5
1481

1076518
N/A
N/A
122341
122356
GATAAGCACCACCATA
25
1482

1076550
N/A
N/A
120573
120588
TACCAACCTGTATCCA
61
1483

TABLE 21

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074119
132
147
3592
3607
GCACTCGGACCTGCGG
71
1484

1074151
300
315
3760
3775
GGGCCGAGGTGGAGAA
81
1485

1074183
407
422
3867
3882
CCGGTTGAGGCGGCGG
90
1486

1074215
674
689
4134
4149
GCTCCGGCGGCTTGAA
77
1487

1074247
955
970
N/A
N/A
ATCGATGTGATTTAAG
43
1488

1074279
1165
1180
79106
79121
GTCAAGCCTTGGGTCT
13
1489

1074311
1380
1395
N/A
N/A
TTCCGCATTGCCTGTG
24
1490

1074343
1498
1513
116687
116702
AGACATCCCGGGAGAA
18
1491

1074375
1688
1703
122713
122728
GCAGGGTGCTTTGGTT
33
1492

1074407
2033
2048
123058
123073
TAAAGTATCTTGCTGG
6
1493

1074439
2283
2298
123308
123323
CTGTGACATGAAGCAT
2*
1494

1074471
2658
2673
123683
123698
CCCCCCCACCGACCCT
69
1495

1074503
2750
2765
123775
123790
CAACTACAATAACCAT
29
1496

1074535
3042
3057
124067
124082
GTAATAGCTCTTTCTA
5
1497

1074567
3189
3204
124214
124229
AACCTACTCACTGAAT
38
1498

1074599
3423
3438
124448
124463
GCTAACTCAAAACCTT
12
1499

1074631
3765
3780
124790
124805
CATAGCAGCTTTTGCC
9
1500

1074663
4069
4084
125094
125109
CATTCTAGGTAGAATT
79
1501

1074695
4266
4281
125291
125306
CCCCCTAAATCTTCAC
49
1502

1074727
4440
4455
125465
125480
GAGGTATAACTGGGCA
9
1503

1074759
4619
4634
125644
125659
CAACCAAGAAGCAGTT
43
1504

1074791
4767
4782
125792
125807
CTCCATCAACCATAAG
20
1505

1074823
5080
5095
126105
126120
GAGCACTCATTTCTCA
77
1506

1074855
5213
5228
126238
126253
GTGCATTAAAGAATTC
29
1507

1074887
N/A
N/A
5450
5465
TAGCCTGAAGCAAGTT
57
1508

1074919
N/A
N/A
5535
5550
CTCAAGTTACATCCCG
48
1509

1074951
N/A
N/A
5653
5668
CATCAGGTTAAGTGAT
85
1510

1074983
N/A
N/A
126501
126516
CACCTTTTATTGCCAG
11
1511

1075015
N/A
N/A
6067
6082
CAGAATAAGTATGATT
55
1512

1075047
N/A
N/A
7847
7862
TAAAATTAGACTCCCC
7
1513

1075079
N/A
N/A
10149
10164
CACCAAAAGCTTAGTT
40
1514

1075111
N/A
N/A
11385
11400
TAGGAATATGGGTAGT
5
1515

1075143
N/A
N/A
13883
13898
CCTTATTAGTCAGTTC
2
1516

1075175
N/A
N/A
17507
17522
ACTGAAAGATTCCATG
99
1517

1075207
N/A
N/A
22162
22177
CTATTAAATGAGCACC
4
1518

1075239
N/A
N/A
25597
25612
TCTTAAACAGGTGCCA
27
1519

1075271
N/A
N/A
27652
27667
GATGTGATCTGTGAGA
11
1520

1075303
N/A
N/A
31554
31569
TAAACTAATCTACAAC
100
1521

1075335
N/A
N/A
32543
32558
CTTAATAATCTACCAG
30
1522

1075367
N/A
N/A
34502
34517
CATTACTTAGGGCTTA
12
1523

1075399
N/A
N/A
36614
36629
CATATATATGGCCCTT
15
1524

1075431
N/A
N/A
39045
39060
TAACTAAACTGATTCC
74
1525

1075463
N/A
N/A
41370
41385
CTTAATCCAAAGCTTC
34
1526

1075495
N/A
N/A
43489
43504
CTTAATTGGTAACTGA
19
1527

1075527
N/A
N/A
45521
45536
ATTTAATTAAGGGCCC
82
1528

1075559
N/A
N/A
47657
47672
GATATTAAGGTGGCTT
24
1529

1075591
N/A
N/A
49541
49556
GTAATAATCACCTTAC
76
1530

1075623
N/A
N/A
51815
51830
CATAATCAAAATGGGC
48
1531

1075655
N/A
N/A
53502
53517
CTATTAAGACGAATCC
38
1532

1075687
N/A
N/A
55642
55657
TAAACGAGTAATGACT
23
1533

1075719
N/A
N/A
58015
58030
CTAAAACCGGCTGGAC
76
1534

1075751
N/A
N/A
59839
59854
GAGGAACAAGATCTCA
72
1535

1075783
N/A
N/A
62684
62699
CTTAATTTACCTGAAC
36
1536

1075815
N/A
N/A
64822
64837
GTATAAAGCAGGGCAT
36
1537

1075847
N/A
N/A
67823
67838
CTTTATAGCAGATGCC
14
1538

1075879
N/A
N/A
71353
71368
GAATAAAGAAGTCACC
77
1539

1075911
N/A
N/A
74637
74652
TGACAAAACAGGCACC
41
1540

1075943
N/A
N/A
77361
77376
GTATATCAAACCTTTT
15
1541

1075975
N/A
N/A
80592
80607
GGAAAAAAATTCCGCA
84
1542

1076007
N/A
N/A
82293
82308
CATTAGGCCTTTTACT
27
1543

1076039
N/A
N/A
85200
85215
GATTAGAGCTGTATTC
29
1544

1076071
N/A
N/A
87435
87450
TATTAGTAATGCACAG
14
1545

1076103
N/A
N/A
90614
90629
GCTTAACAAATCAGCC
79
1546

1076135
N/A
N/A
92319
92334
CATAATTGACAGGTAT
14
1547

1076167
N/A
N/A
93999
94014
AAATTTACACCACCGC
33
1548

1076199
N/A
N/A
96382
96397
TATCAAAAGTCCATCC
37
1549

1076231
N/A
N/A
98106
98121
TTAGAAATGGACTGGG
16
1550

1076263
N/A
N/A
101298
101313
AATAACCAAGTGAGTT
21
1551

1076295
N/A
N/A
103630
103645
GTATATTAGTGCCCCC
2
1552

1076327
N/A
N/A
106694
106709
GATAAGCAAGGTTCTC
7
1553

1076359
N/A
N/A
109776
109791
ATTTATCCTAGTTACC
29
1554

1076391
N/A
N/A
111530
111545
CAAATATAGTTAGCCT
22
1555

1076423
N/A
N/A
114068
114083
CCTGAACCTTCTGGAT
93
1556

1076455
N/A
N/A
117635
117650
ACTAAATACTTTTAGC
86
1557

1076487
N/A
N/A
119786
119801
GTACGAAACGAAACGG
21
1558

1076519
N/A
N/A
122375
122390
ACACAACACGACAGCA
31
1559

1076551
N/A
N/A
5268
5283
GTGGAATAGCAGCCAT
67
1560

TABLE 22

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074120
137
152
3597
3612
GCGAGGCACTCGGACC
50
1561

1074152
301
316
3761
3776
CGGGCCGAGGTGGAGA
77
1562

1074184
408
423
3868
3883
GCCGGTTGAGGCGGCG
100
1563

1074216
681
696
4141
4156
GATTTGGGCTCCGGCG
58
1564

1074248
956
971
N/A
N/A
GATCGATGTGATTTAA
29
1565

1074280
1166
1181
79107
79122
GGTCAAGCCTTGGGTC
43
1566

1074312
1383
1398
102515
102530
ATATTCCGCATTGCCT
18
1567

1074344
1500
1515
116689
116704
TGAGACATCCCGGGAG
99
1568

1074376
1706
1721
122731
122746
AACGGTTCTGCTGTGA
44
1569

1074408
2036
2051
123061
123076
GATTAAAGTATCTTGC
23
1570

1074440
2284
2299
123309
123324
GCTGTGACATGAAGCA
38*
1571

1074472
2660
2675
123685
123700
AACCCCCCCACCGACC
107
1572

1074504
2804
2819
123829
123844
TCGAGATTTAAATAAG
76
1573

1074536
3043
3058
124068
124083
AGTAATAGCTCTTTCT
6
1574

1074568
3190
3205
124215
124230
GAACCTACTCACTGAA
12
1575

1074600
3425
3440
124450
124465
CAGCTAACTCAAAACC
29
1576

1074632
3766
3781
124791
124806
TCATAGCAGCTTTTGC
12
1577

1074664
4070
4085
125095
125110
GCATTCTAGGTAGAAT
49
1578

1074696
4268
4283
125293
125308
GTCCCCCTAAATCTTC
38
1579

1074728
4441
4456
125466
125481
TGAGGTATAACTGGGC
3
1580

1074760
4620
4635
125645
125660
ACAACCAAGAAGCAGT
11
1581

1074792
4776
4791
125801
125816
ATCAATGTGCTCCATC
4
1582

1074824
5083
5098
126108
126123
CCTGAGCACTCATTTC
53
1583

1074856
5223
5238
126248
126263
TTTGACAAGTGTGCAT
15
1584

1074888
N/A
N/A
5453
5468
GTTTAGCCTGAAGCAA
58
1585

1074920
N/A
N/A
5536
5551
ACTCAAGTTACATCCC
68
1586

1074952
N/A
N/A
5661
5676
GTTTTTGTCATCAGGT
42
1587

1074984
N/A
N/A
126503
126518
ATCACCTTTTATTGCC
31
1588

1075016
N/A
N/A
6068
6083
TCAGAATAAGTATGAT
100
1589

1075048
N/A
N/A
7848
7863
GTAAAATTAGACTCCC
4
1590

1075080
N/A
N/A
10219
10234
ATTACAAAGACAGCCC
18
1591

1075112
N/A
N/A
11388
11403
ATATAGGAATATGGGT
6
1592

1075144
N/A
N/A
14659
14674
ACCCTATATCCTATAT
82
1593

1075176
N/A
N/A
17544
17559
AATTACCCGGGAACTA
70
1594

1075208
N/A
N/A
22191
22206
ACTGAACACAGGCTAC
24
1595

1075240
N/A
N/A
25749
25764
TAAACGGTTTATATTC
16
1596

1075272
N/A
N/A
28023
28038
AATTAGCCAGCATGCA
110
1597

1075304
N/A
N/A
31613
31628
CACGGGTACCAGAAAA
50
1598

1075336
N/A
N/A
32544
32559
GCTTAATAATCTACCA
32
1599

1075368
N/A
N/A
34751
34766
GAGAATAAGCAATCAG
24
1600

1075400
N/A
N/A
36641
36656
TAGCAATAGTCAGGTA
11
1601

1075432
N/A
N/A
39046
39061
CTAACTAAACTGATTC
121
1602

1075464
N/A
N/A
41448
41463
CCACTAAACCACCTAA
77
1603

1075496
N/A
N/A
43503
43518
TTATATAATGCAGGCT
22
1604

1075528
N/A
N/A
45616
45631
ATCGAAGGGCAAACTC
42
1605

1075560
N/A
N/A
47723
47738
GCTAAATAAAGGTTAC
86
1606

1075592
N/A
N/A
49542
49557
CGTAATAATCACCTTA
55
1607

1075624
N/A
N/A
51848
51863
ATCTATAACCCTTATT
91
1608

1075656
N/A
N/A
53591
53606
AAAACGGTTTTTCTAA
103
1609

1075688
N/A
N/A
55673
55688
GACAATAAACATCACC
12
1610

1075720
N/A
N/A
58458
58473
CTTTACTACATATAGC
47
1611

1075752
N/A
N/A
60020
60035
CATAATTATACTGATC
19
1612

1075784
N/A
N/A
62703
62718
ATTTTATAGGGCCATT
3
1613

1075816
N/A
N/A
64824
64839
TAGTATAAAGCAGGGC
7
1614

1075848
N/A
N/A
67963
67978
GATTACAATGGGCAGT
9
1615

1075880
N/A
N/A
71412
71427
ATTAACTACACCACGA
30
1616

1075912
N/A
N/A
74743
74758
AGTTATACACAACCAC
13
1617

1075944
N/A
N/A
77599
77614
TATTAGGAACAGATCA
25
1618

1075976
N/A
N/A
80964
80979
ATTAAAAGTCGGGCCA
92
1619

1076008
N/A
N/A
82386
82401
AGCGAAAATAACATTA
33
1620

1076040
N/A
N/A
85319
85334
CTTAAAGAAGCACTAG
105
1621

1076072
N/A
N/A
87726
87741
CACAAAAACTGGTCTG
18
1622

1076104
N/A
N/A
90640
90655
ACGAAATAGTAACTGT
24
1623

1076136
N/A
N/A
92372
92387
CAACAACCTCATGTAA
60
1624

1076168
N/A
N/A
94000
94015
CAAATTTACACCACCG
23
1625

1076200
N/A
N/A
96417
96432
GATTACACTATCAAAA
67
1626

1076232
N/A
N/A
98125
98140
GTAATACACCATTTGG
15
1627

1076264
N/A
N/A
101302
101317
ACCCAATAACCAAGTG
40
1628

1076296
N/A
N/A
103670
103685
TATAAAGACCCAATGC
68
1629

1076328
N/A
N/A
107005
107020
ACTGAACCGCTGCCTC
33
1630

1076360
N/A
N/A
109778
109793
CTATTTATCCTAGTTA
59
1631

1076392
N/A
N/A
111564
111579
TATTAATCAAATAGGG
64
1632

1076424
N/A
N/A
114085
114100
ACTTAACCTGACAGCT
76
1633

1076456
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC
2
1634

1076488
N/A
N/A
119867
119882
GCCAATAAGATAAGAA
19
1635

1076520
N/A
N/A
122407
122422
AATTATATGCAGCAGC
21
1636

1076552
N/A
N/A
11807
11822
ATGTATAAATACCAGG
7
1637

TABLE 23

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074121
138
153
3598
3613
TGCGAGGCACTCGGAC
87
1638

1074153
303
318
3763
3778
CACGGGCCGAGGTGGA
78
1639

1074185
409
424
3869
3884
GGCCGGTTGAGGCGGC
91
1640

1074217
682
697
4142
4157
GGATTTGGGCTCCGGC
74
1641

1074249
957
972
N/A
N/A
TGATCGATGTGATTTA
23
1642

1074281
1169
1184
79110
79125
GAGGGTCAAGCCTTGG
91
1643

1074313
1385
1400
102517
102532
TGATATTCCGCATTGC
5
1644

1074345
1533
1548
116722
116737
TCTGAGCTATTGGTCG
8
1645

1074377
1707
1722
122732
122747
AAACGGTTCTGCTGTG
52
1646

1074409
2037
2052
123062
123077
GGATTAAAGTATCTTG
6
1647

1074441
2294
2309
123319
123334
CAAACTAAATGCTGTG
5*
1648

1074473
2661
2676
123686
123701
CAACCCCCCCACCGAC
82
1649

1074505
2806
2821
123831
123846
AATCGAGATTTAAATA
83
1650

1074537
3044
3059
124069
124084
CAGTAATAGCTCTTTC
3
1651

1074569
3191
3206
124216
124231
TGAACCTACTCACTGA
8
1652

1074601
3426
3441
124451
124466
CCAGCTAACTCAAAAC
24
1653

1074633
3774
3789
124799
124814
GAGGCTTTTCATAGCA
78
1654

1074665
4072
4087
125097
125112
TTGCATTCTAGGTAGA
17
1655

1074697
4274
4289
125299
125314
ATCAAGGTCCCCCTAA
44
1656

1074729
4445
4460
125470
125485
ACACTGAGGTATAACT
9
1657

1074761
4628
4643
125653
125668
TACCCAATACAACCAA
15
1658

1074793
4777
4792
125802
125817
AATCAATGTGCTCCAT
9
1659

1074825
5084
5099
126109
126124
ACCTGAGCACTCATTT
36
1660

1074857
5245
5260
126270
126285
ACATTGGTACTATATA
25
1661

1074889
N/A
N/A
5454
5469
AGTTTAGCCTGAAGCA
42
1662

1074921
N/A
N/A
5537
5552
CACTCAAGTTACATCC
65
1663

1074953
N/A
N/A
5663
5678
GGGTTTTTGTCATCAG
32
1664

1074985
N/A
N/A
126504
126519
AATCACCTTTTATTGC
49
1665

1075017
N/A
N/A
6099
6114
CTTAAAGTGATACACC
19
1666

1075049
N/A
N/A
7912
7927
GAAATATTGGTAAGTC
10
1667

1075081
N/A
N/A
10220
10235
GATTACAAAGACAGCC
7
1668

1075113
N/A
N/A
11804
11819
TATAAATACCAGGTAC
67
1669

1075145
N/A
N/A
15306
15321
TCCCAAAAGGAGTAGC
58
1670

1075177
N/A
N/A
17546
17561
GAAATTACCCGGGAAC
27
1671

1075209
N/A
N/A
22213
22228
CATCAACAATGGTCTA
11
1672

1075241
N/A
N/A
25786
25801
GATAATTACTAACTGA
31
1673

1075273
N/A
N/A
28145
28160
AAATTATGGTCAGGCT
18
1674

1075305
N/A
N/A
31621
31636
AAACGAAACACGGGTA
66
1675

1075337
N/A
N/A
32561
32576
GCTTATATCCTGTAAC
48
1676

1075369
N/A
N/A
34752
34767
GGAGAATAAGCAATCA
31
1677

1075401
N/A
N/A
36720
36735
CGATTAAAACACTGGT
3
1678

1075433
N/A
N/A
39050
39065
TTAACTAACTAAACTG
124
1679

1075465
N/A
N/A
41471
41486
GATTTATTGAACTGAG
7
1680

1075497
N/A
N/A
43504
43519
ATTATATAATGCAGGC
14
1681

1075529
N/A
N/A
45618
45633
AAATCGAAGGGCAAAC
84
1682

1075561
N/A
N/A
47742
47757
GTAAGTAAGGGAACCC
32
1683

1075593
N/A
N/A
49605
49620
CATTAGAGTATGAACT
99
1684

1075625
N/A
N/A
51849
51864
AATCTATAACCCTTAT
49
1685

1075657
N/A
N/A
53594
53609
TAAAAAACGGTTTTTC
84
1686

1075689
N/A
N/A
55744
55759
CAACTATACAAGGCAA
4
1687

1075721
N/A
N/A
58637
58652
TTAAATACCTTCTAGC
67
1688

1075753
N/A
N/A
60167
60182
CTAGAACCTTTTCCAG
65
1689

1075785
N/A
N/A
62704
62719
CATTTTATAGGGCCAT
2
1690

1075817
N/A
N/A
65591
65606
CCTAAAGAAGTCTTGG
100
1691

1075849
N/A
N/A
67996
68011
CTAGAACACGCTGATG
55
1692

1075881
N/A
N/A
71413
71428
GATTAACTACACCACG
23
1693

1075913
N/A
N/A
75193
75208
CCCCTATACTTTTTGA
46
1694

1075945
N/A
N/A
77600
77615
GTATTAGGAACAGATC
11
1695

1075977
N/A
N/A
80965
80980
GATTAAAAGTCGGGCC
73
1696

1076009
N/A
N/A
82387
82402
TAGCGAAAATAACATT
69
1697

1076041
N/A
N/A
85661
85676
GTTAAAGAGTGGAAAT
47
1698

1076073
N/A
N/A
88094
88109
CTTTAAGGTCTAGTTA
47
1699

1076105
N/A
N/A
90641
90656
TACGAAATAGTAACTG
13
1700

1076137
N/A
N/A
92375
92390
CACCAACAACCTCATG
45
1701

1076169
N/A
N/A
94082
94097
CTACTATATCTTTGGG
10
1702

1076201
N/A
N/A
96469
96484
CTAAAAAGACAGGGCC
99
1703

1076233
N/A
N/A
98280
98295
CCAATAAAGCAAGTAG
13
1704

1076265
N/A
N/A
101306
101321
TATTACCCAATAACCA
9
1705

1076297
N/A
N/A
103671
103686
TTATAAAGACCCAATG
52
1706

1076329
N/A
N/A
107153
107168
AATTATACTGGCTACT
14
1707

1076361
N/A
N/A
109944
109959
TGGGAAAAGCTACCAC
87
1708

1076393
N/A
N/A
111591
111606
CTTTACTTACTGGTGG
4
1709

1076425
N/A
N/A
114175
114190
CGGGAAAATTCTGGAG
32
1710

1076457
N/A
N/A
117800
117815
GAACTATAATCTTATA
74
1711

1076489
N/A
N/A
119885
119900
CAAAATAGGTGAGTCA
2
1712

1076521
N/A
N/A
122446
122461
ACTAAAGGAGTCATGA
67
1713

1076553
N/A
N/A
37304
37319
TGGGAATAATTTGGCC
69
1714

TABLE 24

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074122
139
154
3599
3614
CTGCGAGGCACTCGGA
73
1715

1074154
304
319
3764
3779
CCACGGGCCGAGGTGG
100
1716

1074186
410
425
3870
3885
GGGCCGGTTGAGGCGG
74
1717

1074218
726
741
7160
7175
AGGGCTCCTGCAGTGC
70
1718

1074250
958
973
N/A
N/A
CTGATCGATGTGATTT
6
1719

1074282
1170
1185
79111
79126
CGAGGGTCAAGCCTTG
83
1720

1074314
1387
1402
102519
102534
ATTGATATTCCGCATT
12
1721

1074346
1534
1549
116723
116738
ATCTGAGCTATTGGTC
10
1722

1074378
1708
1723
122733
122748
GAAACGGTTCTGCTGT
31
1723

1074410
2041
2056
123066
123081
TAGAGGATTAAAGTAT
32
1724

1074442
2351
2366
123376
123391
GACCAGTAAATCATGT
21
1725

1074474
2662
2677
123687
123702
CCAACCCCCCCACCGA
71
1726

1074506
2807
2822
123832
123847
TAATCGAGATTTAAAT
107
1727

1074538
3049
3064
124074
124089
ATCCACAGTAATAGCT
31
1728

1074570
3192
3207
124217
124232
ATGAACCTACTCACTG
12
1729

1074602
3427
3442
124452
124467
TCCAGCTAACTCAAAA
24
1730

1074634
3777
3792
124802
124817
GCTGAGGCTTTTCATA
55
1731

1074666
4085
4100
125110
125125
CATATACCCAATTTTG
16
1732

1074698
4275
4290
125300
125315
TATCAAGGTCCCCCTA
78
1733

1074730
4463
4478
125488
125503
TATCACAGTACTGCTA
46
1734

1074762
4630
4645
125655
125670
GCTACCCAATACAACC
6
1735

1074794
4779
4794
125804
125819
CAAATCAATGTGCTCC
5
1736

1074826
5090
5105
126115
126130
AAATCCACCTGAGCAC
51
1737

1074858
5246
5261
126271
126286
AACATTGGTACTATAT
23
1738

1074890
N/A
N/A
5456
5471
GAAGTTTAGCCTGAAG
58
1739

1074922
N/A
N/A
5542
5557
CTTTCCACTCAAGTTA
87
1740

1074954
N/A
N/A
5665
5680
CCGGGTTTTTGTCATC
91
1741

1074986
N/A
N/A
126511
126526
CTACTGTAATCACCTT
78
1742

1075018
N/A
N/A
6100
6115
CCTTAAAGTGATACAC
29
1743

1075050
N/A
N/A
8047
8062
ACCCAACGGTCATGTT
94
1744

1075082
N/A
N/A
10252
10267
CTTTAGATACAAGAGG
80
1745

1075114
N/A
N/A
11805
11820
GTATAAATACCAGGTA
26
1746

1075146
N/A
N/A
15570
15585
GTATTAAGGGATTTTC
8
1747

1075178
N/A
N/A
17552
17567
CTGGAAGAAATTACCC
47
1748

1075210
N/A
N/A
22314
22329
GTATTTTAACCTAAAC
100
1749

1075242
N/A
N/A
25790
25805
CAGGGATAATTACTAA
7
1750

1075274
N/A
N/A
28203
28218
AATAATCCAGCCTAGG
86
1751

1075306
N/A
N/A
31622
31637
TAAACGAAACACGGGT
30
1752

1075338
N/A
N/A
32572
32587
CCCAAAAACTAGCTTA
56
1753

1075370
N/A
N/A
34931
34946
CTTACGAATCACATAT
32
1754

1075402
N/A
N/A
36792
36807
GAGCAACACAAGCATA
45
1755

1075434
N/A
N/A
39406
39421
GTAAAAGAGGTGCATC
96
1756

1075466
N/A
N/A
41511
41526
TCCAAAAACCATCAGT
28
1757

1075498
N/A
N/A
43505
43520
CATTATATAATGCAGG
9
1758

1075530
N/A
N/A
45619
45634
GAAATCGAAGGGCAAA
30
1759

1075562
N/A
N/A
47824
47839
GTATTTATGGCAACAT
15
1760

1075594
N/A
N/A
49676
49691
TGAGAATATTCCTCCC
64
1761

1075626
N/A
N/A
51926
51941
CATTAGCCAAAGCTCA
34
1762

1075658
N/A
N/A
53595
53610
GTAAAAAACGGTTTTT
103
1763

1075690
N/A
N/A
55750
55765
CGTTAACAACTATACA
33
1764

1075722
N/A
N/A
58638
58653
GTTAAATACCTTCTAG
88
1765

1075754
N/A
N/A
60230
60245
CTTAAATGGCACAGTT
20
1766

1075786
N/A
N/A
62749
62764
CTATATTGATTCCAGA
19
1767

1075818
N/A
N/A
65659
65674
CATAACTTAGAACCAT
35
1768

1075850
N/A
N/A
68030
68045
CTATAGGTACTTAGAA
N.D.
1769

1075882
N/A
N/A
71422
71437
GAAAATCCTGATTAAC
73
1770

1075914
N/A
N/A
75298
75313
ATTTAGGATGCCTTTA
14
1771

1075946
N/A
N/A
77683
77698
GCTGAATAAGTAACTT
20
1772

1075978
N/A
N/A
80966
80981
AGATTAAAAGTCGGGC
11
1773

1076010
N/A
N/A
82396
82411
TATAAACAATAGCGAA
44
1774

1076042
N/A
N/A
85704
85719
CTTAAGCAAGAGTCCA
35
1775

1076074
N/A
N/A
88162
88177
CTAATTAGCTTTCAGC
92
1776

1076106
N/A
N/A
90642
90657
CTACGAAATAGTAACT
77
1777

1076138
N/A
N/A
92409
92424
AGCCAACAATTTTTGG
113
1778

1076170
N/A
N/A
94131
94146
AGTAAAGAGTACTGTA
16
1779

1076202
N/A
N/A
96470
96485
TCTAAAAAGACAGGGC
32
1780

1076234
N/A
N/A
98304
98319
CCTTAATATATCCACA
24
1781

1076266
N/A
N/A
101308
101323
ATTATTACCCAATAAC
72
1782

1076298
N/A
N/A
103672
103687
GTTATAAAGACCCAAT
10
1783

1076330
N/A
N/A
107154
107169
GAATTATACTGGCTAC
3
1784

1076362
N/A
N/A
110095
110110
CCACTAAATAAAGCAG
16
1785

1076394
N/A
N/A
111629
111644
CCTAAATTAGACTTGA
20
1786

1076426
N/A
N/A
114176
114191
ACGGGAAAATTCTGGA
9
1787

1076458
N/A
N/A
117825
117840
CTTAATTAGCCTCAGT
6
1788

1076490
N/A
N/A
119886
119901
CCAAAATAGGTGAGTC
2
1789

1076522
N/A
N/A
122448
122463
GCACTAAAGGAGTCAT
35
1790

1076554
N/A
N/A
38773
38788
TGGGAATAGTGAATTT
30
1791

TABLE 25

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compound
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5′ to 3′)
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074123
140
155
3600
3615
GCTGCGAGGCACTCGG
72
1792

1074155
311
326
3771
3786
CCCGGCTCCACGGGCC
87
1793

1074187
439
454
3899
3914
CTGCGAAGGCGGCTGC
47
1794

1074219
730
745
7164
7179
AGTCAGGGCTCCTGCA
30
1795

1074251
959
974
N/A
N/A
TCTGATCGATGTGATT
7
1796

1074283
1174
1189
79115
79130
AAAACGAGGGTCAAGC
12
1797

1074315
1388
1403
102520
102535
GATTGATATTCCGCAT
3
1798

1074347
1546
1561
116735
116750
GTTAAGGAAAGGATCT
34
1799

1074379
1711
1726
122736
122751
TGGGAAACGGTTCTGC
20
1800

1074411
2095
2110
123120
123135
TGTGAAAGAGGTCAGC
3
1801

1074443
2354
2369
123379
123394
TCAGACCAGTAAATCA
7
1802

1074475
2663
2678
123688
123703
ACCAACCCCCCCACCG
72
1803

1074507
2808
2823
123833
123848
ATAATCGAGATTTAAA
74
1804

1074539
3051
3066
124076
124091
CTATCCACAGTAATAG
62
1805

1074571
3193
3208
124218
124233
TATGAACCTACTCACT
37
1806

1074603
3428
3443
124453
124468
TTCCAGCTAACTCAAA
17
1807

1074635
3783
3798
124808
124823
TCCCAAGCTGAGGCTT
31
1808

1074667
4107
4122
125132
125147
CCCAACAACATGCTAT
15
1809

1074699
4276
4291
125301
125316
CTATCAAGGTCCCCCT
27
1810

1074731
4467
4482
125492
125507
CAGGTATCACAGTACT
19
1811

1074763
4631
4646
125656
125671
TGCTACCCAATACAAC
25
1812

1074795
4780
4795
125805
125820
CCAAATCAATGTGCTC
4
1813

1074827
5092
5107
126117
126132
TAAAATCCACCTGAGC
39
1814

1074859
5248
5263
126273
126288
GTAACATTGGTACTAT
16
1815

1074891
N/A
N/A
5457
5472
TGAAGTTTAGCCTGAA
31
1816

1074923
N/A
N/A
5556
5571
GGGCGGTAACTCTTCT
73
1817

1074955
N/A
N/A
5666
5681
CCCGGGTTTTTGTCAT
93
1818

1074987
N/A
N/A
4228
4243
GCCGCGGCTCCCGAGC
94
1819

1075019
N/A
N/A
6185
6200
CATTAGAGTTTGATTA
64
1820

1075051
N/A
N/A
8055
8070
AATAAACAACCCAACG
56
1821

1075083
N/A
N/A
10265
10280
CAACAACACTCCTCTT
54
1822

1075115
N/A
N/A
11890
11905
GTATAGCCTTATTCTT
6
1823

1075147
N/A
N/A
15583
15598
TATAAACCTTACAGTA
57
1824

1075179
N/A
N/A
18169
18184
AATTAGCCGGTCCCAG
107
1825

1075211
N/A
N/A
22668
22683
AATAAAGGGTCCTAAC
91
1826

1075243
N/A
N/A
26237
26252
CTTAGTAAGAATTGTC
4
1827

1075275
N/A
N/A
28517
28532
CTAGAAAGGCCATGTA
76
1828

1075307
N/A
N/A
31624
31639
ATTAAACGAAACACGG
28
1829

1075339
N/A
N/A
32573
32588
ACCCAAAAACTAGCTT
70
1830

1075371
N/A
N/A
34942
34957
CTGCAAAAGTTCTTAC
90
1831

1075403
N/A
N/A
36942
36957
CTTAATCAGGTACTAT
18
1832

1075435
N/A
N/A
39516
39531
CTTAAACGATAAAGTA
93
1833

1075467
N/A
N/A
41522
41537
CATTAATGCCATCCAA
60
1834

1075499
N/A
N/A
43601
43616
GCTAAAAAATGAGTAG
99
1835

1075531
N/A
N/A
45685
45700
CTTAATAGTTTAACCT
66
1836

1075563
N/A
N/A
47947
47962
CCATATAACCAGTTTT
12
1837

1075595
N/A
N/A
49869
49884
TATAATACATCTCCCC
50
1838

1075627
N/A
N/A
51985
52000
ATAAGATAGTCGGTTC
19
1839

1075659
N/A
N/A
53597
53612
AAGTAAAAAACGGTTT
125
1840

1075691
N/A
N/A
55841
55856
CGTCAAAATTAACAGA
46
1841

1075723
N/A
N/A
58758
58773
TTATCCTATCCCTGGT
32
1842

1075755
N/A
N/A
60231
60246
ACTTAAATGGCACAGT
73
1843

1075787
N/A
N/A
62761
62776
CTTAAGGATTGGCTAT
28
1844

1075819
N/A
N/A
65672
65687
GTATATCCGTTCTCAT
2
1845

1075851
N/A
N/A
68466
68481
GCCGAATATGGGAAAA
70
1846

1075883
N/A
N/A
71454
71469
ACTAAAACCATTTGCC
20
1847

1075915
N/A
N/A
75299
75314
AATTTAGGATGCCTTT
16
1848

1075947
N/A
N/A
78266
78281
CTTTATAGGAATAGAG
95
1849

1075979
N/A
N/A
81132
81147
CATAATCCACTATGCA
18
1850

1076011
N/A
N/A
82397
82412
ATATAAACAATAGCGA
61
1851

1076043
N/A
N/A
85727
85742
CAAAAAGGCTATTGAG
36
1852

1076075
N/A
N/A
88209
88224
ACACAAGGGTTGCTAA
38
1853

1076107
N/A
N/A
90801
90816
CATTACCAACTTCTTC
23
1854

1076139
N/A
N/A
92416
92431
CGAAAAAAGCCAACAA
18
1855

1076171
N/A
N/A
94134
94149
ATTAGTAAAGAGTACT
30
1856

1076203
N/A
N/A
96576
96591
GTTAATACATGGCCAA
29
1857

1076235
N/A
N/A
98318
98333
TCAAAATAATCAGCCC
34
1858

1076267
N/A
N/A
101345
101360
ATTTAAGGTGCATAAG
13
1859

1076299
N/A
N/A
103673
103688
CGTTATAAAGACCCAA
3
1860

1076331
N/A
N/A
107265
107280
CATTATTCAGTAGTTG
71
1861

1076363
N/A
N/A
110104
110119
CATAAAAGTCCACTAA
72
1862

1076395
N/A
N/A
111649
111664
GTAACTAACCTAAGGA
34
1863

1076427
N/A
N/A
114212
114227
CAAATTTACTGATCTC
3
1864

1076459
N/A
N/A
117903
117918
CTTCAACAAGACAGGT
4
1865

1076491
N/A
N/A
119888
119903
AGCCAAAATAGGTGAG
12
1866

1076523
N/A
N/A
122559
122574
ATTTATATCAGGTCAA
5
1867

1076555
N/A
N/A
74684
74699
TGGGAATAGTACACAG
19
1868

TABLE 26

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074124
141
156
3601
3616
GGCTGCGAGGCACTCG
94
1869

1074156
329
344
3789
3804
AGGGCTACGCCCGGAC
96
1870

1074188
440
455
3900
3915
GCTGCGAAGGCGGCTG
113
1871

1074220
752
767
7186
7201
AATGAGCTCGAACATG
22
1872

1074252
997
1012
55492
55507
GGACAGCATGGCCTTC
50
1873

1074284
1175
1190
79116
79131
CAAAACGAGGGTCAAG
21
1874

1074316
1389
1404
102521
102536
GGATTGATATTCCGCA
33
1875

1074348
1578
1593
120483
120498
GTACTCTCATCTCGAG
100
1876

1074380
1714
1729
122739
122754
GTCTGGGAAACGGTTC
11
1877

1074412
2096
2111
123121
123136
CTGTGAAAGAGGTCAG
55
1878

1074444
2368
2383
123393
123408
ACATTTTTGGCTTGTC
3
1879

1074476
2685
2700
123710
123725
TTCCGACAAAACCAAC
18
1880

1074508
2818
2833
123843
123858
GAGAGAGCAGATAATC
7
1881

1074540
3052
3067
124077
124092
ACTATCCACAGTAATA
26
1882

1074572
3194
3209
124219
124234
TTATGAACCTACTCAC
17
1883

1074604
3446
3461
124471
124486
TTATTAATCTGATCAC
12
1884

1074636
3791
3806
124816
124831
ATCTATCTTCCCAAGC
56
1885

1074668
4108
4123
125133
125148
TCCCAACAACATGCTA
20
1886

1074700
4320
4335
125345
125360
GTAAGACAAGTCTTTA
26
1887

1074732
4468
4483
125493
125508
CCAGGTATCACAGTAC
30
1888

1074764
4632
4647
125657
125672
ATGCTACCCAATACAA
18
1889

1074796
4782
4797
125807
125822
CTCCAAATCAATGTGC
22
1890

1074828
5093
5108
126118
126133
ATAAAATCCACCTGAG
58
1891

1074860
5252
5267
126277
126292
AAAGGTAACATTGGTA
9
1892

1074892
N/A
N/A
5458
5473
CTGAAGTTTAGCCTGA
42
1893

1074924
N/A
N/A
5585
5600
CCTGCAAATAGGAGAG
87
1894

1074956
N/A
N/A
5667
5682
ACCCGGGTTTTTGTCA
104
1895

1074988
N/A
N/A
4324
4339
ACCGCGGCGGAGTGGA
94
1896

1075020
N/A
N/A
6193
6208
TTAATTAGCATTAGAG
30
1897

1075052
N/A
N/A
8204
8219
ATATATACTTGATCCA
3
1898

1075084
N/A
N/A
10268
10283
TGACAACAACACTCCT
9
1899

1075116
N/A
N/A
11969
11984
CTTAACATTTAATGGC
15
1900

1075148
N/A
N/A
16000
16015
CGGAAAAAACACCTAG
66
1901

1075180
N/A
N/A
18759
18774
TATTACTACAACCATA
56
1902

1075212
N/A
N/A
22669
22684
CAATAAAGGGTCCTAA
76
1903

1075244
N/A
N/A
26292
26307
ACCCAAAAATTCTGTG
76
1904

1075276
N/A
N/A
28647
28662
GACCAATACAATGGGA
78
1905

1075308
N/A
N/A
31625
31640
AATTAAACGAAACACG
97
1906

1075340
N/A
N/A
32580
32595
CCCGAACACCCAAAAA
103
1907

1075372
N/A
N/A
34997
35012
ATATATAGACTTGAGA
27
1908

1075404
N/A
N/A
37268
37283
ATATAACCTGAACTAA
102
1909

1075436
N/A
N/A
39517
39532
CCTTAAACGATAAAGT
89
1910

1075468
N/A
N/A
41570
41585
CACCAATACTGAGTAT
91
1911

1075500
N/A
N/A
43668
43683
TAAATTAAGCCAACAC
26
1912

1075532
N/A
N/A
45686
45701
ACTTAATAGTTTAACC
121
1913

1075564
N/A
N/A
48028
48043
ATATAACAGGCCACCA
81
1914

1075596
N/A
N/A
49870
49885
ATATAATACATCTCCC
91
1915

1075628
N/A
N/A
52040
52055
CCGCAAAATATTAATT
118
1916

1075660
N/A
N/A
53599
53614
CAAAGTAAAAAACGGT
72
1917

1075692
N/A
N/A
55999
56014
TAAGAACACCATAGCA
11
1918

1075724
N/A
N/A
58769
58784
CTATCTGTCAGTTATC
44
1919

1075756
N/A
N/A
60243
60258
ATTTACCCTGCCACTT
49
1920

1075788
N/A
N/A
62762
62777
TCTTAAGGATTGGCTA
15
1921

1075820
N/A
N/A
65896
65911
TCTGAACGGGCTGTTG
27
1922

1075852
N/A
N/A
68471
68486
GATAAGCCGAATATGG
58
1923

1075884
N/A
N/A
71468
71483
ATTAGTAATGACTAAC
116
1924

1075916
N/A
N/A
75300
75315
CAATTTAGGATGCCTT
6
1925

1075948
N/A
N/A
78306
78321
GGACTAAAGAATACAG
31
1926

1075980
N/A
N/A
81219
81234
CAATATCCTACACCAT
43
1927

1076012
N/A
N/A
82398
82413
AATATAAACAATAGCG
34
1928

1076044
N/A
N/A
85729
85744
ATCAAAAAGGCTATTG
73
1929

1076076
N/A
N/A
88372
88387
TATCAATACTTTAGTC
57
1930

1076108
N/A
N/A
90863
90878
AAACAAAACCGGCTTT
116
1931

1076140
N/A
N/A
92417
92432
ACGAAAAAAGCCAACA
28
1932

1076172
N/A
N/A
94135
94150
TATTAGTAAAGAGTAC
98
1933

1076204
N/A
N/A
96620
96635
GATAATGAATCCTTGT
11
1934

1076236
N/A
N/A
98440
98455
GGAGAACCTTATTTAT
51
1935

1076268
N/A
N/A
101514
101529
GTACAATAATGCTTCC
10
1936

1076300
N/A
N/A
103687
103702
AAAAAATGGCTTCACG
22
1937

1076332
N/A
N/A
107285
107300
TATAAGGAATGGCAAC
107
1938

1076364
N/A
N/A
110105
110120
CCATAAAAGTCCACTA
30
1939

1076396
N/A
N/A
111672
111687
CTATATTTGAGCCATG
2
1940

1076428
N/A
N/A
114406
114421
ATTAAAAAGAAGCACG
53
1941

1076460
N/A
N/A
117914
117929
TAATATAGCCCCTTCA
7
1942

1076492
N/A
N/A
120180
120195
AAAAGATACCCCCAGT
47
1943

1076524
N/A
N/A
122560
122575
AATTTATATCAGGTCA
6
1944

1076556
N/A
N/A
116991
117006
GTATAGGCAGAAGCAA
9
1945

TABLE 27

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074125
160
175
3620
3635
GCGGCTGCGCCTCGGG
94
1946

1074157
333
348
3793
3808
AGCGAGGGCTACGCCC
103
1947

1074189
441
456
3901
3916
GGCTGCGAAGGCGGCT
96
1948

1074221
753
768
7187
7202
GAATGAGCTCGAACAT
6
1949

1074253
1001
1016
55496
55511
TCTGGGACAGCATGGC
11
1950

1074285
1176
1191
N/A
N/A
GCAAAACGAGGGTCAA
17
1951

1074317
1406
1421
102538
102553
GAGAATTTGCTGTGCT
12
1952

1074349
1580
1595
120485
120500
CTGTACTCTCATCTCG
30
1953

1074381
1715
1730
122740
122755
AGTCTGGGAAACGGTT
16
1954

1074413
2097
2112
123122
123137
ACTGTGAAAGAGGTCA
4
1955

1074445
2471
2486
123496
123511
TGATAGCACTAGGAGG
6
1956

1074477
2686
2701
123711
123726
GTTCCGACAAAACCAA
10
1957

1074509
2850
2865
123875
123890
TGTTATGTTTGGGTGT
5
1958

1074541
3053
3068
124078
124093
CACTATCCACAGTAAT
23
1959

1074573
3195
3210
124220
124235
ATTATGAACCTACTCA
14
1960

1074605
3464
3479
124489
124504
TCAACTACCAATATAC
20
1961

1074637
3792
3807
124817
124832
AATCTATCTTCCCAAG
36
1962

1074669
4109
4124
125134
125149
ATCCCAACAACATGCT
13
1963

1074701
4322
4337
125347
125362
GTGTAAGACAAGTCTT
17
1964

1074733
4469
4484
125494
125509
GCCAGGTATCACAGTA
47
1965

1074765
4634
4649
125659
125674
CAATGCTACCCAATAC
34
1966

1074797
4783
4798
125808
125823
ACTCCAAATCAATGTG
31
1967

1074829
5095
5110
126120
126135
GGATAAAATCCACCTG
92
1968

1074861
5279
5294
126304
126319
TGCTCTTACATCTAAA
23
1969

1074893
N/A
N/A
5459
5474
GCTGAAGTTTAGCCTG
78
1970

1074925
N/A
N/A
5586
5601
GCCTGCAAATAGGAGA
94
1971

1074957
N/A
N/A
5668
5683
AACCCGGGTTTTTGTC
102
1972

1074989
N/A
N/A
4423
4438
GAGGGAAAGCACGCCC
105
1973

1075021
N/A
N/A
6245
6260
TTACAACCTAGATTTG
68
1974

1075053
N/A
N/A
8205
8220
AATATATACTTGATCC
4
1975

1075085
N/A
N/A
10318
10333
TGCGGAAACAAGTGTA
11
1976

1075117
N/A
N/A
12081
12096
CCTCAATAGCAAGACA
48
1977

1075149
N/A
N/A
16001
16016
GCGGAAAAAACACCTA
50
1978

1075181
N/A
N/A
18762
18777
TTATATTACTACAACC
15
1979

1075213
N/A
N/A
22670
22685
ACAATAAAGGGTCCTA
33
1980

1075245
N/A
N/A
26692
26707
CCTAATATGCTATTGT
34
1981

1075277
N/A
N/A
28762
28777
TTATAAGAACTGTGGC
13
1982

1075309
N/A
N/A
31626
31641
TAATTAAACGAAACAC
110
1983

1075341
N/A
N/A
32592
32607
GCTGAACAATCTCCCG
31
1984

1075373
N/A
N/A
34998
35013
TATATATAGACTTGAG
13
1985

1075405
N/A
N/A
37270
37285
CTATATAACCTGAACT
84
1986

1075437
N/A
N/A
39572
39587
TATTAGTACGAGCTAC
85
1987

1075469
N/A
N/A
41723
41738
TGATATAATGACCAAG
25
1988

1075501
N/A
N/A
43670
43685
CATAAATTAAGCCAAC
67
1989

1075533
N/A
N/A
45730
45745
GATTACTCAGCTATGT
65
1990

1075565
N/A
N/A
48029
48044
TATATAACAGGCCACC
52
1991

1075597
N/A
N/A
49954
49969
ATTAACATTTGCCCGC
47
1992

1075629
N/A
N/A
52041
52056
GCCGCAAAATATTAAT
100
1993

1075661
N/A
N/A
53794
53809
GAATAGGATACAAGCA
74
1994

1075693
N/A
N/A
56014
56029
CATTAAAAGTTGGGTT
36
1995

1075725
N/A
N/A
58772
58787
ATCCTATCTGTCAGTT
18
1996

1075757
N/A
N/A
60324
60339
CTTAATACATTATTCC
2
1997

1075789
N/A
N/A
62993
63008
AATTACAAGCTAATGC
79
1998

1075821
N/A
N/A
66155
66170
CTTAACTTCCCACTCG
22
1999

1075853
N/A
N/A
68653
68668
GAGCGATAAGCTGTAT
72
2000

1075885
N/A
N/A
71469
71484
CATTAGTAATGACTAA
112
2001

1075917
N/A
N/A
75472
75487
AGCAAAAAGTGATATG
55
2002

1075949
N/A
N/A
78635
78650
TAGGAACACCAAGGTT
48
2003

1075981
N/A
N/A
81222
81237
AAGCAATATCCTACAC
40
2004

1076013
N/A
N/A
82644
82659
GTTTAATACCTCTGAC
76
2005

1076045
N/A
N/A
85776
85791
GTGCAATAAATAGTTC
11
2006

1076077
N/A
N/A
88420
88435
GGATTAAAGTTTTCAC
5
2007

1076109
N/A
N/A
91026
91041
CTTAAATGACCAATTC
23
2008

1076141
N/A
N/A
92418
92433
TACGAAAAAAGCCAAC
29
2009

1076173
N/A
N/A
94244
94259
CAATATATCCTGAGAT
91
2010

1076205
N/A
N/A
96783
96798
TAGTATAATTCATGAC
51
2011

1076237
N/A
N/A
98456
98471
ACTAAAGGACAAAGGT
109
2012

1076269
N/A
N/A
101560
101575
GACGAAAAATATTCTT
28
2013

1076301
N/A
N/A
104195
104210
GTATAAGACCTTGGGA
34
2014

1076333
N/A
N/A
107286
107301
CTATAAGGAATGGCAA
97
2015

1076365
N/A
N/A
110141
110156
TAAGAAGGGCCAATGG
15
2016

1076397
N/A
N/A
111675
111690
AACCTATATTTGAGCC
4
2017

1076429
N/A
N/A
114456
114471
CATTACAAGCATAGGC
26
2018

1076461
N/A
N/A
117917
117932
GATTAATATAGCCCCT
3
2019

1076493
N/A
N/A
120197
120212
TGACAATAAGGGACAA
34
2020

1076525
N/A
N/A
122561
122576
GAATTTATATCAGGTC
3
2021

1076557
N/A
N/A
55411
55426
AACAAATACCAGGTTC
111
2022

TABLE 28

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074126
163
178
3623
3638
CTGGCGGCTGCGCCTC
111
2023

1074158
334
349
3794
3809
GAGCGAGGGCTACGCC
72
2024

1074190
463
478
3923
3938
CGGCGGGCCCTGCCCC
114
2025

1074222
755
770
7189
7204
AGGAATGAGCTCGAAC
5
2026

1074254
1002
1017
55497
55512
ATCTGGGACAGCATGG
13
2027

1074286
1193
1208
98895
98910
TGATTCTCTGGTTCAT
32
2028

1074318
1407
1422
102539
102554
GGAGAATTTGCTGTGC
4
2029

1074350
1591
1606
120496
120511
TAGTCCACTGTCTGTA
14
2030

1074382
1719
1734
122744
122759
AGGTAGTCTGGGAAAC
8
2031

1074414
2098
2113
123123
123138
AACTGTGAAAGAGGTC
6
2032

1074446
2472
2487
123497
123512
ATGATAGCACTAGGAG
3
2033

1074478
2691
2706
123716
123731
CCTAGGTTCCGACAAA
69
2034

1074510
2878
2893
123903
123918
ATACATTCCACTACCA
10
2035

1074542
3056
3071
124081
124096
AGGCACTATCCACAGT
21
2036

1074574
3196
3211
124221
124236
CATTATGAACCTACTC
17
2037

1074606
3500
3515
124525
124540
GGTATAATCATGATTA
4
2038

1074638
3816
3831
124841
124856
AGATTTTGTAATTGGG
2
2039

1074670
4141
4156
125166
125181
AAGTAGCTTTGATCTT
49
2040

1074702
4323
4338
125348
125363
GGTGTAAGACAAGTCT
16
2041

1074734
4470
4485
125495
125510
TGCCAGGTATCACAGT
51
2042

1074766
4638
4653
125663
125678
ATCCCAATGCTACCCA
8
2043

1074798
4800
4815
125825
125840
GCTTTGGAAGATCTGA
4
2044

1074830
5097
5112
126122
126137
GAGGATAAAATCCACC
89
2045

1074862
5287
5302
126312
126327
TATGAGCATGCTCTTA
56
2046

1074894
N/A
N/A
5460
5475
TGCTGAAGTTTAGCCT
79
2047

1074926
N/A
N/A
5592
5607
CAACAGGCCTGCAAAT
111
2048

1074958
N/A
N/A
5669
5684
TAACCCGGGTTTTTGT
107
2049

1074990
N/A
N/A
4687
4702
GCCGCAAAGGAAAGGG
108
2050

1075022
N/A
N/A
6247
6262
ATTTACAACCTAGATT
91
2051

1075054
N/A
N/A
8206
8221
CAATATATACTTGATC
48
2052

1075086
N/A
N/A
10392
10407
AGTTATAGACTTTGTA
25
2053

1075118
N/A
N/A
12281
12296
CTATTTACTCTGTCAC
4
2054

1075150
N/A
N/A
16002
16017
AGCGGAAAAAACACCT
35
2055

1075182
N/A
N/A
18766
18781
GATATTATATTACTAC
61
2056

1075214
N/A
N/A
22671
22686
AACAATAAAGGGTCCT
45
2057

1075246
N/A
N/A
26760
26775
GATAACTAGTAACCGT
6
2058

1075278
N/A
N/A
28866
28881
TATACTAACATTCACG
48
2059

1075310
N/A
N/A
31627
31642
GTAATTAAACGAAACA
84
2060

1075342
N/A
N/A
32636
32651
ACTAAAAGGGAGTAGG
87
2061

1075374
N/A
N/A
35122
35137
GAAAATACTCCTCCTA
27
2062

1075406
N/A
N/A
37271
37286
ACTATATAACCTGAAC
99
2063

1075438
N/A
N/A
39657
39672
CATATTAGAGTTGAGG
22
2064

1075470
N/A
N/A
41860
41875
GCCAATAAGTTATCAA
50
2065

1075502
N/A
N/A
44236
44251
CTTAACATGATTCTAG
61
2066

1075534
N/A
N/A
45787
45802
ACCCAAGGACAGCACA
53
2067

1075566
N/A
N/A
48030
48045
ATATATAACAGGCCAC
50
2068

1075598
N/A
N/A
49955
49970
AATTAACATTTGCCCG
62
2069

1075630
N/A
N/A
52052
52067
TATAACCAAATGCCGC
60
2070

1075662
N/A
N/A
53888
53903
AAGGGATACAAGTGTT
78
2071

1075694
N/A
N/A
56015
56030
ACATTAAAAGTTGGGT
11
2072

1075726
N/A
N/A
58776
58791
AGTTATCCTATCTGTC
14
2073

1075758
N/A
N/A
60403
60418
GTAATTTAATAGACTA
73
2074

1075790
N/A
N/A
63026
63041
TCAGAAGAACTCCCAT
14
2075

1075822
N/A
N/A
66205
66220
CTTAGTAATTGCCCAT
35
2076

1075854
N/A
N/A
68837
68852
CTTATAATAGAGCTAA
52
2077

1075886
N/A
N/A
71526
71541
CATAACACTGAAGGTG
60
2078

1075918
N/A
N/A
75510
75525
CTTAAACTAACTGTTG
82
2079

1075950
N/A
N/A
78649
78664
TGACAATACCTTCCTA
30
2080

1075982
N/A
N/A
81227
81242
CATGAAAGCAATATCC
23
2081

1076014
N/A
N/A
82658
82673
AATCAACCTATGAGGT
98
2082

1076046
N/A
N/A
85784
85799
CTTAAATGGTGCAATA
28
2083

1076078
N/A
N/A
89187
89202
CTTTAGCCTCTATACC
23
2084

1076110
N/A
N/A
91091
91106
CTTTACCTAAATGTTG
53
2085

1076142
N/A
N/A
92419
92434
ATACGAAAAAAGCCAA
38
2086

1076174
N/A
N/A
94299
94314
GATATATGGTAGCATA
3
2087

1076206
N/A
N/A
96835
96850
CAATAAACTTACCCTT
55
2088

1076238
N/A
N/A
98513
98528
GATGAATAGCTAAGAA
30
2089

1076270
N/A
N/A
101571
101586
TAACAATAGTAGACGA
28
2090

1076302
N/A
N/A
104337
104352
AATAAGCCTCACCTTT
74
2091

1076334
N/A
N/A
107288
107303
ACCTATAAGGAATGGC
108
2092

1076366
N/A
N/A
110167
110182
ATTTACATGAGAGGAG
4
2093

1076398
N/A
N/A
111707
111722
CTTGAAGGGCTATGGA
62
2094

1076430
N/A
N/A
114752
114767
CGTTATAAGATGTGCT
4
2095

1076462
N/A
N/A
117971
117986
TCAGAAGGATATGCAG
6
2096

1076494
N/A
N/A
120254
120269
CTAATTGAAGCTGGCA
3
2097

1076526
N/A
N/A
102684
102699
GTAGAAAGATGGCTCA
3
2098

1076558
N/A
N/A
82852
82867
GCCAAATATTTAACTC
30
2099

TABLE 29

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074127
171
186
3631
3646
CCACTGGTCTGGCGGC
57
2100

1074159
335
350
3795
3810
CGAGCGAGGGCTACGC
77
2101

1074191
464
479
3924
3939
ACGGCGGGCCCTGCCC
80
2102

1074223
786
801
7220
7235
GAAACAGCTCCCAACT
48
2103

1074255
1004
1019
55499
55514
TCATCTGGGACAGCAT
16
2104

1074287
1195
1210
98897
98912
ACTGATTCTCTGGTTC
11
2105

1074319
1425
1440
N/A
N/A
GCTAACTCCTGACATT
47
2106

1074351
1596
1611
120501
120516
ATGCTTAGTCCACTGT
7
2107

1074383
1722
1737
122747
122762
TCAAGGTAGTCTGGGA
40
2108

1074415
2101
2116
123126
123141
GCCAACTGTGAAAGAG
10
2109

1074447
2473
2488
123498
123513
AATGATAGCACTAGGA
4
2110

1074479
2697
2712
123722
123737
CATTTGCCTAGGTTCC
2
2111

1074511
2879
2894
123904
123919
GATACATTCCACTACC
9
2112

1074543
3059
3074
124084
124099
CCTAGGCACTATCCAC
57
2113

1074575
3197
3212
124222
124237
ACATTATGAACCTACT
14
2114

1074607
3502
3517
124527
124542
AAGGTATAATCATGAT
4
2115

1074639
3817
3832
124842
124857
TAGATTTTGTAATTGG
3
2116

1074671
4142
4157
125167
125182
CAAGTAGCTTTGATCT
8
2117

1074703
4324
4339
125349
125364
CGGTGTAAGACAAGTC
16
2118

1074735
4483
4498
125508
125523
GATCAAAGCACTGTGC
117
2119

1074767
4640
4655
125665
125680
TTATCCCAATGCTACC
12
2120

1074799
4801
4816
125826
125841
TGCTTTGGAAGATCTG
8
2121

1074831
5098
5113
126123
126138
CGAGGATAAAATCCAC
35
2122

1074863
5288
5303
126313
126328
ATATGAGCATGCTCTT
41
2123

1074895
N/A
N/A
5465
5480
TCCTATGCTGAAGTTT
60
2124

1074927
N/A
N/A
5594
5609
TACAACAGGCCTGCAA
74
2125

1074959
N/A
N/A
5670
5685
TTAACCCGGGTTTTTG
128
2126

1074991
N/A
N/A
4727
4742
AATTATTTGACTCCCC
60
2127

1075023
N/A
N/A
6249
6264
GTATTTACAACCTAGA
18
2128

1075055
N/A
N/A
8271
8286
CTATTAAGTGAGCTTT
4
2129

1075087
N/A
N/A
10400
10415
TCTCAATAAGTTATAG
39
2130

1075119
N/A
N/A
12305
12320
AGGGAATATGTTAATC
8
2131

1075151
N/A
N/A
16014
16029
TTTAAAAGTACCAGCG
60
2132

1075183
N/A
N/A
18905
18920
ATTACTAAGACAGTGG
15
2133

1075215
N/A
N/A
22672
22687
AAACAATAAAGGGTCC
44
2134

1075247
N/A
N/A
26764
26779
CTAAGATAACTAGTAA
101
2135

1075279
N/A
N/A
28867
28882
CTATACTAACATTCAC
52
2136

1075311
N/A
N/A
31628
31643
AGTAATTAAACGAAAC
100
2137

1075343
N/A
N/A
32637
32652
AACTAAAAGGGAGTAG
89
2138

1075375
N/A
N/A
35237
35252
CTAAATATCAACTCCC
35
2139

1075407
N/A
N/A
37273
37288
GAACTATATAACCTGA
32
2140

1075439
N/A
N/A
39815
39830
AATTAGAGATATGGAC
77
2141

1075471
N/A
N/A
41861
41876
AGCCAATAAGTTATCA
55
2142

1075503
N/A
N/A
44248
44263
GCTGAAAAAGGGCTTA
66
2143

1075535
N/A
N/A
45791
45806
AATTACCCAAGGACAG
53
2144

1075567
N/A
N/A
48031
48046
GATATATAACAGGCCA
65
2145

1075599
N/A
N/A
49979
49994
ACCCTATAGCTTTAGG
90
2146

1075631
N/A
N/A
52055
52070
CCCTATAACCAAATGC
104
2147

1075663
N/A
N/A
53926
53941
CTAAATAGGTGGTTAT
80
2148

1075695
N/A
N/A
56025
56040
GAATAACACCACATTA
30
2149

1075727
N/A
N/A
58798
58813
TTATCGGAGGCTTCGC
31
2150

1075759
N/A
N/A
60742
60757
CCTTATAAATTATGAC
44
2151

1075791
N/A
N/A
63059
63074
CTTTATCAGCCATCAC
10
2152

1075823
N/A
N/A
66222
66237
TATTAGAGGTTCCAGG
30
2153

1075855
N/A
N/A
68937
68952
GATTTTTAGGCAGACG
7
2154

1075887
N/A
N/A
71602
71617
TATTACTTGATTGACA
10
2155

1075919
N/A
N/A
75511
75526
TCTTAAACTAACTGTT
78
2156

1075951
N/A
N/A
78699
78714
CACGGAAGAGCTTGCA
34
2157

1075983
N/A
N/A
81249
81264
ATCGAAAAGCAAACTC
5
2158

1076015
N/A
N/A
82981
82996
ATTTAGTTGGTTGTTA
8
2159

1076047
N/A
N/A
85785
85800
ACTTAAATGGTGCAAT
34
2160

1076079
N/A
N/A
89467
89482
AAGCAATATATGGCCT
37
2161

1076111
N/A
N/A
91203
91218
AATTAGTTAGGATATC
67
2162

1076143
N/A
N/A
92420
92435
GATACGAAAAAAGCCA
8
2163

1076175
N/A
N/A
94392
94407
CAATAGGTAACAGGTA
15
2164

1076207
N/A
N/A
96838
96853
AGTCAATAAACTTACC
58
2165

1076239
N/A
N/A
98583
98598
GTTTAAAAAAAACGGG
75
2166

1076271
N/A
N/A
101685
101700
CGGCAACAACAAAATG
18
2167

1076303
N/A
N/A
104339
104354
CTAATAAGCCTCACCT
34
2168

1076335
N/A
N/A
107289
107304
CACCTATAAGGAATGG
80
2169

1076367
N/A
N/A
110169
110184
CTATTTACATGAGAGG
3
2170

1076399
N/A
N/A
111771
111786
GATAACTTAGAGATGT
4
2171

1076431
N/A
N/A
114853
114868
CACCAATAGAACATAT
31
2172

1076463
N/A
N/A
118082
118097
GATTAGTAACACTGAT
38
2173

1076495
N/A
N/A
120353
120368
GATTAGTGAAAATTCC
30
2174

1076527
N/A
N/A
117218
117233
GCACAACCTTACATTT
6
2175

1076559
N/A
N/A
111532
111547
AACAAATATAGTTAGC
74
2176

TABLE 30

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074128
173
188
3633
3648
CTCCACTGGTCTGGCG
76
2177

1074160
336
351
3796
3811
GCGAGCGAGGGCTACG
86
2178

1074192
465
480
3925
3940
GACGGCGGGCCCTGCC
108
2179

1074224
821
836
7255
7270
CAGAGACTACTCCAGT
16
2180

1074256
1033
1048
55528
55543
CACTGGTGGACTGGTG
64
2181

1074288
1196
1211
98898
98913
GACTGATTCTCTGGTT
48
2182

1074320
1426
1441
N/A
N/A
GGCTAACTCCTGACAT
80
2183

1074352
1597
1612
120502
120517
CATGCTTAGTCCACTG
69
2184

1074384
1723
1738
122748
122763
TTCAAGGTAGTCTGGG
35
2185

1074416
2108
2123
123133
123148
CTTTAGAGCCAACTGT
9
2186

1074448
2474
2489
123499
123514
TAATGATAGCACTAGG
3
2187

1074480
2698
2713
123723
123738
TCATTTGCCTAGGTTC
3
2188

1074512
2880
2895
123905
123920
GGATACATTCCACTAC
64
2189

1074544
3063
3078
124088
124103
CTCCCCTAGGCACTAT
34
2190

1074576
3201
3216
124226
124241
ATGCACATTATGAACC
7
2191

1074608
3529
3544
124554
124569
GTTACATCATCTCTTC
5
2192

1074640
3828
3843
124853
124868
GCCAAAATACTTAGAT
26
2193

1074672
4143
4158
125168
125183
CCAAGTAGCTTTGATC
6
2194

1074704
4326
4341
125351
125366
CACGGTGTAAGACAAG
16
2195

1074736
4504
4519
125529
125544
TCAGTACAGAGGGCAT
4
2196

1074768
4641
4656
125666
125681
CTTATCCCAATGCTAC
11
2197

1074800
4808
4823
125833
125848
CAAATAGTGCTTTGGA
6
2198

1074832
5099
5114
126124
126139
GCGAGGATAAAATCCA
17
2199

1074864
5289
5304
126314
126329
CATATGAGCATGCTCT
47
2200

1074896
N/A
N/A
5472
5487
GCAAAGTTCCTATGCT
99
2201

1074928
N/A
N/A
5595
5610
ATACAACAGGCCTGCA
83
2202

1074960
N/A
N/A
5671
5686
CTTAACCCGGGTTTTT
81
2203

1074992
N/A
N/A
4728
4743
CAATTATTTGACTCCC
63
2204

1075024
N/A
N/A
6368
6383
ACTGAACAAGTATCTT
32
2205

1075056
N/A
N/A
8297
8312
CTTTATTATCTCAACC
21
2206

1075088
N/A
N/A
10433
10448
ATTTATAGTCAGGTTC
2
2207

1075120
N/A
N/A
12519
12534
AATTAGCCTACCACCT
42
2208

1075152
N/A
N/A
16101
16116
TATAATGGGAGGATTA
99
2209

1075184
N/A
N/A
18998
19013
CAAGAACACTGGTATT
67
2210

1075216
N/A
N/A
23247
23262
TATTTTACACGAACTA
55
2211

1075248
N/A
N/A
26930
26945
GTACAAAAAGCGGTCG
64
2212

1075280
N/A
N/A
28870
28885
GAACTATACTAACATT
57
2213

1075312
N/A
N/A
31662
31677
TTAATTGAACTCAGGG
37
2214

1075344
N/A
N/A
32638
32653
TAACTAAAAGGGAGTA
91
2215

1075376
N/A
N/A
35238
35253
CCTAAATATCAACTCC
72
2216

1075408
N/A
N/A
37387
37402
CTAAAATGGCATAAGG
23
2217

1075440
N/A
N/A
39843
39858
AAATTATTAGTTGTCG
28
2218

1075472
N/A
N/A
41890
41905
GATTATAGTTAAACAG
92
2219

1075504
N/A
N/A
44291
44306
CTTAAATGAGAGAACC
71
2220

1075536
N/A
N/A
45793
45808
TTAATTACCCAAGGAC
55
2221

1075568
N/A
N/A
48108
48123
TTATTTAAGTTGGGAG
23
2222

1075600
N/A
N/A
49991
50006
CACTATAATCTGACCC
68
2223

1075632
N/A
N/A
52056
52071
TCCCTATAACCAAATG
95
2224

1075664
N/A
N/A
53927
53942
GCTAAATAGGTGGTTA
87
2225

1075696
N/A
N/A
56066
56081
TTACAAAAGTTACTGC
28
2226

1075728
N/A
N/A
58800
58815
CTTTATCGGAGGCTTC
15
2227

1075760
N/A
N/A
61106
61121
GAGAAAAACTACGGAT
39
2228

1075792
N/A
N/A
63072
63087
GATTAGAAAGTGCCTT
6
2229

1075824
N/A
N/A
66223
66238
GTATTAGAGGTTCCAG
3
2230

1075856
N/A
N/A
68965
68980
CCTAATCAAGTTCTGC
40
2231

1075888
N/A
N/A
71648
71663
ACTTAAACTTGAGGGA
22
2232

1075920
N/A
N/A
75749
75764
AAAGAAAGCTGCGCAC
108
2233

1075952
N/A
N/A
78848
78863
CTATATACCTGCTTCT
41
2234

1075984
N/A
N/A
81250
81265
TATCGAAAAGCAAACT
44
2235

1076016
N/A
N/A
83002
83017
TAATAGGATGGATTCT
8
2236

1076048
N/A
N/A
85859
85874
GATTAAAGGCTGGAAG
32
2237

1076080
N/A
N/A
89574
89589
CATTAGCAGTTCACTA
55
2238

1076112
N/A
N/A
91226
91241
ATTCAAAACCACGGAA
98
2239

1076144
N/A
N/A
92435
92450
TTTTATAGGGCAATGG
7
2240

1076176
N/A
N/A
94395
94410
CTCCAATAGGTAACAG
43
2241

1076208
N/A
N/A
97037
97052
GAGGAATATTACAGAC
15
2242

1076240
N/A
N/A
98611
98626
ATTAAAAGCAAGGTGC
56
2243

1076272
N/A
N/A
101702
101717
TTAGAACAACTACTAC
53
2244

1076304
N/A
N/A
104340
104355
ACTAATAAGCCTCACC
30
2245

1076336
N/A
N/A
107295
107310
CATTACCACCTATAAG
31
2246

1076368
N/A
N/A
110251
110266
CATTTTATGTAAGGCC
15
2247

1076400
N/A
N/A
111869
111884
GTTAAAAGCCGTGAAA
10
2248

1076432
N/A
N/A
114880
114895
CATTAGTATTCACTGT
18
2249

1076464
N/A
N/A
118102
118117
CATATACAATTCTGCC
2
2250

1076496
N/A
N/A
120437
120452
GTTAAAGACCAACACA
81
2251

1076528
N/A
N/A
16102
16117
TTATAATGGGAGGATT
86
2252

1076560
N/A
N/A
113259
113274
TCCAAATATGGCATAC
10
2253

TABLE 31

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074129
178
193
3638
3653
CCCGGCTCCACTGGTC
77
2254

1074161
337
352
3797
3812
GGCGAGCGAGGGCTAC
98
2255

1074193
471
486
3931
3946
GGTCCGGACGGCGGGC
74
2256

1074225
822
837
7256
7271
CCAGAGACTACTCCAG
11
2257

1074257
1034
1049
55529
55544
GCACTGGTGGACTGGT
29
2258

1074289
1197
1212
98899
98914
TGACTGATTCTCTGGT
13
2259

1074321
1427
1442
N/A
N/A
GGGCTAACTCCTGACA
73
2260

1074353
1612
1627
120517
120532
GACACTGTAGCTGCTC
17
2261

1074385
1724
1739
122749
122764
CTTCAAGGTAGTCTGG
17
2262

1074417
2109
2124
123134
123149
TCTTTAGAGCCAACTG
2
2263

1074449
2475
2490
123500
123515
CTAATGATAGCACTAG
36
2264

1074481
2705
2720
123730
123745
AATATGGTCATTTGCC
14
2265

1074513
2881
2896
123906
123921
AGGATACATTCCACTA
47
2266

1074545
3064
3079
124089
124104
ACTCCCCTAGGCACTA
18
2267

1074577
3211
3226
124236
124251
TATTTCTGTCATGCAC
3
2268

1074609
3532
3547
124557
124572
CTAGTTACATCATCTC
8
2269

1074641
3829
3844
124854
124869
GGCCAAAATACTTAGA
107
2270

1074673
4154
4169
125179
125194
AGGCACTCCTTCCAAG
43
2271

1074705
4327
4342
125352
125367
GCACGGTGTAAGACAA
20
2272

1074737
4510
4525
125535
125550
TTCAGGTCAGTACAGA
7
2273

1074769
4642
4657
125667
125682
TCTTATCCCAATGCTA
12
2274

1074801
4809
4824
125834
125849
ACAAATAGTGCTTTGG
8
2275

1074833
5100
5115
126125
126140
TGCGAGGATAAAATCC
17
2276

1074865
5290
5305
126315
126330
ACATATGAGCATGCTC
46
2277

1074897
N/A
N/A
5473
5488
GGCAAAGTTCCTATGC
76
2278

1074929
N/A
N/A
5596
5611
TATACAACAGGCCTGC
79
2279

1074961
N/A
N/A
5676
5691
TCCTCCTTAACCCGGG
93
2280

1074993
N/A
N/A
4755
4770
TCTAATCAACACTGGA
65
2281

1075025
N/A
N/A
6468
6483
ACTTAAGAACTCACAC
58
2282

1075057
N/A
N/A
8351
8366
CCTTAGGAGTAGACTG
14
2283

1075089
N/A
N/A
10434
10449
CATTTATAGTCAGGTT
2
2284

1075121
N/A
N/A
12521
12536
AAAATTAGCCTACCAC
40
2285

1075153
N/A
N/A
16103
16118
ATTATAATGGGAGGAT
38
2286

1075185
N/A
N/A
19001
19016
GCCCAAGAACACTGGT
78
2287

1075217
N/A
N/A
23248
23263
TTATTTTACACGAACT
71
2288

1075249
N/A
N/A
27029
27044
ATTACGATTAGATCAG
5
2289

1075281
N/A
N/A
29105
29120
CAGCAAAAGTACCATG
36
2290

1075313
N/A
N/A
31663
31678
CTTAATTGAACTCAGG
28
2291

1075345
N/A
N/A
32639
32654
GTAACTAAAAGGGAGT
29
2292

1075377
N/A
N/A
35267
35282
CTAGAAAGGTTGGCCC
108
2293

1075409
N/A
N/A
37405
37420
CTTTAAATAGCAGAGG
22
2294

1075441
N/A
N/A
40002
40017
GAATTAAAGCAGTGCC
24
2295

1075473
N/A
N/A
41930
41945
AGTTATAACTGTACTA
89
2296

1075505
N/A
N/A
44322
44337
GCTAAATTACAGAGGT
18
2297

1075537
N/A
N/A
45795
45810
CTTTAATTACCCAAGG
82
2298

1075569
N/A
N/A
48125
48140
GTAGAAAGGCATTAGA
45
2299

1075601
N/A
N/A
49992
50007
ACACTATAATCTGACC
50
2300

1075633
N/A
N/A
52118
52133
CTATATTGGCTCCTAG
82
2301

1075665
N/A
N/A
53953
53968
ATTTAGTTGTGCACAG
87
2302

1075697
N/A
N/A
56110
56125
AATAATCCATGCTTGC
16
2303

1075729
N/A
N/A
58853
58868
TATTTAAAAATAGCGC
88
2304

1075761
N/A
N/A
61107
61122
GGAGAAAAACTACGGA
13
2305

1075793
N/A
N/A
63128
63143
CATTAGTTGCCCTGAC
31
2306

1075825
N/A
N/A
66353
66368
CCCCTAAAGAAGATTT
44
2307

1075857
N/A
N/A
68976
68991
CTTAAACAATCCCTAA
69
2308

1075889
N/A
N/A
72204
72219
ATTAAAAGTAGGCCCT
71
2309

1075921
N/A
N/A
75750
75765
GAAAGAAAGCTGCGCA
93
2310

1075953
N/A
N/A
78851
78866
AACCTATATACCTGCT
36
2311

1075985
N/A
N/A
81251
81266
ATATCGAAAAGCAAAC
82
2312

1076017
N/A
N/A
83003
83018
CTAATAGGATGGATTC
5
2313

1076049
N/A
N/A
85860
85875
AGATTAAAGGCTGGAA
4
2314

1076081
N/A
N/A
89730
89745
GATAATTCACCCTTGT
15
2315

1076113
N/A
N/A
91298
91313
TGACAATAGCCAATGC
16
2316

1076145
N/A
N/A
92457
92472
CCTTATAGGTTATAGT
41
2317

1076177
N/A
N/A
94422
94437
CTTTATTTCCCACCCG
37
2318

1076209
N/A
N/A
97241
97256
CATTAGCACACCTTTT
12
2319

1076241
N/A
N/A
98642
98657
CAATAAGGAACAGTTT
42
2320

1076273
N/A
N/A
101849
101864
AAACAAAATGGCGAAT
84
2321

1076305
N/A
N/A
104341
104356
TACTAATAAGCCTCAC
37
2322

1076337
N/A
N/A
107326
107341
ATTAAACCAGGGACTG
25
2323

1076369
N/A
N/A
110591
110606
TATTCGGTATTTTCTA
2
2324

1076401
N/A
N/A
112117
112132
TCTAAAGACTCTCATT
31
2325

1076433
N/A
N/A
114928
114943
ATTAACTTTCGCTAAA
69
2326

1076465
N/A
N/A
118550
118565
GCTTAAGGAATATACA
5
2327

1076497
N/A
N/A
120579
120594
AAAGAATACCAACCTG
72
2328

1076529
N/A
N/A
40252
40267
CTATAATGAGGATTAC
108
2329

1076561
N/A
N/A
11318
11333
GTATACCAAGCTACTC
22
2330

TABLE 32

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074130
214
229
3674
3689
ATCCCCCGCCCCGGCG
119
2331

1074162
338
353
3798
3813
AGGCGAGCGAGGGCTA
101
2332

1074194
474
489
3934
3949
CCGGGTCCGGACGGCG
57
2333

1074226
859
874
7293
7308
CTGTCGAAGATGCTGA
10
2334

1074258
1044
1059
55539
55554
ATATTCTGCTGCACTG
36
2335

1074290
1198
1213
98900
98915
CTGACTGATTCTCTGG
5
2336

1074322
1428
1443
N/A
N/A
AGGGCTAACTCCTGAC
94
2337

1074354
1613
1628
120518
120533
GGACACTGTAGCTGCT
24
2338

1074386
1733
1748
122758
122773
CAGGAATGGCTTCAAG
39
2339

1074418
2110
2125
123135
123150
TTCTTTAGAGCCAACT
4
2340

1074450
2476
2491
123501
123516
ACTAATGATAGCACTA
5
2341

1074482
2706
2721
123731
123746
TAATATGGTCATTTGC
12
2342

1074514
2882
2897
123907
123922
AAGGATACATTCCACT
25
2343

1074546
3065
3080
124090
124105
CACTCCCCTAGGCACT
33
2344

1074578
3214
3229
124239
124254
GCTTATTTCTGTCATG
8
2345

1074610
3533
3548
124558
124573
TCTAGTTACATCATCT
5
2346

1074642
3830
3845
124855
124870
GGGCCAAAATACTTAG
78
2347

1074674
4157
4172
125182
125197
TATAGGCACTCCTTCC
22
2348

1074706
4336
4351
125361
125376
TTAATGGCAGCACGGT
48
2349

1074738
4511
4526
125536
125551
CTTCAGGTCAGTACAG
12
2350

1074770
4643
4658
125668
125683
ATCTTATCCCAATGCT
15
2351

1074802
4836
4851
125861
125876
GGCACTACATTTAGAA
37
2352

1074834
5101
5116
126126
126141
TTGCGAGGATAAAATC
14
2353

1074866
5291
5306
126316
126331
AACATATGAGCATGCT
30
2354

1074898
N/A
N/A
5481
5496
AACTTTTGGGCAAAGT
101
2355

1074930
N/A
N/A
5597
5612
CTATACAACAGGCCTG
84
2356

1074962
N/A
N/A
5709
5724
AGGCAAGCAGCTAAAT
78
2357

1074994
N/A
N/A
4784
4799
AAACTAAATGGACCGG
94
2358

1075026
N/A
N/A
6556
6571
CTTAAAAGCCATCTAC
55
2359

1075058
N/A
N/A
8466
8481
ATTACAAAGTAGCAAC
66
2360

1075090
N/A
N/A
10590
10605
GCTTATAATCTTTCAG
9
2361

1075122
N/A
N/A
12522
12537
GAAAATTAGCCTACCA
16
2362

1075154
N/A
N/A
16104
16119
CATTATAATGGGAGGA
13
2363

1075186
N/A
N/A
19097
19112
AAATCGATTATTCAGA
73
2364

1075218
N/A
N/A
23347
23362
CTTAACACTGGTAAGA
97
2365

1075250
N/A
N/A
27030
27045
AATTACGATTAGATCA
55
2366

1075282
N/A
N/A
29645
29660
GAAAAATGAGCCCGGT
103
2367

1075314
N/A
N/A
31708
31723
AATAAAGTCTAATCCA
54
2368

1075346
N/A
N/A
32705
32720
GTAAGTAAAACTGCTG
16
2369

1075378
N/A
N/A
35289
35304
AAAACTAATCATCGAT
83
2370

1075410
N/A
N/A
37572
37587
GATTAACAGCCCTTTA
36
2371

1075442
N/A
N/A
40105
40120
TATTAGTTCTACGATT
71
2372

1075474
N/A
N/A
41975
41990
TTTAATAGGCTCTATC
68
2373

1075506
N/A
N/A
44427
44442
CATAAAGGTGACAGCC
66
2374

1075538
N/A
N/A
46165
46180
GAATTGGAACACCTCA
66
2375

1075570
N/A
N/A
48306
48321
GATACTAAGCACAGAG
16
2376

1075602
N/A
N/A
50018
50033
TATTATAAGTCTACAA
114
2377

1075634
N/A
N/A
52121
52136
AGACTATATTGGCTCC
65
2378

1075666
N/A
N/A
53955
53970
AAATTTAGTTGTGCAC
106
2379

1075698
N/A
N/A
56114
56129
GTTTAATAATCCATGC
10
2380

1075730
N/A
N/A
58854
58869
GTATTTAAAAATAGCG
92
2381

1075762
N/A
N/A
61391
61406
GATAAATGGGTTGATT
20
2382

1075794
N/A
N/A
63266
63281
CATAATGAATGTGGGT
38
2383

1075826
N/A
N/A
66375
66390
TAGGGAAAACCATAGC
23
2384

1075858
N/A
N/A
68977
68992
CCTTAAACAATCCCTA
23
2385

1075890
N/A
N/A
72205
72220
GATTAAAAGTAGGCCC
92
2386

1075922
N/A
N/A
75778
75793
GCCCAAAATAGGATAC
60
2387

1075954
N/A
N/A
78881
78896
ATTTAAGGCTGTGTTC
50
2388

1075986
N/A
N/A
81253
81268
GAATATCGAAAAGCAA
26
2389

1076018
N/A
N/A
83004
83019
ACTAATAGGATGGATT
15
2390

1076050
N/A
N/A
85864
85879
CTTTAGATTAAAGGCT
45
2391

1076082
N/A
N/A
89791
89806
TCTCAATACACTATAT
38
2392

1076114
N/A
N/A
91589
91604
ATTAGTAAGCTGAGGA
3
2393

1076146
N/A
N/A
92471
92486
GCTAAAACTTTCATCC
23
2394

1076178
N/A
N/A
94474
94489
CCTGAAATACAGGTGT
100
2395

1076210
N/A
N/A
97442
97457
ATTTATATGCTCCCTC
20
2396

1076242
N/A
N/A
98645
98660
ATGCAATAAGGAACAG
33
2397

1076274
N/A
N/A
102073
102088
TGAGAATAGAGCAGGT
9
2398

1076306
N/A
N/A
104347
104362
CTTTACTACTAATAAG
99
2399

1076338
N/A
N/A
107327
107342
CATTAAACCAGGGACT
33
2400

1076370
N/A
N/A
110594
110609
GATTATTCGGTATTTT
2
2401

1076402
N/A
N/A
112324
112339
CGTAATTATTTTTGCT
38
2402

1076434
N/A
N/A
115047
115062
CTTTAGGTTTATGCCT
25
2403

1076466
N/A
N/A
118557
118572
ATTTAGAGCTTAAGGA
5
2404

1076498
N/A
N/A
120644
120659
TTACAATACCTTATGA
70
2405

1076530
N/A
N/A
64823
64838
AGTATAAAGCAGGGCA
5
2406

1076562
N/A
N/A
12922
12937
TATTACAGAGGGTAGC
17
2407

TABLE 33

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
4
810

1074131
222
237
3682
3697
GGCCCCGCATCCCCCG
72
2408

1074163
339
354
3799
3814
CAGGCGAGCGAGGGCT
118
2409

1074195
475
490
3935
3950
CCCGGGTCCGGACGGC
79
2410

1074227
860
875
7294
7309
ACTGTCGAAGATGCTG
10
2411

1074259
1046
1061
55541
55556
TCATATTCTGCTGCAC
38
2412

1074291
1202
1217
98904
98919
CACTCTGACTGATTCT
11
2413

1074323
1429
1444
N/A
N/A
CAGGGCTAACTCCTGA
116
2414

1074355
1615
1630
120520
120535
AGGGACACTGTAGCTG
55
2415

1074387
1734
1749
122759
122774
CCAGGAATGGCTTCAA
32
2416

1074419
2111
2126
123136
123151
ATTCTTTAGAGCCAAC
4
2417

1074451
2477
2492
123502
123517
GACTAATGATAGCACT
6
2418

1074483
2709
2724
123734
123749
CACTAATATGGTCATT
15
2419

1074515
2908
2923
123933
123948
TAACTGGAAAGCAGGG
9
2420

1074547
3068
3083
124093
124108
GAGCACTCCCCTAGGC
71
2421

1074579
3224
3239
124249
124264
CCACTATAAAGCTTAT
6
2422

1074611
3621
3636
124646
124661
TAGCTTATATTGAAGA
19
2423

1074643
3835
3850
124860
124875
TTGAAGGGCCAAAATA
68
2424

1074675
4161
4176
125186
125201
AAATTATAGGCACTCC
6
2425

1074707
4337
4352
125362
125377
TTTAATGGCAGCACGG
36
2426

1074739
4525
4540
125550
125565
GACTCTTAGGTCTCCT
24
2427

1074771
4644
4659
125669
125684
AATCTTATCCCAATGC
18
2428

1074803
4837
4852
125862
125877
AGGCACTACATTTAGA
32
2429

1074835
5102
5117
126127
126142
CTTGCGAGGATAAAAT
30
2430

1074867
5292
5307
126317
126332
TAACATATGAGCATGC
40
2431

1074899
N/A
N/A
5482
5497
TAACTTTTGGGCAAAG
52
2432

1074931
N/A
N/A
5601
5616
GAGACTATACAACAGG
35
2433

1074963
N/A
N/A
5710
5725
TAGGCAAGCAGCTAAA
76
2434

1074995
N/A
N/A
4785
4800
AAAACTAAATGGACCG
50
2435

1075027
N/A
N/A
6578
6593
AAATTTGAACTGCCCA
28
2436

1075059
N/A
N/A
8749
8764
ATTTACTTTGGATGTC
11
2437

1075091
N/A
N/A
10609
10624
AAACAACGAATGATTG
65
2438

1075123
N/A
N/A
12563
12578
CTTTAGGAAAGGGTAT
21
2439

1075155
N/A
N/A
16105
16120
TCATTATAATGGGAGG
5
2440

1075187
N/A
N/A
19108
19123
GCCCAAGGAGGAAATC
77
2441

1075219
N/A
N/A
23348
23363
CCTTAACACTGGTAAG
117
2442

1075251
N/A
N/A
27031
27046
TAATTACGATTAGATC
79
2443

1075283
N/A
N/A
29653
29668
CGAATATAGAAAAATG
90
2444

1075315
N/A
N/A
31772
31787
CATAACTTGATGACTC
27
2445

1075347
N/A
N/A
32821
32836
CATAGGTAGGCAACAA
20
2446

1075379
N/A
N/A
35306
35321
TACCAAAACTACAACC
75
2447

1075411
N/A
N/A
37768
37783
CAAAAAGGGTAAGGCA
39
2448

1075443
N/A
N/A
40138
40153
GATTAACAGAGCTAGA
29
2449

1075475
N/A
N/A
42037
42052
TAGCAACACATGAAGA
64
2450

1075507
N/A
N/A
44455
44470
GTACAACCTAGTGATA
82
2451

1075539
N/A
N/A
46198
46213
CTTAAGGGATGGAACA
79
2452

1075571
N/A
N/A
48312
48327
CAAATAGATACTAAGC
54
2453

1075603
N/A
N/A
50064
50079
TATGAACAAGTATGAG
35
2454

1075635
N/A
N/A
52207
52222
AATAAACACCTCGCCA
97
2455

1075667
N/A
N/A
53956
53971
CAAATTTAGTTGTGCA
109
2456

1075699
N/A
N/A
56158
56173
GATTTATACTCAGGTT
4
2457

1075731
N/A
N/A
58878
58893
CCCCAATATTATCTAC
40
2458

1075763
N/A
N/A
61435
61450
ATTTAGGCTTTGGGTT
16
2459

1075795
N/A
N/A
63289
63304
GTAATTATATACCCAC
66
2460

1075827
N/A
N/A
66457
66472
ATACTATACCTAAGGA
60
2461

1075859
N/A
N/A
69260
69275
ACTTATCACTCTGCCC
20
2462

1075891
N/A
N/A
72206
72221
AGATTAAAAGTAGGCC
89
2463

1075923
N/A
N/A
75823
75838
TTTAATACTCTCTGGG
42
2464

1075955
N/A
N/A
79005
79020
GACCTATAATACAGAA
85
2465

1075987
N/A
N/A
81256
81271
GAAGAATATCGAAAAG
13
2466

1076019
N/A
N/A
83005
83020
CACTAATAGGATGGAT
12
2467

1076051
N/A
N/A
85945
85960
CTTAACTATTCAGCCC
21
2468

1076083
N/A
N/A
89966
89981
CGCTATAAAGTGGCAT
46
2469

1076115
N/A
N/A
91590
91605
CATTAGTAAGCTGAGG
7
2470

1076147
N/A
N/A
92516
92531
ATTAACTCACGAAGAC
25
2471

1076179
N/A
N/A
94487
94502
AATTAGCCAACCACCT
38
2472

1076211
N/A
N/A
97443
97458
AATTTATATGCTCCCT
22
2473

1076243
N/A
N/A
98790
98805
ATATTCGATGTAACTT
41
2474

1076275
N/A
N/A
102220
102235
GTATTAGATAAAGCAG
10
2475

1076307
N/A
N/A
104378
104393
GTAATTACCTCTAATC
38
2476

1076339
N/A
N/A
107352
107367
CAGCAATACTGTGGGC
13
2477

1076371
N/A
N/A
110712
110727
TAAGAACGAACCTCCA
49
2478

1076403
N/A
N/A
112457
112472
ATTTAAGACCTGGTGA
26
2479

1076435
N/A
N/A
115328
115343
CGTAAACATCATCTCT
12
2480

1076467
N/A
N/A
118559
118574
GTATTTAGAGCTTAAG
5
2481

1076499
N/A
N/A
121073
121088
GCTAATATATCCAATT
37
2482

1076531
N/A
N/A
66739
66754
ACTATAAAGGGTTTAG
66
2483

1076563
N/A
N/A
31631
31646
CAAAGTAATTAAACGA
91
2484

TABLE 34

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074132
223
238
3683
3698
CGGCCCCGCATCCCCC
96
2485

1074164
340
355
3800
3815
CCAGGCGAGCGAGGGC
135
2486

1074196
476
491
3936
3951
GCCCGGGTCCGGACGG
99
2487

1074228
861
876
7295
7310
GACTGTCGAAGATGCT
17
2488

1074260
1051
1066
55546
55561
GTTCATCATATTCTGC
48
2489

1074292
1216
1231
98918
98933
CTGTTTCACTGGAGCA
10
2490

1074324
1430
1445
N/A
N/A
GCAGGGCTAACTCCTG
116
2491

1074356
1616
1631
120521
120536
GAGGGACACTGTAGCT
43
2492

1074388
1805
1820
122830
122845
GACTTGGCATCAGCTC
16
2493

1074420
2112
2127
123137
123152
GATTCTTTAGAGCCAA
2
2494

1074452
2478
2493
123503
123518
TGACTAATGATAGCAC
3
2495

1074484
2710
2725
123735
123750
TCACTAATATGGTCAT
3
2496

1074516
2909
2924
123934
123949
TTAACTGGAAAGCAGG
22
2497

1074548
3093
3108
124118
124133
ATCTACCGTATGCCCA
4
2498

1074580
3225
3240
124250
124265
ACCACTATAAAGCTTA
5
2499

1074612
3622
3637
124647
124662
ATAGCTTATATTGAAG
12
2500

1074644
3836
3851
124861
124876
ATTGAAGGGCCAAAAT
93
2501

1074676
4162
4177
125187
125202
CAAATTATAGGCACTC
4
2502

1074708
4338
4353
125363
125378
CTTTAATGGCAGCACG
55
2503

1074740
4526
4541
125551
125566
GGACTCTTAGGTCTCC
75
2504

1074772
4650
4665
125675
125690
AGTTAAAATCTTATCC
80
2505

1074804
4874
4889
125899
125914
TAGCAAAGTCACTTCC
15
2506

1074836
5111
5126
126136
126151
AACAACATGCTTGCGA
27
2507

1074868
5297
5312
126322
126337
GTACCTAACATATGAG
74
2508

1074900
N/A
N/A
5484
5499
ATTAACTTTTGGGCAA
40
2509

1074932
N/A
N/A
5602
5617
GGAGACTATACAACAG
88
2510

1074964
N/A
N/A
5711
5726
TTAGGCAAGCAGCTAA
112
2511

1074996
N/A
N/A
4843
4858
AATAAATGCTTACGGG
60
2512

1075028
N/A
N/A
6670
6685
AAAAATCAAGCCCTCG
103
2513

1075060
N/A
N/A
8896
8911
GTTTAACAATCTCCCC
70
2514

1075092
N/A
N/A
10612
10627
TTAAAACAACGAATGA
63
2515

1075124
N/A
N/A
12652
12667
GTAAAAACCTGGGTTT
58
2516

1075156
N/A
N/A
16175
16190
ATTATATGACTCTGCT
22
2517

1075188
N/A
N/A
19193
19208
AGTCAACCTGTAATTA
14
2518

1075220
N/A
N/A
23362
23377
AATTTTAACTGTGACC
24
2519

1075252
N/A
N/A
27032
27047
TTAATTACGATTAGAT
90
2520

1075284
N/A
N/A
29658
29673
CTTTTCGAATATAGAA
76
2521

1075316
N/A
N/A
31797
31812
GTATATAGATACCCAC
25
2522

1075348
N/A
N/A
32855
32870
TCACAAAACCCTACAC
96
2523

1075380
N/A
N/A
35609
35624
ACTAAAACTGACTGTC
94
2524

1075412
N/A
N/A
37770
37785
TCCAAAAAGGGTAAGG
48
2525

1075444
N/A
N/A
40268
40283
ATAAATCCTCATGTGG
112
2526

1075476
N/A
N/A
42291
42306
TCTTATCCTACAGCTT
75
2527

1075508
N/A
N/A
44490
44505
GAAAAAGGTTTAGGGT
84
2528

1075540
N/A
N/A
46199
46214
GCTTAAGGGATGGAAC
78
2529

1075572
N/A
N/A
48372
48387
CAATTTAACTGTTACA
84
2530

1075604
N/A
N/A
50104
50119
ATAATTAAGCTATCAC
81
2531

1075636
N/A
N/A
52208
52223
CAATAAACACCTCGCC
91
2532

1075668
N/A
N/A
54032
54047
AATTATTGGTGACACT
80
2533

1075700
N/A
N/A
56179
56194
GCCAAATAAGAGGTAG
22
2534

1075732
N/A
N/A
58998
59013
AATAACCTCGAGTGCT
36
2535

1075764
N/A
N/A
61668
61683
CTTCAAGGAAGGTGCT
103
2536

1075796
N/A
N/A
63290
63305
AGTAATTATATACCCA
64
2537

1075828
N/A
N/A
66513
66528
TTAGAATAGTTCTACC
59
2538

1075860
N/A
N/A
69290
69305
AACTATAAGCTATGTG
73
2539

1075892
N/A
N/A
72236
72251
CACCAATACCAAAGTC
54
2540

1075924
N/A
N/A
75824
75839
ATTTAATACTCTCTGG
21
2541

1075956
N/A
N/A
79218
79233
TATAAAGCAATGCGAT
27
2542

1075988
N/A
N/A
81357
81372
AATTAAGCTTCTCTAG
90
2543

1076020
N/A
N/A
83011
83026
CCCCAACACTAATAGG
60
2544

1076052
N/A
N/A
86023
86038
GCAATAAAGCTGAACT
23
2545

1076084
N/A
N/A
89980
89995
CATCAATAGAGAGTCG
7
2546

1076116
N/A
N/A
91600
91615
GAAAATAGCCCATTAG
25
2547

1076148
N/A
N/A
92517
92532
TATTAACTCACGAAGA
52
2548

1076180
N/A
N/A
94489
94504
ATAATTAGCCAACCAC
42
2549

1076212
N/A
N/A
97445
97460
CAAATTTATATGCTCC
15
2550

1076244
N/A
N/A
98799
98814
CAATTTGGGATATTCG
14
2551

1076276
N/A
N/A
102282
102297
CTTTAGGAGTCAGAAC
59
2552

1076308
N/A
N/A
104379
104394
AGTAATTACCTCTAAT
32
2553

1076340
N/A
N/A
107364
107379
TAATATCCTCATCAGC
8
2554

1076372
N/A
N/A
110715
110730
CAATAAGAACGAACCT
76
2555

1076404
N/A
N/A
112458
112473
TATTTAAGACCTGGTG
13
2556

1076436
N/A
N/A
115413
115428
CATTACTACTCTGTCC
39
2557

1076468
N/A
N/A
118602
118617
CATTACTACTAAGAGT
91
2558

1076500
N/A
N/A
121129
121144
CAATTAAGATCAACAT
99
2559

1076532
N/A
N/A
68936
68951
ATTTTTAGGCAGACGC
12
2560

1076564
N/A
N/A
39617
39632
TAAAGTAATGCTACAG
77
2561

TABLE 35

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074133
224
239
3684
3699
GCGGCCCCGCATCCCC
101
2562

1074165
341
356
3801
3816
CCCAGGCGAGCGAGGG
90
2563

1074197
477
492
3937
3952
TGCCCGGGTCCGGACG
91
2564

1074229
864
879
7298
7313
GAAGACTGTCGAAGAT
5
2565

1074261
1055
1070
55550
55565
CCGAGTTCATCATATT
19
2566

1074293
1217
1232
98919
98934
GCTGTTTCACTGGAGC
54
2567

1074325
1431
1446
116620
116635
CGCAGGGCTAACTCCT
42
2568

1074357
1617
1632
120522
120537
CGAGGGACACTGTAGC
12
2569

1074389
1808
1823
122833
122848
GCAGACTTGGCATCAG
14
2570

1074421
2113
2128
123138
123153
TGATTCTTTAGAGCCA
3
2571

1074453
2479
2494
123504
123519
GTGACTAATGATAGCA
4
2572

1074485
2711
2726
123736
123751
TTCACTAATATGGTCA
4
2573

1074517
2939
2954
123964
123979
AATGCATACAAAGCGC
55
2574

1074549
3094
3109
124119
124134
TATCTACCGTATGCCC
6
2575

1074581
3226
3241
124251
124266
AACCACTATAAAGCTT
18
2576

1074613
3623
3638
124648
124663
CATAGCTTATATTGAA
7
2577

1074645
3837
3852
124862
124877
AATTGAAGGGCCAAAA
81
2578

1074677
4169
4184
125194
125209
CTACTGGCAAATTATA
22
2579

1074709
4352
4367
125377
125392
TCTAGAACAGCTGCCT
71
2580

1074741
4528
4543
125553
125568
AAGGACTCTTAGGTCT
78
2581

1074773
4651
4666
125676
125691
CAGTTAAAATCTTATC
94
2582

1074805
4875
4890
125900
125915
GTAGCAAAGTCACTTC
9
2583

1074837
5112
5127
126137
126152
TAACAACATGCTTGCG
11
2584

1074869
5298
5313
126323
126338
AGTACCTAACATATGA
31
2585

1074901
N/A
N/A
5485
5500
TATTAACTTTTGGGCA
61
2586

1074933
N/A
N/A
5603
5618
AGGAGACTATACAACA
72
2587

1074965
N/A
N/A
5715
5730
GTGTTTAGGCAAGCAG
20
2588

1074997
N/A
N/A
4854
4869
GCCGCGAGGAAAATAA
119
2589

1075029
N/A
N/A
7004
7019
ATATTCGACACTGGAG
33
2590

1075061
N/A
N/A
8954
8969
CCTTATACTTTTAGCC
5
2591

1075093
N/A
N/A
10664
10679
CAAAGTAAGGTATGAG
3
2592

1075125
N/A
N/A
12777
12792
CTTAAGGTACAAGGCA
84
2593

1075157
N/A
N/A
16192
16207
CCAGAAAATCATAGTA
19
2594

1075189
N/A
N/A
19238
19253
GCTAATAGTCACTGTT
11
2595

1075221
N/A
N/A
23384
23399
CATTATCCGGGAGAGC
10
2596

1075253
N/A
N/A
27033
27048
GTTAATTACGATTAGA
20
2597

1075285
N/A
N/A
29702
29717
TATACATAGTCAATTC
60
2598

1075317
N/A
N/A
31832
31847
GTATTCGCCTCCTGCA
27
2599

1075349
N/A
N/A
33000
33015
ATTAAAGCTCATTGAT
81
2600

1075381
N/A
N/A
35767
35782
TATTACCCTACTCATA
89
2601

1075413
N/A
N/A
37807
37822
CATAACTACATCGACA
34
2602

1075445
N/A
N/A
40269
40284
TATAAATCCTCATGTG
84
2603

1075477
N/A
N/A
42405
42420
CTTTATCTCACTAGCT
86
2604

1075509
N/A
N/A
44622
44637
CATAATCCCTGACTTG
81
2605

1075541
N/A
N/A
46250
46265
GCTCAAAACTGACATA
47
2606

1075573
N/A
N/A
48504
48519
AAGGAACCTTCTGTGT
72
2607

1075605
N/A
N/A
50176
50191
CGTAAACATTTTGCCT
38
2608

1075637
N/A
N/A
52219
52234
CCACAACCTGTCAATA
100
2609

1075669
N/A
N/A
54033
54048
AAATTATTGGTGACAC
70
2610

1075701
N/A
N/A
56296
56311
AATTACTAGAGGCTTC
3
2611

1075733
N/A
N/A
58999
59014
CAATAACCTCGAGTGC
28
2612

1075765
N/A
N/A
61721
61736
CTTAAGGCAGCTCTAT
58
2613

1075797
N/A
N/A
63378
63393
GATAATCATGATACTC
3
2614

1075829
N/A
N/A
66603
66618
ACTCAATAGATCATTG
41
2615

1075861
N/A
N/A
69291
69306
TAACTATAAGCTATGT
78
2616

1075893
N/A
N/A
72284
72299
CGTGAAAAAGATGTGG
7
2617

1075925
N/A
N/A
75907
75922
AACCTATATTATTTGC
28
2618

1075957
N/A
N/A
79219
79234
CTATAAAGCAATGCGA
28
2619

1075989
N/A
N/A
81362
81377
GCTAAAATTAAGCTTC
78
2620

1076021
N/A
N/A
83058
83073
CATTAATAAAGTTACC
95
2621

1076053
N/A
N/A
86047
86062
TACCAACAAGGCATCA
55
2622

1076085
N/A
N/A
90079
90094
ACTAATAGGCCATCTG
7
2623

1076117
N/A
N/A
91603
91618
CTAGAAAATAGCCCAT
15
2624

1076149
N/A
N/A
92518
92533
TTATTAACTCACGAAG
24
2625

1076181
N/A
N/A
94490
94505
TATAATTAGCCAACCA
26
2626

1076213
N/A
N/A
97518
97533
TCTCAAGGAATTGCCT
27
2627

1076245
N/A
N/A
98849
98864
CCTAAAAAACTAGTGA
101
2628

1076277
N/A
N/A
102574
102589
GCTAAAACATCAGATA
24
2629

1076309
N/A
N/A
104525
104540
GATAACTTTCCACAAT
9
2630

1076341
N/A
N/A
107422
107437
ATTAACTACAACTGTG
18
2631

1076373
N/A
N/A
111082
111097
AACGGATATACAATAA
10
2632

1076405
N/A
N/A
112459
112474
TTATTTAAGACCTGGT
12
2633

1076437
N/A
N/A
115843
115858
GAAGAATAGCATCTGA
19
2634

1076469
N/A
N/A
118627
118642
GTAAAAGGGAACTAAG
69
2635

1076501
N/A
N/A
121268
121283
CATAACACTTAAGGTG
97
2636

1076533
N/A
N/A
75580
75595
ATTTTTAGTCCAGTGG
9
2637

1076565
N/A
N/A
55334
55349
CATTAAGTCACAGCAT
74
2638

TABLE 36

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
1
810

1074134
225
240
3685
3700
CGCGGCCCCGCATCCC
79
2639

1074166
342
357
3802
3817
ACCCAGGCGAGCGAGG
72
2640

1074198
478
493
3938
3953
TTGCCCGGGTCCGGAC
112
2641

1074230
866
881
7300
7315
AAGAAGACTGTCGAAG
4
2642

1074262
1056
1071
55551
55566
GCCGAGTTCATCATAT
48
2643

1074294
1275
1290
98977
98992
TTGGAGTTGCTGCCAC
80
2644

1074326
1432
1447
116621
116636
ACGCAGGGCTAACTCC
36
2645

1074358
1618
1633
120523
120538
TCGAGGGACACTGTAG
17
2646

1074390
1810
1825
122835
122850
CTGCAGACTTGGCATC
64
2647

1074422
2189
2204
123214
123229
AAACAGGCTCACTTCC
9*
2648

1074454
2480
2495
123505
123520
TGTGACTAATGATAGC
1
2649

1074486
2712
2727
123737
123752
ATTCACTAATATGGTC
4
2650

1074518
2940
2955
123965
123980
AAATGCATACAAAGCG
13
2651

1074550
3095
3110
124120
124135
ATATCTACCGTATGCC
23
2652

1074582
3228
3243
124253
124268
TAAACCACTATAAAGC
18
2653

1074614
3624
3639
124649
124664
TCATAGCTTATATTGA
49
2654

1074646
3838
3853
124863
124878
AAATTGAAGGGCCAAA
39
2655

1074678
4179
4194
125204
125219
TAATCTGTGGCTACTG
7
2656

1074710
4353
4368
125378
125393
CTCTAGAACAGCTGCC
42
2657

1074742
4529
4544
125554
125569
AAAGGACTCTTAGGTC
25
2658

1074774
4661
4676
125686
125701
CAAGAATACCCAGTTA
16
2659

1074806
4877
4892
125902
125917
TTGTAGCAAAGTCACT
8
2660

1074838
5113
5128
126138
126153
ATAACAACATGCTTGC
9
2661

1074870
5301
5316
126326
126341
GTAAGTACCTAACATA
20
2662

1074902
N/A
N/A
5486
5501
CTATTAACTTTTGGGC
54
2663

1074934
N/A
N/A
5604
5619
CAGGAGACTATACAAC
74
2664

1074966
N/A
N/A
5721
5736
ATTGAAGTGTTTAGGC
9
2665

1074998
N/A
N/A
4998
5013
CACGCGACCTACTAAG
61
2666

1075030
N/A
N/A
7007
7022
TTAATATTCGACACTG
37
2667

1075062
N/A
N/A
8960
8975
CTTTAACCTTATACTT
58
2668

1075094
N/A
N/A
10705
10720
GATAAATGTAACTAGC
10
2669

1075126
N/A
N/A
12890
12905
CTTAAATCTTAGCAAC
20
2670

1075158
N/A
N/A
16240
16255
CGGCAAAAACAAAATC
76
2671

1075190
N/A
N/A
19295
19310
TATCAAGGATTCAGTA
45
2672

1075222
N/A
N/A
23766
23781
GTATTTGGACAACTCT
3
2673

1075254
N/A
N/A
27099
27114
TCCCAAAAGTCATCGC
28
2674

1075286
N/A
N/A
29807
29822
ATTACGGACAGAAGTG
48
2675

1075318
N/A
N/A
31850
31865
ATCCTAAAGCCACTGC
72
2676

1075350
N/A
N/A
33001
33016
GATTAAAGCTCATTGA
62
2677

1075382
N/A
N/A
35769
35784
ATTATTACCCTACTCA
33
2678

1075414
N/A
N/A
37990
38005
CATACTAATCCCTCTT
41
2679

1075446
N/A
N/A
40270
40285
CTATAAATCCTCATGT
87
2680

1075478
N/A
N/A
42416
42431
CATTTTGAACCCTTTA
20
2681

1075510
N/A
N/A
44630
44645
GAATAACACATAATCC
83
2682

1075542
N/A
N/A
46607
46622
TGAGAAAGGTTCCTGA
66
2683

1075574
N/A
N/A
48508
48523
AGTCAAGGAACCTTCT
47
2684

1075606
N/A
N/A
50368
50383
GCTAAACCTACACGCT
82
2685

1075638
N/A
N/A
52324
52339
ATTAACCAGAAGCCTG
79
2686

1075670
N/A
N/A
54501
54516
TATATATGATGGACTG
39
2687

1075702
N/A
N/A
56442
56457
GAGGAAGGGCACCTTT
81
2688

1075734
N/A
N/A
59002
59017
AGGCAATAACCTCGAG
26
2689

1075766
N/A
N/A
61741
61756
GGAGAACACAAGAGGC
5
2690

1075798
N/A
N/A
63396
63411
ATTTAGATAGTTACTG
21
2691

1075830
N/A
N/A
66610
66625
GATGAACACTCAATAG
12
2692

1075862
N/A
N/A
70001
70016
CTAATAACTTGTCTAC
67
2693

1075894
N/A
N/A
72305
72320
CTCGAAAGCTGGGCCC
100
2694

1075926
N/A
N/A
75911
75926
GTAGAACCTATATTAT
25
2695

1075958
N/A
N/A
79351
79366
CATTATGACATTCCCC
12
2696

1075990
N/A
N/A
81490
81505
CGTTATTATGCAGCAA
1
2697

1076022
N/A
N/A
83093
83108
TAATTAGATGCTGACA
2
2698

1076054
N/A
N/A
86104
86119
CATTAGACTTTCTGTC
21
2699

1076086
N/A
N/A
90080
90095
AACTAATAGGCCATCT
31
2700

1076118
N/A
N/A
91688
91703
CGTAAATTGAGGCCCA
45
2701

1076150
N/A
N/A
92520
92535
ATTTATTAACTCACGA
11
2702

1076182
N/A
N/A
94491
94506
CTATAATTAGCCAACC
15
2703

1076214
N/A
N/A
97543
97558
ATCCTATACATTAAGA
67
2704

1076246
N/A
N/A
98850
98865
TCCTAAAAAACTAGTG
75
2705

1076278
N/A
N/A
102644
102659
AATAAGGACAGGACCC
29
2706

1076310
N/A
N/A
104554
104569
ACCCTATACTTGAATT
36
2707

1076342
N/A
N/A
107423
107438
CATTAACTACAACTGT
33
2708

1076374
N/A
N/A
111084
111099
ATAACGGATATACAAT
15
2709

1076406
N/A
N/A
112460
112475
ATTATTTAAGACCTGG
4
2710

1076438
N/A
N/A
115846
115861
TAGGAAGAATAGCATC
13
2711

1076470
N/A
N/A
118843
118858
GATAAAGAGGTTAACA
34
2712

1076502
N/A
N/A
121320
121335
CAAAGTAAGTGAGCCC
17
2713

1076534
N/A
N/A
79220
79235
ACTATAAAGCAATGCG
4
2714

1076566
N/A
N/A
55576
55591
AATTACAGTGTCTCAC
63
2715

TABLE 37

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2

SEQ ID
SEQ ID
SEQ ID
SEQ ID

NO: 1
NO: 1
NO: 2
NO: 2

YAP1

Compund
Start
Stop
Start
Stop

(%
SEQ

Number
Site
Site
Site
Site
Sequence (5' to 3')
UTC)
ID NO

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
2
810

1074135
226
241
3686
3701
CCGCGGCCCCGCATCC
91
2716

1074167
353
368
3813
3828
CGCACCCCCTGACCCA
58
2717

1074199
483
498
3943
3958
GCCGGTTGCCCGGGTC
101
2718

1074231
867
882
7301
7316
AAAGAAGACTGTCGAA
8
2719

1074263
1057
1072
55552
55567
AGCCGAGTTCATCATA
34
2720

1074295
1278
1293
98980
98995
TGGTTGGAGTTGCTGC
15
2721

1074327
1433
1448
116622
116637
TACGCAGGGCTAACTC
39
2722

1074359
1619
1634
120524
120539
TTCGAGGGACACTGTA
18
2723

1074391
1828
1843
122853
122868
GTCAGAACTCAAAGCT
14
2724

1074423
2190
2205
123215
123230
CAAACAGGCTCACTTC
4*
2725

1074455
2485
2500
123510
123525
CATTATGTGACTAATG
67
2726

1074487
2714
2729
123739
123754
AGATTCACTAATATGG
7
2727

1074519
2959
2974
123984
123999
ACTACTAGTCATGTAT
45
2728

1074551
3096
3111
124121
124136
AATATCTACCGTATGC
58
2729

1074583
3229
3244
124254
124269
GTAAACCACTATAAAG
30
2730

1074615
3625
3640
124650
124665
TTCATAGCTTATATTG
8
2731

1074647
3839
3854
124864
124879
CAAATTGAAGGGCCAA
27
2732

1074679
4182
4197
125207
125222
TCTTAATCTGTGGCTA
5
2733

1074711
4354
4369
125379
125394
ACTCTAGAACAGCTGC
28
2734

1074743
4530
4545
125555
125570
GAAAGGACTCTTAGGT
16
2735

1074775
4681
4696
125706
125721
GGTTTATTGTAAAAGC
3
2736

1074807
4927
4942
125952
125967
CCATATAGAAGGCATG
75
2737

1074839
5114
5129
126139
126154
TATAACAACATGCTTG
33
2738

1074871
5302
5317
126327
126342
TGTAAGTACCTAACAT
70
2739

1074903
N/A
N/A
5487
5502
CCTATTAACTTTTGGG
87
2740

1074935
N/A
N/A
5605
5620
ACAGGAGACTATACAA
80
2741

1074967
N/A
N/A
5726
5741
GACAAATTGAAGTGTT
116
2742

1074999
N/A
N/A
5004
5019
AACCAACACGCGACCT
77
2743

1075031
N/A
N/A
7009
7024
ATTTAATATTCGACAC
52
2744

1075063
N/A
N/A
9104
9119
TACGGAAGGCCAACTG
16
2745

1075095
N/A
N/A
10722
10737
CTTGAAAACAAGCCAC
63
2746

1075127
N/A
N/A
12934
12949
GCTAAATTATGCTATT
79
2747

1075159
N/A
N/A
16250
16265
CAAAAAATCACGGCAA
63
2748

1075191
N/A
N/A
19412
19427
ACGGGAAAGAAAGGCC
83
2749

1075223
N/A
N/A
23854
23869
GTTAAAAGTGAACCCA
19
2750

1075255
N/A
N/A
27113
27128
AAATATCCGTGTCCTC
16
2751

1075287
N/A
N/A
29808
29823
TATTACGGACAGAAGT
58
2752

1075319
N/A
N/A
31860
31875
TATAACAATCATCCTA
59
2753

1075351
N/A
N/A
33002
33017
AGATTAAAGCTCATTG
38
2754

1075383
N/A
N/A
35770
35785
AATTATTACCCTACTC
45
2755

1075415
N/A
N/A
38069
38084
CATTAAATGACAGCCT
52
2756

1075447
N/A
N/A
40272
40287
CACTATAAATCCTCAT
96
2757

1075479
N/A
N/A
42463
42478
GACAATAAATCTGCCT
77
2758

1075511
N/A
N/A
44708
44723
CAATATTATCTGAGCT
106
2759

1075543
N/A
N/A
46674
46689
ATATATTAGGAGTTTC
22
2760

1075575
N/A
N/A
48710
48725
TTACAACACAAGTCTA
55
2761

1075607
N/A
N/A
50539
50554
AAAACGGTGTGAAGAA
45
2762

1075639
N/A
N/A
52325
52340
AATTAACCAGAAGCCT
101
2763

1075671
N/A
N/A
54503
54518
GATATATATGATGGAC
37
2764

1075703
N/A
N/A
56609
56624
GGAGAAAGCCATCAAG
10
2765

1075735
N/A
N/A
59100
59115
GAATCGATGTGTTGCG
17
2766

1075767
N/A
N/A
61758
61773
TATTACACAGGCAGGC
12
2767

1075799
N/A
N/A
63412
63427
CCTCAACACATTTGAG
85
2768

1075831
N/A
N/A
66680
66695
TATTAGCCTTCTAACC
59
2769

1075863
N/A
N/A
70002
70017
CCTAATAACTTGTCTA
71
2770

1075895
N/A
N/A
72306
72321
ACTCGAAAGCTGGGCC
38
2771

1075927
N/A
N/A
75923
75938
GCTTAAAATCATGTAG
32
2772

1075959
N/A
N/A
79446
79461
GATTATTATTGCAGCT
15
2773

1075991
N/A
N/A
81533
81548
ATATAGGACCACGACT
62
2774

1076023
N/A
N/A
83094
83109
ATAATTAGATGCTGAC
4
2775

1076055
N/A
N/A
86186
86201
AATTACTAACAATCTC
45
2776

1076087
N/A
N/A
90082
90097
CAAACTAATAGGCCAT
10
2777

1076119
N/A
N/A
91742
91757
GTTAAATATGAATTGG
7
2778

1076151
N/A
N/A
92521
92536
TATTTATTAACTCACG
14
2779

1076183
N/A
N/A
94494
94509
CTTCTATAATTAGCCA
7
2780

1076215
N/A
N/A
97620
97635
TTATAACAGACTGGCT
47
2781

1076247
N/A
N/A
99297
99312
GACCAAAACAGCTCTT
11
2782

1076279
N/A
N/A
102645
102660
CAATAAGGACAGGACC
71
2783

1076311
N/A
N/A
104558
104573
TATAACCCTATACTTG
56
2784

1076343
N/A
N/A
107707
107722
AGACTAAATCTTCCCT
8
2785

1076375
N/A
N/A
111085
111100
TATAACGGATATACAA
22
2786

1076407
N/A
N/A
112462
112477
GTATTATTTAAGACCT
22
2787

1076439
N/A
N/A
115906
115921
CTTATATGGTTTTGTG
4
2788

1076471
N/A
N/A
118862
118877
CATTAGACTAGGCTTT
5
2789

1076503
N/A
N/A
121702
121717
AATTACCCCTGTGAGG
77
2790

1076535
N/A
N/A
83322
83337
ATTTTTAGCTCGCAAT
28
2791

1076567
N/A
N/A
59365
59380
GATTACAGTGACATTC
10
2792

TABLE 32

Inhibition of Yap1 mRNA by 3-10-3 cEt gapmers

targeting SEQ ID NO.: 3

SEQ ID
SEQ ID

NO: 3
NO: 3

YAP1

Compund
Start
Stop

%
SEQ

Number
Site
Site
Sequence (5' to 3')
UTC)
ID NO

1074880
1246
1261
CTCCTGCCGAAGCAGT
101
2793

1074881
1250
1265
CTAACTCCTGCCGAAG
76
2794

1074882
1251
1266
GCTAACTCCTGCCGAA
73
2795

1074883
1252
1267
GGCTAACTCCTGCCGA
107
2796

1074884
1253
1268
GGGCTAACTCCTGCCG
110
2797

1074885
1254
1269
AGGGCTAACTCCTGCC
115
2798

1074886
1255
1270
CAGGGCTAACTCCTGC
104
2799

Example 5
Antisense Inhibition of Human Yap1 in SNU-449 Cells by Modified Oligonucleotides

Modified oligonucleotides with additional chemistry modifications were designed to target a Yap1 nucleic acid and were tested for their effect on Yap1 mRNA level in SNU-449 cells. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured SNU-449 cells at a density of 10,000 cells per well were treated using free uptake with 2,000 nM of modified oligonucleotide. After a treatment period of approximately 48 hours, RNA was isolated from the cells and Yap1 mRNA levels were measured by quantitative real-time RTPCR. Human primer probe set RTS36584 was used to measure mRNA levels. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides targeting the amplicon region.

Several different chemistry modifications were tested, which are specified in the Chemistry Notation column of the tables below, wherein the notation “d” refers to a 2′-deoxyribose sugar, the notation “s” refers to a phosphorothioate (P═S) internucleoside linkage, the notation “k” refers to a cEt modified sugar, the notation “y” refers to a 2′-O-methyl ribose sugar, the notation “e” refers to a MOE modified sugar, and the notation “^mC” refers to a 5-methylcytosine.

“Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either SEQ ID NO.: 1 or SEQ ID NO.: 2. ‘N/A’ indicates that the modified oligonucleotide does not target that particular gene sequence with 100% complementarity. ‘N.D.’ indicates that the % UTC is not defined for that particular modified oligonucleotide in that particular experiment. Activity of the modified oligonucleotide may be defined in a different experiment.

TABLE 39

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
12
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
8
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_ds
7
2800

T_ds^mC_dsA_dsT_dsG_ks^mC_ks^mC_k

1095379
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_dsT_dsG_dsA_dsG_dsG_dsT_dsA_ds
52
392

T_dsA_dsA_ks^mC_esT_ksG_esG_k

1095397
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_dsA_dsG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
53
1580

C_dsT_ksG_esG_ksG_es^mC_k

1095398
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_dsG_dsA_dsG_dsG_dsT_dsA_dsT_ds
38
2801

A_dsA_ds^mC_ksT_esG_ksG_esG_k

1095399
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ds^mC_dsT_dsG_dsA_dsG_dsG_dsT_ds
46
2802

A_dsT_dsA_ksA_es^mC_ksT_esG_k

1198370
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_dsT_ds^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
20
2803

C_ds^mC_dsT_ksT_esA_ksT_esA_k

1198371
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^mC_dsA_ds
15
2804

T_dsG_ds^mC_ks^mC_esT_ksT_esA_k

1198372
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^mC_ds
21
2805

A_dsT_dsG_ks^mC_es^mC_ksT_esT_k

1198373
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
40
443

C_dsA_dsT_ksG_es^mC_ks^mC_esT_k

1198374
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
24
2800

T_ds^mC_dsA_ksT_esG_ks^mC_es^mC_k

1198375
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
22
2806

C_dsT_ds^mC_ksA_esT_ksG_es^mC_k

1198376
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
36
2807

C_dsT_ks^mC_esA_ksT_esG_k

1198377
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_dsG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_ds
30
2808

T_ds^mC_ksT_es^mC_ksA_esT_k

1198378
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_dsA_dsT_dsG_dsG_dsA_dsA_dsA_dsT_ds
39
656

T_dsG_ksT_es^mC_ksT_es^mC_k

1198379
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_dsT_dsA_dsT_dsG_dsT_dsG_dsG_ds^m
45
2809

C_dsA_dsA_ksT_esA_ksA_esT_k

1198380
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_dsA_dsG_dsT_dsA_dsT_dsG_dsT_dsG_ds
18
2810

G_ds^mC_ksA_esA_ksT_esA_k

1198381
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_dsG_dsA_dsG_dsT_dsA_dsT_dsG_dsT_ds
19
2811

G_dsG_ks^mC_esA_ksA_esT_k

1198382
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_dsA_dsG_dsA_dsG_dsT_dsA_dsT_dsG_ds
19
963

T_dsG_ksG_es^mC_ksA_esA_k

1198383
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_dsT_dsA_dsG_dsA_dsG_dsT_dsA_dsT_ds
31
810

G_dsT_ksG_esG_ks^mC_esA_k

1198384
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_dsT_dsT_dsA_dsG_dsA_dsG_dsT_dsA_ds
6
2812

T_dsG_ksT_esG_ksG_es^mC_k

1198385
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_dsA_dsT_dsT_dsA_dsG_dsA_dsG_dsT_ds
30
2813

A_dsT_ksG_esT_ksG_esG_k

1198386
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_dsT_dsA_dsT_dsT_dsA_dsG_dsA_dsG_ds
77
2814

T_dsA_ksT_esG_ksT_esG_k

1198387
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_dsT_dsA_dsT_dsA_dsT_dsT_dsA_dsG_ds
84
887

A_dsG_ksT_esA_ksT_esG_k

1198388
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_dsT_dsA_dsA_ds^mC_dsT_dsG_dsG_ds
90
2815

G_ds^mC_dsA_ksA_esA_ksT_esT_k

1198389
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
28
1427

G_dsG_dsG_ks^mC_esA_ksA_esA_k

1198390
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
37
905

T_dsG_dsG_ksG_es^mC_ksA_esA_k

1198391
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_dsG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
29
1503

C_dsT_dsG_ksG_esG_ks^mC_esA_k

1198392
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ds^mC_dsA_ds^mC_dsT_dsG_dsA_dsG_ds
48
2816

G_dsT_dsA_ksT_esA_ksA_es^mC_k

1198393
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_dsA_ds^mC_dsA_dsT_dsT_dsA_dsG_ds
58
2817

G_dsA_dsA_ks^mC_esA_ksA_esG_k

1198394
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_dsT_dsT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
63
2818

G_dsG_ksA_esA_ks^mC_esA_k

1198395
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_dsT_dsT_dsT_dsA_ds^mC_dsA_dsT_ds
35
1124

T_dsA_dsG_ksG_esA_ksA_es^mC_k

1198396
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_dsA_ds
25
2819

T_dsT_dsA_ksG_esG_ksA_esA_k

1198397
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_ds
17
1200

A_dsT_dsT_ksA_esG_ksG_esA_k

1198398
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_dsA_dsC_dsT_dsT_dsT_dsT_dsA_ds^m
18
1276

C_dsA_dsT_ksT_esA_ksG_esG_k

1198399
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ds^mC_dsA_ds^mC_dsT_dsT_dsT_dsT_ds
35
2820

A_ds^mC_dsA_ksT_esT_ksA_esG_k

1198400
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_dsG_ds^mC_dsA_ds^mC_dsT_dsT_dsT_ds
62
2821

T_dsA_ds^mC_ksA_esT_ksT_esA_k

1198401
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_dsA_dsA_dsG_ds^mC_dsA_ds^mC_dsT_ds
63
2822

T_dsT_dsT_ksA_es^mC_ksA_esT_k

1198402
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_dsA_dsA_dsG_dsA_dsT_ds^mC_dsT_ds
32
2823

G_dsA_dsA_ksA_es^mC_ksT_es^mC_k

1198403
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_dsG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
54
2824

C_dsT_dsG_ksA_esA_ksA_es^mC_k

1198404
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_dsT_dsG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
55
2825

C_dsT_ksG_esA_ksA_esA_k

1198405
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_dsG_ds
36
2826

A_dsT_ds^mC_ksT_esG_ksA_esA_k

1198406
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_dsA_ds
17
2044

G_dsA_dsT_ks^mC_esT_ksG_esA_k

1198407
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
23
2121

A_dsG_dsA_ksT_es^mC_ksT_esG_k

1198408
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_dsG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
41
2827

A_dsA_dsG_ksA_esT_ks^mC_esT_k

1198409
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_dsT_dsG_ds^mC_dsT_dsT_dsT_dsG_ds
19
2828

G_dsA_dsA_ksG_esA_ksT_es^mC_k

1198410
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_dsA_dsG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
48
2829

G_dsG_ksA_esA_ksG_esA_k

1198411
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_dsG_dsA_dsT_dsG_ds^mC_dsA_dsT_ds
33
2830

G_dsG_dsT_ksT_esT_ksT_esT_k

1198412
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
17
2831

A_dsT_dsG_ksG_esT_ksT_esT_k

1198413
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_dsT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
29
2832

C_dsA_dsT_ksG_esG_ksT_esT_k

1198414
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_dsT_dsT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
20
2833

C_dsA_ksT_esG_ksG_esT_k

1198415
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_dsT_dsT_dsT_dsA_dsG_dsG_dsA_dsT_ds
29
2834

G_ds^mC_ksA_esT_ksG_esG_k

1198416
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_dsA_dsT_dsT_dsT_dsA_dsG_dsG_dsA_ds
29
2835

T_dsG_ks^mC_esA_ksT_esG_k

1198417
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_dsG_dsA_dsT_dsT_dsT_dsA_dsG_ds
40
2836

G_dsA_dsT_ksG_es^mC_ksA_esT_k

1198418
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_dsA_dsG_dsA_dsT_dsT_dsT_dsA_ds
67
2837

G_dsG_dsA_ksT_esG_ks^mC_esA_k

1198419
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_dsT_ds^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
78
2838

A_dsG_ksG_esA_ksT_esG_k

1198420
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_dsA_dsT_dsG_dsG_dsT_dsT_dsT_dsT_ds
41
2839

G_dsT_ksG_esT_ksG_esT_k

1198421
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_dsA_dsT_dsA_dsT_dsG_dsG_dsT_dsT_ds
36
2840

T_dsT_ksG_esT_ksG_esT_k

1198422
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_dsT_dsA_dsT_sA_dsT_dsG_dsG_dsT_ds
18
2788

T_dsT_ksT_esG_ksT_esG_k

1198423
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_dsT_ds+lTsA_dsT_dsA_dsT_dsG_dsG_ds
10
2841

T_dsT_ksT_esT_ksG_esT_k

1198424
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_dsA_dsT_ds
15
2842

G_dsG_dsT_ksT_esT_ksT_esG_k

1198429
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^mC_ds
48
2843

T_dsG_dsT_ks^mC_esT_ksG_esA_k

1198430
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_dsA_dsT_dsT_dsC_ds^mC_dsA_dsA_ds
49
2844

T_ds^mC_dsT_ksG_esT_ks^mC_esT_k

1198431
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
35
2845

A_dsT_ds^mC_ksT_esG_ksT_es^mC_k

1198432
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
70
2846

A_dsA_dsT_ks^mC_esT_ksG_esT_k

1198433
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_dsA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
36
1404

C_dsA_dsA_ksT_es^mC_ksT_esG_k

1198434
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_dsT_dsA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
78
2847

C_dsA_ksA_esT_ks^mC_esT_k

1198435
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_dsG_dsT_dsA_dsA_dsT_dsA_dsT_dsT_ds
57
2848

G_ds^mC_ksA_esA_ksT_es^mC_k

1198436
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_dsT_dsG_dsT_dsA_dsA_dsT_dsA_dsT_ds
69
2849

T_dsG_ks^mC_esA_ksA_esT_k

1198437
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_dsT_dsA_dsT_dsG_dsT_dsA_dsA_dsT_ds
63
2850

A_dsT_ksT_esG_ks^mC_esA_k

1198447
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_dsA_dsG_dsG_dsT_dsT_dsT_s^mC_ds^m
63
2851

C_ds^mC_dsA_ksG_esA_ksT_esT_k

1198448
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_dsT_dsA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
36
2852

C_ds^mC_ks^mC_esA_ksG_esA_k

1198449
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_dsG_dsT_dsA_dsA_dsG_dsG_dsT_dsT_ds
37
2853

T_ds^mC_ks^mC_es^mC_ksA_esG_k

1198450
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_dsA_dsG_dsT_dsA_dsA_dsG_dsG_dsT_ds
42
2854

T_dsT_ks^mC_es^mC_ks^mC_esA_k

1198451
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_dsG_ds
48
1101

G_dsT_dsT_ksT_es^mC_ks^mC_es^mC_k

1198452
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_dsA_ds
38
2855

G_dsG_dsT_ksT_esT_ks^mC_es^mC_k

1198453
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ds^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
48
2856

A_dsG_dsG_ksT_esT_ksT_es^mC_k

1198454
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_dsA_ds^mC_dsT_dsA_dsA_dsG_dsT_ds
39
2857

A_dsA_dsG_ksG_esT_ksT_esT_k

1198455
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_dsA_dsG_dsA_ds^mC_dsT_dsA_dsA_ds
42
2858

G_dsT_dsA_ksA_esG_ksG_esT_k

TABLE 40

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
28
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
15
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
9
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1198425
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_dsA_ds
35
2859

T_dsG_dsG_ksT_esT_ksT_esT_k

1198426
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ds^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_ds
111
2860

A_dsT_dsG_ksG_esT_ksT_esT_k

1198427
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_dsA_ds^mC_dsT_ds^mC_dsT_dsT_dsA_ds
62
2861

T_dsA_dsT_ksG_esG_ksT_esT_k

1198428
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ds^mC_dsA_dsA_ds^mC_dsT_ds^mC_dsT_ds
62
2862

T_dsA_dsT_ksA_esT_ksG_esG_k

1198438
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_dsT_dsA_dsT_dsG_dsT_ds^mC_dsA_dsG_ds
7
2863

A_dsA_ksG_esA_ksG_esT_k

1198439
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_dsT_dsG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
6
2864

A_dsG_ksA_esA_ksG_esA_k

1198440
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_dsG_dsT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
5
2865

C_dsA_ksG_esA_ksA_esG_k

1198441
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_dsA_dsG_dsT_dsG_dsT_dsA_dsT_dsG_ds
19
2866

T_ds^mC_ksA_esG_ksA_esA_k

1198442
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_dsA_dsA_dsG_dsT_dsG_dsT_dsA_dsT_ds
44
2867

G_dsT_ks^mC_esA_ksG_esA_k

1198443
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_dsA_dsA_dsA_dsG_dsT_dsG_dsT_dsA_ds
39
2868

T_dsG_ksT_es^mC_ksA_esG_k

1198444
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_dsT_dsA_dsA_dsA_dsG_dsT_dsG_dsT_ds
70
2869

A_dsT_ksG_esT_ks^mC_esA_k

1198445
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_dsT_dsT_dsA_dsA_dsA_dsG_dsT_dsG_ds
61
1634

T_dsA_ksT_esG_ksT_es^mC_k

1198446
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ds^mC_dsT_dsT_dsT_dsA_dsA_dsA_dsG_ds
83
2870

T_dsG_ksT_esA_ksT_esG_k

1198714
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_esT_ks^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
20
2803

C_ds^mC_dsT_dsT_esA_esT_ksA_k

1198715
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_esT_ksG_dsT_ds^mC_dsT_ds^mC_dsA_ds
33
2804

T_dsG_ds^mC_ds^mC_esT_esT_ksA_k

1198716
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_esT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_ds
27
2805

A_dsT_dsG_ds^mC_es^mC_esT_ksT_k

1198717
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_esA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^m
41
443

C_dsA_dsT_dsG_es^mC_es^mC_ksT_k

1198718
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_esA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
9
2800

C_dsA_dsT_esG_es^mC_ks^mC_k

1198719
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_esA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
14
2806

T_ds^mC_dsA_esT_esG_ks^mC_k

1198720
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_esG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
21
2807

C_dsT_ds^mC_esA_esT_ksG_k

1198721
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_esG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_ds
48
2808

T_ds^mC_dsT_es^mC_esA_ksT_k

1198722
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_esA_ksT_dsG_dsG_dsA_dsA_dsA_dsT_ds
48
656

T_dsG_dsT_es^mC_esT_ks^mC_k

1198723
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_esT_ksA_dsT_dsG_dsT_dsG_dsG_ds^mC_ds
57
2809

A_dsA_dsT_esA_esA_ksT_k

1198724
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_esA_ksG_dsT_dsA_dsT_dsG_dsT_dsG_ds
16
2810

G_ds^mC_dsA_esA_esT_ksA_k

1198725
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_esG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_ds
23
2811

G_dsG_ds^mC_esA_esA_ksT_k

1198726
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_esA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_ds
28
963

T_dsG_dsG_es^mC_esA_ksA_k

1198727
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_esT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
19
810

G_dsT_dsG_esG_es^mC_ksA_k

1198728
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_esT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_ds
17
2812

T_dsG_dsT_esG_esG_ks^mC_k

1198729
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_esA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_ds
21
2813

A_dsT_dsG_esT_esG_ksG_k

1198730
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_esT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_ds
57
2814

T_dsA_dsT_esG_esT_ksG_k

1198731
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_esT_ksA_dsT_dsA_dsT_dsT_dsA_dsG_ds
59
887

A_dsG_dsT_esA_esT_ksG_k

1198732
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_esT_ksA_dsA_ds^mC_dsT_dsG_dsG_dsG_ds^m
86
2815

C_dsA_dsA_esA_esT_ksT_k

1198741
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_esA_ks^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
60
2817

A_dsA_ds^mC_esA_esA_ksG_k

1198742
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_esT_ksT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
143
2818

G_dsG_dsA_esA_es^mC_ksA_k

1198743
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_esT_ksT_dsT_dsA_ds^mC_dsA_dsT_ds
86
1124

T_dsA_dsG_dsG_esA_esA_ks^mC_k

1198744
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_esT_ksT_dsT_dsT_dsA_ds^mC_dsA_ds
66
2819

T_dsT_dsA_dsG_esG_esA_ksA_k

1198745
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_es^mC_ksT_dsT_dsT_dsT_dsA_ds^mC_ds
57
1200

A_dsT_dsT_dsA_esG_esG_ksA_k

1198746
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_esA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^m
7
1276

^mC_dsA_dsT_dsT_esA_esG_ksG_k

1198747
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_es^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_ds
38
2820

A_ds^mC_dsA_dsT_esT_esA_ksG_k

1198748
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_esG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_ds
81
2821

T_dsA_ds^mC_dsA_esT_esT_ksA_k

1198749
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_esA_ksA_dsG_ds^mC_dsA_ds^mC_dsT_ds
73
2822

T_dsT_dsT_dsA_es^mC_esA_ksT_k

1198750
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_esA_ksA_dsG_dsA_dsT_ds^mC_dsT_ds
32
2823

G_dsA_dsA_dsA_es^mC_esT_ks^mC_k

1198751
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_esG_ksG_dsA_dsA_dsG_dsA_dsT_ds^mC_ds
76
2824

T_dsG_dsA_esA_esA_ks^mC_k

1198752
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_esT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
111
2825

C_dsT_dsG_esA_esA_ksA_k

1198753
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_esT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_ds
58
2826

T_ds^mC_dsT_esG_esA_ksA_k

1198754
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_esT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
23
2044

A_dsT_ds^mC_esT_esG_ksA_k

1198755
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_es^mC_ksT_dsT_dsG_dsG_dsA_dsA_ds
32
2121

G_dsA_dsT_es^mC_esT_ksG_k

1198756
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_esG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
50
2827

A_dsG_dsA_esT_es^mC_ksT_k

1198757
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_esT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
4
2828

A_dsA_dsG_esA_esT_ks^mC_k

1198758
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_esA_ksG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
47
2829

G_dsG_dsA_esA_esG_ksA_k

1198759
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_esG_ksA_dsT_dsG_ds^mC_dsA_dsT_ds
27
2830

G_dsG_dsT_dsT_esT_esT_ksT_k

1198760
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_esA_ksG_dsG_dsA_dsT_dsG_ds^mC_dsA_ds
91
2831

T_dsG_dsG_esT_esT_ksT_k

1198761
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_esT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
42
2832

A_dsT_dsG_esG_esT_ksT_k

1198762
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_esT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m30
2833

C_dsA_dsT_esG_esG_ksT_k

1198763
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_esT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_ds
26
2834

G_ds^mC_dsA_esT_esG_ksG_k

1198764
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_esA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_ds
28
2835

T_dsG_ds^mC_esA_esT_ksG_k

1198765
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_esA_ksA_dsT_dsT_dsT_dsA_dsG_dsG_ds
23
2836

A_dsT_dsG_es^mC_esA_ksT_k

1198766
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_esA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
19
2837

G_dsA_dsT_esG_es^mC_ksA_k

1198767
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_esT_ks^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
65
2838

A_dsG_dsG_esA_esT_ksG_k

1198777
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_esT_ksG_ds^mC_dsA_dsA_dsT_ds^mC_ds
84
2843

T_dsG_dsT_ds^mC_esT_esG_ksA_k

1198778
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_esA_ksT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^m
55
2844

C_dsT_dsG_esT_es^mC_ksT_k

1198779
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_esT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
49
2845

T_ds^mC_dsT_esG_esT_ks^mC_k

1198780
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_esA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
80
2846

A_dsT_ds^mC_esT_esG_ksT_k

1198781
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_esA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
25
1404

A_dsA_dsT_es^mC_esT_ksG_k

1198782
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_esT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
61
2847

C_dsA_dsA_esT_es^mC_ksT_k

1198783
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_esG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_ds
78
2848

G_ds^mC_dsA_esA_esT_ks^mC_k

1198784
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_esT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_ds
94
2849

T_dsG_ds^mC_esA_esA_ksT_k

1198785
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_esT_ksA_dsT_dsG_dsT_dsA_dsA_dsT_ds
86
2850

A_dsT_dsT_esG_es^mC_ksA_k

1198795
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_esA_ksG_dsG_dsT_dsT_dsT_ds^mC_ds^m
43
2851

C_ds^mC_dsA_dsG_esA_esT_ksT_k

1198796
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_esT_ksA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
32
2852

C_ds^mC_ds^mC_esA_esG_ksA_k

1198797
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_esG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_ds
31
2853

T_ds^mC_ds^mC_es^mC_esA_ksG_k

1198798
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_esA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_ds
38
2854

T_dsT_ds^mC_es^mC_es^mC_ksA_k

1198799
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_esA_ksA_dsG_dsT_dsA_dsA_dsG_ds
18
1101

G_dsT_dsT_dsT_es^mC_es^mC_ks^mC_k

1198800
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_esT_ksA_dsA_dsG_dsT_dsA_dsA_ds
47
2855

G_dsG_dsT_dsT_esT_es^mC_ks^mC_k

1198801
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_es^mC_ksT_dsA_dsA_dsG_dsT_dsA_ds
47
2856

A_dsG_dsG_dsT_esT_esT_ks^mC_k

1198802
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_esA_ks^mC_dsT_dsA_dsA_dsG_dsT_ds
83
2857

A_dsA_dsG_dsG_esT_esT_ksT_k

1198803
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_esA_ksG_dsA_ds^mC_dsT_dsA_dsA_dsG_ds
62
2858

T_dsA_dsA_esG_esG_ksT_k

TABLE 41

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
28
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
14
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
12
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1198628
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG
27
2803

C_ds^mC_dsT_dsT_ksA_esT_ksA_e

1198629
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_dsA_ds
22
2804

T_dsG_ds^mC_ds^mC_ksT_esT_ksA_e

1198630
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^mC_ds
37
2805

A_dsT_dsG_ds^mC_ks^mC_esT_ksT_e

1198631
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
53
443

C_dsA_dsT_dsG_ks^mC_es^mC_ksT_e

1198632
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
21
2800

C_dsA_dsT_ksG_es^mC_ks^mC_e

1198633
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
46
2806

C_dsT_ds^mC_dsA_ksT_esG_ks^mC_e

1198634
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
34
2807

C_dsT_ds^mC_ksA_esT_ksG_e

1198635
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_ds
57
2808

T_ds^mC_dsT_ks^mC_esA_ksT_e

1198636
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_dsT_dsG_dsG_dsA_dsA_dsA_dsT_ds
41
656

T_dsG_dsT_ks^mC_esT_ks^mC_e

1198637
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_dsA_dsT_dsG_dsT_dsG_dsG_ds^m
64
2809

C_dsA_dsA_dsT_ksA_esA_ksT_e

1198638
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_dsG_ds
18
2810

G_ds^mC_dsA_ksA_esT_ksA_e

1198639
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_dsT_ds
32
2811

G_dsG_ds^mC_ksA_esA_ksT_e

1198640
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_dsG_ds
26
963

T_dsG_dsG_ks^mC_esA_ksA_e

1198641
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_dsT_ds
15
810

G_dsT_dsG_ksG_es^mC_ksA_e

1198642
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_dsA_ds
19
2812

T_dsG_dsT_ksG_esG_ks^mC_e

1198643
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_dsT_ds
25
2813

A_dsT_dsG_ksT_esG_ksG_e

1198644
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_dsA_dsT_dsT_dsA_dsG_dsA_dsG_ds
73
2814

T_dsA_dsT_ksG_esT_ksG_e

1198645
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_dsA_dsT_dsA_dsT_dsT_dsA_dsG_ds
73
887

A_dsG_dsT_ksA_esT_ksG_e

1198651
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ds^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
94
2817

A_dsA_ds^mC_ksA_esA_ksG_e

1198652
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
68
2818

G_dsG_dsA_ksA_es^mC_ksA_e

1198653
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_dsT_dsT_dsA_ds^mC_dsA_dsT_ds
64
1124

T_dsA_dsG_dsG_ksA_esA_ks^mC_e

1198654
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_ksT_dsT_dsT_dsT_dsA_ds^mC_dsA_ds
91
2819

T_dsT_dsA_dsG_ksG_esA_ksA_e

1198655
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_ds
30
1200

A_dsT_dsT_dsA_ksG_esG_ksA_e

1198656
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_dsA_ds^m
11
1276

C_dsA_dsT_dsT_ksA_esG_ksG_e

1198657
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_dsT_ds
95
2820

A_ds^mC_dsA_dsT_ksT_esA_ksG_e

1198658
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ds^mC_dsA_ds^mC_dsT_dsT_dsT_ds
62
2821

T_dsA_ds^mC_dsA_ksT_esT_ksA_e

1198659
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_dsA_dsG_ds^mC_dsA_ds^mC_dsT_ds
58
2822

T_dsT_dsT_dsA_ks^mC_esA_ksT_e

1198660
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_dsA_dsG_dsA_dsT_ds^mC_dsT_ds
66
2823

G_dsA_dsA_dsA_ks^mC_esT_ks^mC_e

1198661
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
111
2824

C_dsT_dsG_dsA_ksA_esA_ks^mC_e

1198662
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
83
2825

C_dsT_dsG_ksA_esA_ksA_e

1198663
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
76
2826

A_dsT_ds^mC_dsT_ksG_esA_ksA_e

1198664
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
18
2044

G_dsA_dsT_ds^mC_ksT_esG_ksA_e

1198665
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_dsA_ds
38
2121

G_dsA_dsT_ks^mC_esT_ksG_e

1198666
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_d sG_dsA_ds
44
2827

A_dsG_dsA_ksT_es^mC_ksT_e

1198667
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_dsG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
40
2828

A_dsA_dsG_ksA_esT_ks^mC_e

1198668
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_dsG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
72
2829

G_dsG_dsA_ksA_esG_ksA_e

1198669
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_dsA_dsT_dsG_ds^mC_dsA_dsT_ds
61
2830

G_dsG_dsT_dsT_ksT_esT_ksT_e

1198670
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
55
2831

A_dsT_dsG_dsG_ksT_esT_ksT_e

1198671
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
26
2832

A_dsT_dsG_ksG_esT_ksT_e

1198672
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
41
2833

C_dsA_dsT_ksG_esG_ksT_e

1198673
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_dsT_ds
10
2834

G_ds^mC_dsA_ksT_esG_ksG_e

1198674
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_dsA_ds
21
2835

T_dsG_ds^mC_ksA_esT_ksG_e

1198675
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
35
2836

G_dsA_dsT_dsG_ks^mC_esA_ksT_e

1198676
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_dsG_dsA_dsT_dsT_dsT_dsA_dsG_ds
52
2837

G_dsA_dsT_ksG_es^mC_ksA_e

1198677
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ds^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
87
2838

A_dsG_dsG_ksA_esT_ksG_e

1198687
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_dsG_ds^mC_dsA_dsA_dsT_ds^mC_ds
55
2843

T_dsG_dsT_ds^mC_ksT_esG_ksA_e

1198688
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^m
48
2844

C_dsT_dsG_ksT_es^mC_ksT_e

1198689
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
91
2845

A_dsT_ds^mC_dsT_ksG_esT_ks^mC_e

1198690
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
64
2846

A_dsT_ds^mC_ksT_esG_ksT_e

1198691
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
38
1404

A_dsA_dsT_ks^mC_esT_ksG_e

1198692
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
120
2847

C_dsA_dsA_ksT_es^mC_ksT_e

1198733
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_esT_ksA_dsT_dsA_dsA_ds^mC_dsT_dsG_ds
47
1427

G_dsG_ds^mC_esA_esA_ksA_k

1198734
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_esG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
29
905

G_dsG_dsG_es^mC_esA_ksA_k

1198735
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_esG_ksG_dsT_dsA_dsT_dsA_dsA_ds^m
34
1503

C_dsT_dsG_dsG_esG_es^mC_ksA_k

1198736
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_esA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
20
1580

C_dsT_dsG_esG_esG_ks^mC_k

1198737
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_esG_ksA_dsG_dsG_dsT_dsA_dsT_ds
24
2801

A_dsA_ds^mC_dsT_esG_esG_ksG_k

1198738
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_esT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
38
392

A_dsA_ds^mC_esT_esG_ksG_k

1198739
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_es^mC_ksT_dsG_dsA_dsG_dsG_dsT_ds
94
2802

A_dsT_dsA_dsA_es^mC_esT_ksG_k

1198740
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksAmC_ksA_ds^mC_dsT_dsG_dsA_dsG_ds
39
2816

G_dsT_dsA_dsT_esA_esA_ks^mC_k

1198768
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_esA_ksT_dsG_dsG_dsT_dsT_dsT_dsT_ds
61
2839

G_dsT_dsG_esT_esG_ksT_k

1198769
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_esA_ksT_dsA_dsT_dsG_dsG_dsT_dsT_ds
77
2840

T_dsT_dsG_esT_esG_ksT_k

1198770
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_esT_ksA_dsT_dsA_dsT_dsG_dsG_ds
40
2788

T_dsT_dsT_dsT_esG_esT_ksG_k

1198771
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_esT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_ds
85
2841

T_dsT_dsT_esT_esG_ksT_k

1198772
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_es^mC_ksT_dsT_dsA_dsT_dsA_dsT_ds
41
2842

G_dsG_dsT_dsT_esT_esT_ksG_k

1198773
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_esT_ks^mC_dsT_dsT_dsA_dsT_dsA_ds
58
2859

T_dsG_dsG_dsT_esT_esT_ksT_k

1198774
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_es^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_ds
106
2860

A_dsT_dsG_dsG_esT_esT_ksT_k

1198775
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_esA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_ds
113
2861

T_dsA_dsT_dsG_esG_esT_ksT_k

1198776
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_es^m+lC_ksA_dsA_ds^mC_dsT_ds^mC_dsT_ds
57
2862

T_dsA_dsT_dsA_esT_esG_ksG_k

1198786
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_esT_ksA_dsT_dsG_dsT_dshu mC_dsA_dsG_ds
16
2863

A_dsA_dsG_esA_esG_ksT_k

1198787
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_esT_ksG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
9
2864

A_dsG_dsA_esA_esG_ksA_k

1198788
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_esG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
17
2865

C_dsA_dsG_esA_esA_ksG_k

1198789
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_esA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_ds
22
2866

T_ds^mC_dsA_esG_esA_ksA_k

1198790
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_esA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_ds
27
2867

G_dsT_ds^mC_esA_esG_ksA_k

1198791
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksA T_esA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_ds
39
2868

T_dsG_dsT_es^mC_esA_ksG_k

1198792
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_esT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_ds
48
2869

A_dsT_dsG_esT_es^mC_ksA_k

1198793
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_esT_ksT_dsA_dsA_dsA_dsG_dsT_ds
34
1634

G_dsT_dsA_dsT_esG_esT_ks^mC_k

1198794
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_es^mC_ksT_dsT_dsT_dsA_dsA_dsA_dsG_ds
74
2870

T_dsG_dsT_esA_esT_ksG_k

TABLE 42

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
29
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
15
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
11
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1095463
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_dsA_ds
37
392

T_dsA_dsA_ds^mC_ksT_esG_ksG_e

1095481
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
21
1580

C_dsT_dsG_ksG_esG_ks^mC_e

1095482
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
72
2801

A_dsA_ds^mC_dsT_ksG_esG_ksG_e

1095483
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_dsT_dsG_dsA_dsG_dsG_dsT_ds
101
2802

A_dsT_dsA_dsA_ks^mC_esT_ksG_e

1198198
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ds^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
29
2803

C_ds^mC_dsT_esT_esA_esT_ksA_k

1198199
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_dsA_ds
38
2804

T_dsG_ds^mC_es^mC_esT_esT_ksA_k

1198200
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^mC_ds
49
2805

A_dsT_dsG_es^mC_es^mC_esT_ksT_k

1198201
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
34
443

C_dsA_dsT_esG_es^mC_es^mC_ksT_k

1198202
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
14
2800

C_dsA_esT_esG_es^mC_ks^mC_k

1198203
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
19
2806

C_dsT_ds^mC_esA_esT_esG_ks^mC_k

1198204
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
31
2807

C_dsT_es^mC_esA_esT_ksG_k

1198205
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_ds
64
2808

T_ds^mC_esT_es^mC_esA_ksT_k

1198206
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_dsT_dsG_dsG_dsA_dsA_dsA_dsT_ds
43
656

T_dsG_esT_es^mC_esT_ks^mC_k

1198207
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_dsA_dsT_dsG_dsT_dsG_dsG_ds^m
91
2809

C_dsA_dsA_esT_esA_esA_ksT_k

1198208
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_dsG_ds
25
2810

G_ds^mC_esA_esA_esT_ksA_k

1198209
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_dsT_ds
45
2811

G_dsG_es^mC_esA_esA_ksT_k

1198210
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_dsG_ds
28
963

T_dsG_esG_es^mC_esA_ksA_k

1198211
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_dsT_ds
19
810

G_dsT_esG_esG_es^mC_ksA_k

1198212
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_dsA_ds
17
2812

T_dsG_esT_esG_esG_ks^mC_k

1198213
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_dsT_ds
16
2813

A_dsT_esG_esT_esG_ksG_k

1198214
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_dsA_dsT_dsT_dsA_dsG_dsA_dsG_ds
91
2814

T_dsA_esT_esG_esT_ksG_k

1198215
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_dsA_dsT_dsA_dsT_dsT_dsA_dsG_ds
120
887

A_dsG_esT_esA_esT_ksG_k

1198221
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ds^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
95
2817

A_dsA_es^mC_esA_esA_ksG_k

1198222
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
87
2818

G_dsG_esA_esA_es^mC_ksA_k

1198223
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_dsT_dsT_dsA_ds^mC_dsA_dsT_ds
94
1124

T_dsA_dsG_esG_esA_esA_ks^mC_k

1198224
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_ksT_dsT_dsT_dsT_dsA_ds^mC_dsA_ds
74
2819

T_dsT_dsA_esG_esG_esA_ksA_k

1198225
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_ds
67
1200

A_dsT_dsT_esA_esG_esG_ksA_k

1198226
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_dsA_ds^m
23
1276

C_dsA_dsT_esT_esA_esG_ksG_k

1198227
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_dsT_ds
104
2820

A_ds^mC_dsA_esT_esT_esA_ksG_k

1198228
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ds^mC_dsA_ds^mC_dsT_dsT_dsT_ds
54
2821

T_dsA_ds^mC_esA_esT_esT_ksA_k

1198229
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_dsA_dsG_ds^mC_dsA_ds^mC_dsT_ds
80
2822

T_dsT_dsT_esA_es^mC_esA_ksT_k

1198230
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_dsA_dsG_dsA_dsT_ds^mC_dsT_ds
81
2823

G_dsA_dsA_esA_es^mC_esT_ks^mC_k

1198231
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
73
2824

C_dsT_dsG_esA_esA_esA_ks^mC_k

1198232
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
92
2825

C_dsT_esG_esA_esA_ksA_k

1198233
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
49
2826

A_dsT_ds^mC_esT_esG_esA_ksA_k

1198234
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
45
2044

G_dsA_dsT_es^mC_esT_esG_ksA_k

1198235
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_dsA_ds
49
2121

G_dsA_esT_es^mC_esT_ksG_k

1198236
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
24
2827

A_dsG_esA_esT_es^mC_ksT_k

1198237
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_dsG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
51
2828

G_dsA_dsA_esG_esT_ks^mC_k

1198238
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_dsG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
88
2829

G_dsG_esA_esA_esG_ksA_k

1198239
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_dsA_dsT_dsG_ds^mC_dsA_dsT_ds
39
2830

G_dsG_dsT_esT_esT_esT_ksT_k

1198240
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
43
2831

A_dsT_dsG_esG_esT_esT_ksT_k

1198646
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_dsA_dsA_ds^mC_dsT_dsG_dsG_ds
80
2815

G_ds^mC_dsA_dsA_ksA_esT_ksT_e

1198647
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
47
1427

G_dsG_dsG_ds^mC_ksA_esA_ksA_e

1198648
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
43
905

T_dsG_dsG_dsG_ks^mC_esA_ksA_e

1198649
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
27
1503

C_dsT_dsG_dsG_ksG_es^mC_ksA_e

1198650
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_dsA_ds^mC_dsT_dsG_dsA_dsG_ds
88
2816

G_dsT_dsA_dsT_Tks+lAesA_ks^mC_e

1198678
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_dsT_dsG_dsG_dsT_dsT_dsT_dsT_ds
58
2839

G_dsT_dsG_ksT_esG_ksT_e

1198679
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_dsT_dsG_dsT_dsG_dsG_dsT_dsT_ds
54
2840

T_dsT_dsG_ksT_esG_ksT_e

1198680
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_dsT_ds
28
2788

T_dsT_dsT_ksG_esT_ksG_e

1198681
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ksC_ksT_dsT_dsA_dsT_dsA_dsT_dsG_dsG_ds
54
2841

T_dsT_dsT_ksT_esG_ksT_e

1198682
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_dsT_ds
25
2842

G_dsG_dsT_dsT_ksT_esT_ksG_e

1198683
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_dsA_ds
27
2859

T_dsG_dsG_dsT_ksT_esT_ksT_e

1198684
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_ds
75
2860

A_dsT_dsG_dsG_ksT_esT_ksT_e

1198685
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ds^mC_dsT_ds^mC_dsT_dsT_dsA_ds
70
2861

T_dsA_dsT_dsG_ksG_esT_ksT_e

1198686
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_dsA_dsA_ds^mC_dsT_ds^mC_dsT_ds
78
2862

T_dsA_dsT_dsA_ksT_esG_ksG_e

1198693
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_dsT_ds
92
2848

G_ds^mC_dsA_ksA_esT_ks^mC_e

1198694
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_dsG_dsT_dsA_dsA_dsT_dsA_dsT_ds
110
2849

T_dsG_ds^mC_ksA_esA_ksT_e

1198695
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_dsA_dsT_dsG_dsT_dsA_dsA_dsT_ds
75
2850

A_dsT_dsT_ksG_es^mC_ksA_e

1198696
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_dsA_dsT_dsG_dsT_ds^mC_dsA_dsG_ds
12
2863

A_dsA_dsG_ksA_esG_ksT_e

1198697
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
12
2864

A_dsG_dsA_ksA_esG_ksA_e

1198698
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
12
2865

C_dsA_dsG_ksA_esA_ksG_e

1198699
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_dsG_ds
30
2866

T_ds^mC_dsA_ksG_esA_ksA_e

1198700
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_dsT_ds
26
2867

G_dsT_ds^mC_ksA_esG_ksA_e

1198701
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_dsA_ds
46
2868

T_dsG_dsT_ks^mC_esA_ksG_e

1198702
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_dsT_ds
74
2869

A_dsT_dsG_ksT_es^mC_ksA_e

1198703
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_dsT_dsA_dsA_dsA_dsG_dsT_dsG_ds
42
1634

T_dsA_dsT_ksG_esT_ks^mC_e

1198704
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_dsT_dsT_dsT_dsA_dsA_dsA_ds
72
2870

G_dsT_dsG_dsT_ksA_esT_ksG_e

1198705
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_dsG_dsG_dsT_dsT_dsT_ds^mC_ds^m
70
2851

C_ds^mC_dsA_dsG_ksA_esT_ksT_e

1198706
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
39
2852

C_ds^mC_ds^mC_ksA_esG_ksA_e

1198707
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_dsT_ds
31
2853

T_ds^mC_ds^mC_ks^mC_esA_ksG_e

1198708
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_dsT_ds
34
2854

T_dsT_ds^mC_ks^mC_es^mC_ksA_e

1198709
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_ds
29
1101

G_dsT_dsT_dsT_ks^mC_es^mC_ks^mC_e

1198710
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_ds
51
2855

G_dsG_dsT_dsT_ksT_es^mC_ks^mC_e

1198711
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
60
2856

A_dsG_dsG_dsT_ksT_esT_ks^mC_e

1198712
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ds^mC_dsT_dsA_dsA_dsG_dsT_ds
110
2857

A_dsA_dsG_dsG_ksT_esT_ksT_e

1198713
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_dsG_dsA_ds^mC_dsT_dsA_dsA_ds
62
2858

G_dsT_dsA_dsA_ksG_esG_ksT_e

TABLE 43

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
25
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
14
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_ds
11
2800

T_ds^mC_dsA_dsT_dsG_ks^mC_ks^mC_k

1095575
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_dsA_ds
55
392

T_dsA_dsA_es^mC_esT_esG_ksG_k

1095593
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
16
1580

C_dsT_esG_esG_esG_ks^mC_k

1095594
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
27
2801

A_dsA_ds^mC_esT_esG_esG_ksG_k

1095595
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_dsT_dsG_dsA_dsG_dsG_dsT_ds
63
2802

A_dsT_dsA_esA_es^mC_esT_ksG_k

1198216
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_dsA_dsA_ds^mC_dsT_dsG_dsG_ds
89
2815

G_ds^mC_dsA_esA_esA_esT_ksT_k

1198217
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
57
1427

G_dsG_dsG_es^mC_esA_esA_ksA_k

1198218
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
40
905

T_dsG_dsG_esG_es^mC_esA_ksA_k

1198219
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
22
1503

C_dsT_dsG_esG_esG_es^mC_ksA_k

1198220
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_dsA_ds^mC_dsT_dsG_dsA_dsG_ds
89
2816

G_dsT_dsA_esT_esA_esA_ks^mC_k

1198241
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
32
2832

C_dsA_dsT_esG_esG_esT_ksT_k

1198242
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
47
2833

C_dsA_esT_esG_esG_ksT_k

1198243
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_dsT_ds
8
2834

G_ds^mC_esA_esT_esG_ksG_k

1198244
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_dsA_ds
24
2835

T_dsG_es^mC_esA_esT_ksG_k

1198245
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
46
2836

G_dsA_dsT_esG_es^mC_esA_ksT_k

1198246
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_dsG_dsA_dsT_dsT_dsT_dsA_ds
30
2837

G_dsG_dsA_esT_esG_es^mC_ksA_k

1198247
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ds^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
99
2838

A_dsG_esG_esA_esT_ksG_k

1198248
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_dsT_dsG_dsG_dsT_dsT_dsT_dsT_ds
64
2839

G_dsT_esG_esT_esG_ksT_k

1198249
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_dsT_ds
42
2840

T_dsT_esG_esT_esG_ksT_k

1198250
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_dsT_ds
50
2788

T_dsT_esT_esG_esT_ksG_k

1198251
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_dsT_dsA_dsT_dsA_dsT_dsG_dsG_ds
83
2841

T_dsT_esT_esT_esG_ksT_k

1198252
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_dsT_ds
26
2842

G_dsG_dsT_esT_esT_esT_ksG_k

1198253
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_dsA_ds
50
2859

T_dsG_dsG_esT_esT_esT_ksT_k

119825 4
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_ds
95
2860

A_dsT_dsG_esG_esT_esT_ksT_k

1198255
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ds^mC_dsT_ds^mC_dsT_dsT_dsA_ds
84
2861

T_dsA_dsT_esG_esG_esT_ksT_k

1198256
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_dsA_dsA_ds^mC_dsT_ds^mC_dsT_ds
78
2862

T_dsA_dsT_esA_esT_esG_ksG_k

1198257
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^mC_ds
85
2843

T_dsG_dsT_es^mC_esT_esG_ksA_k

1198258
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
52
2844

T_ds^mC_dsT_esG_esT_es^mC_ksT_k

1198259
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
51
2845

A_dsT_ds^mC_esT_esG_esT_ks^mC_k

1198260
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
106
2846

A_dsA_dsT_es^mC_esT_esG_ksT_k

1198261
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
54
1404

C_dsA_dsA_esT_es^mC_esT_ksG_k

1198262
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
114
2847

C_dsA_esA_esT_es^mC_ksT_k

1198263
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_dsT_ds
114
2848

G_ds^mC_esA_esA_esT_ks^mC_k

1198264
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_dsG_dsT_dsA_dsA_dsT_dsA_dsT_ds
73
2849

T_dsG_es^mC_esA_esA_ksT_k

1198265
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_dsA_dsT_dsG_dsT_dsA_dsA_dsT_ds
111
2850

A_dsT_esT_esG_es^mC_ksA_k

1198266
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_dsA_dsT_dsG_dsT_ds^mC_dsA_ds
25
2863

G_dsA_dsA_esG_esA_esG_ksT_k

1198267
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
7
2864

C_dsA_dsG_esA_esA_esG_ksA_k

1198268
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
11
2865

C_dsA_esG_esA_esA_ksG_k

1198269
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_dsG_ds
58
2866

T_ds^mC_esA_esG_esA_ksA_k

1198270
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_dsT_ds
52
2867

G_dsT_es^mC_esA_esG_ksA_k

1198271
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_dsA_ds
44
2868

T_dsG_esT_es^mCesA_ksG_k

1198272
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_dsT_ds
37
2869

A_dsT_esG_esT_es^mC_ksA_k

1198273
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_dsT_dsA_dsA_dsA_dsG_dsT_ds
52
1634

G_dsT_dsA_esT_esG_esT_ks^mC_k

1198274
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_dsT_dsT_dsT_dsA_dsA_dsA_ds
69
2870

G_dsT_dsG_esT_esA_esT_ksG_k

1198275
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_dsG_dsG_dsT_dsT_dsT_ds^mC_ds^m
52
2851

C_ds^mC_dsA_esG_esA_esT_ksT_k

1198276
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
52
2852

C_ds^mC_es^mC_esA_esG_ksA_k

1198277
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_dsT_ds
32
2853

T_ds^mC_es^mC_es^mC_esA_ksG_k

1198278
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_dsT_ds
43
2854

T_dsT_es^mC_es^mC_es^mC_ksA_k

1198279
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_ds
43
1101

G_dsT_dsT_esT_es^mC_es^mC_ks^mC_k

1198280
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_ds
40
2855

G_dsG_dsT_esT_esT_es^mC_ks^mC_k

1198281
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
71
2856

A_dsG_dsG_esT_esT_esT_ks^mC_k

1198282
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ds^mC_dsT_dsA_dsA_dsG_dsT_ds
58
2857

A_dsA_dsG_esG_esT_esT_ksT_k

1198283
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_dsG_dsA_ds^mC_dsT_dsA_dsA_ds
99
2858

G_dsT_dsA_esA_esG_esG_ksT_k

1198456
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ds^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
21
2803

C_ds^mC_dsT_esT_ksA_esT_ksA_e

1198457
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_dsA_ds
18
2804

T_dsG_ds^mC_es^mC_ksT_esT_ksA_e

1198458
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^mC_ds
30
2805

A_dsT_dsG_es^mC_ks^mC_esT_ksT_e

1198459
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
28
443

C_dsA_dsT_esG_ks^mC_es^mC_ksT_e

1198460
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
17
2800

T_ds^mC_dsA_esT_ksG_es^mC_ks^mC_e

1198461
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
24
2806

C_dsT_ds^mC_esA_ksT_esG_ks^mC_e

1198462
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
27
2807

C_dsT_es^mC_ksA_esT_ksG_e

1198463
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_ds
59
2808

T_ds^mC_esT_ks^mC_esA_ksT_e

1198464
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_dsT_dsG_dsG_dsA_dsA_dsA_dsT_ds
41
656

T_dsG_esT_ks^mC_esT_ks^mC_e

1198465
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_dsA_dsT_dsG_dsT_dsG_dsG_ds^m
68
2809

C_dsA_dsA_esT_ksA_esA_ksT_e

1198466
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_dsG_ds
12
2810

G_ds^mC_esA_ksA_esT_ksA_e

1198467
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_dsT_ds
27
2811

G_dsG_es^mC_ksA_esA_ksT_e

1198468
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_dsG_ds
22
963

T_dsG_esG_ks^mC_esAlcsA_e

1198469
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_dsT_ds
23
810

G_dsT_esG_ksG_es^mC_ksA_e

1198470
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_dsA_ds
17
2812

T_dsG_esT_ksG_esG_ks^mC_e

1198471
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_dsT_ds
21
2813

A_dsT_esG_ksT_esG_ksG_e

1198472
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_dsA_dsT_dsT_dsA_dsG_dsA_dsG_ds
60
2814

T_dsA_esT_ksG_esT_ksG_e

1198473
2570
2585
123595
123610
TCTATATTAGAGTATG
T_kshu mC_ksT_dsA_dsT_dsA_dsT_dsT_dsA_dsG_ds
66
887

A_dsG_esT_ksA_esT_ksG_e

1198479
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ds^mC_dsA_dsT_dsT_dsA_dsG_ds
65
2817

G_dsA_dsA_es^mC_ksA_esA_ksG_e

1198480
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
75
2818

G_dsG_esA_ksA_es^mC_ksA_e

1198481
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_ds
72
1124

T_dsA_dsG_esG_ksA_esA_ks^mC_e

1198482
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mX_ksT_dsT_dsT_dsA_ds^mC_dsA_ds
63
2819

T_dsT_dsA_esG_ksG_esA_ksA_e

1198483
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_ds
31
1200

A_dsT_dsT_esA_ksG_esG_ksA_e

1198484
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_dsA_ds^m
18
1276

C_dsA_dsT_esT_ksA_esG_ksG_e

1198485
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_dsT_ds
64
2820

A_ds^mC_dsA_esT_ksT_esA_ksG_e

TABLE 44

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_ds
18
52

A_dsT_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_ds
9
810

T_dsG_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_ds
7
2800

T_ds^mC_dsA_dsT_dsG_ks^mC_ks^mC_k

1095603
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_ds
29
2872

A_dsT_dsA_dsA_es^mC_ksT_esG_ksG_e

1095621
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_ds
22
1580

A_ds^mC_dsT_esG_ksG_esG_ks^mC_e

1095622
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
44
2801

A_dsA_ds^mC_esT_ksG_esG_ksG_e

1095623
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_dsT_dsG_dsA_dsG_dsG_ds
57
2802

T_dsA_dsT_dsA_esA_ks^mC_esT_ksG_e

1198474
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_dsA_dsA_ds^mC_dsT_dsG_dsG_ds
68
2815

G_ds^mC_dsA_esA_ksA_esT_ksT_e

1198475
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
25
1427

G_dsG_dsG_es^mC_ksA_esA_ksA_e

1198476
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^m
31
905

C_dsT_dsG_dsG_esG_ks^mC_esA_ksA_e

1198477
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
47
1503

C_dsT_dsG_esG_ksG_es^mC_ksA_e

1198478
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_dsA_ds^mC_dsT_dsG_dsA_ds
60
2816

G_dsG_dsT_dsA_esT_ksA_esA_ks^mC_e

1198486
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ds^mC_dsA_ds^mC_dsT_dsT_ds
39
2821

T_dsT_dsA_ds^mC_esA_ksT_esT_ksA_e

1198487
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_dsA_dsG_ds^mC_dsA_ds^mC_ds
62
2822

T_dsT_dsT_dsT_esA_ks^mC_esA_ksT_e

1198488
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_dsA_dsG_dsA_dsT_ds^mC_ds
66
2823

T_dsG_dsA_dsA_esA_ks^mC_esT_ks^mC_e

1198489
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
50
2824

C_dsT_dsG_esA_ksA_esA_ks^mC_e

1198490
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_ds
53
2825

T_ds^mC_dsT_esG_ksA_esA_ksA_e

1198491
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
22
2826

A_dsT_ds^mC_esT_ksG_esA_ksA_e

1198492
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
15
2044

G_dsA_dsT_es^mC_ksT_esG_ksA_e

1198493
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
28
2121

A_dsG_dsA_esT_ks^mC_esT_ksG_e

1198494
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
15
2827

A_dsA_dsG_esA_ksT_es^mC_ksT_e

1198495
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_dsG_ds^mC_dsT_dsT_dsT_dsG_ds
22
2828

G_dsA_dsA_esG_ksA_esT_ks^mC_e

1198496
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_dsG_dsT_dsG_ds^mC_dsT_dsT_ds
46
2891

T_dsG_dsG_esA_ksA_esG_ksA_e

1198497
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_dsA_dsT_dsG_ds^mC_dsA_ds
22
2830

T_dsG_dsG_dsT_esT_ksT_esT_ksT_e

1198498
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
39
2831

A_dsT_dsG_esG_ksT_esT_ksT_e

1198499
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
13
2832

C_dsA_dsT_esG_ksG_esT_ksT_e

1198500
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_ds
17
2833

G_ds^mC_dsA_esT_ksG_esG_ksT_e

1198501
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_ds
5
2834

T_dsG_ds^mC_esA_ksT_esG_ksG_e

1198502
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_ds
16
2835

A_dsT_dsG_es^mC_ksA_esT_ksG_e

1198503
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
31
2836

G_dsA_dsT_esG_ks^mC_esA_ksT_e

1198504
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_dsG_dsA_dsT_dsT_dsT_dsA_ds
15
2837

G_dsG_dsA_esT_ksG_es^mC_ksA_e

1198505
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ds^mC_dsA_dsG_dsA_dsT_dsT_ds
73
2838

T_dsA_dsG_esG_ksA_esT_ksG_e

1198506
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_dsT_dsG_dsG_dsT_dsT_dsT_ds
47
2839

T_dsG_dsT_esG_ksT_esG_ksT_e

1198507
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_ds
17
2840

T_dsT_dsT_esG_ksT_esG_ksT_e

1198508
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_ds
22
2788

T_dsT_dsT_esT_ksG_esT_ksG_e

1198509
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_dsT_dsA_dsT_dsA_dsT_dsG_ds
20
2841

G_dsT_dsT_esT_ksT_esG_ksT_e

1198510
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_ds
8
2842

T_dsG_dsG_dsT_esT_ksT_esT_ksG_e

1198511
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_ds
53
2859

A_dsT_dsG_dsG_esT_ksT_esT_ksT_e

1198512
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_ds
62
2860

T_dsA_dsT_dsG_esG_ksT_esT_ksT_e

1198513
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ds^mC_dsT_ds^mC_dsT_dsT_ds
63
2861

A_dsT_dsA_dsT_esG_ksG_esT_ksT_e

1198514
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_dsA_dsA_ds^mC_dsT_ds^mC_ds
53
2862

T_dsT_dsA_dsT_esA_ksT_esG_ksG_e

1198515
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_dsG_ds^mC_dsA_dsA_dsT_ds^m
44
2843

C_dsT_dsG_dsT_es^mC_ksT_esG_ksA_e

1198516
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
50
2844

T_ds^mC_dsT_esG_ksT_es^mC_ksT_e

1198517
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
36
2845

A_dsT_ds^mC_esT_ksG_esT_ks^mC_e

1198518
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
71
2846

A_dsA_dsT_es^mC_ksT_esG_ksT_e

1198519
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
20
1404

C_dsA_dsA_esT_ks^mC_esT_ksG_e

1198520
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_ds
51
2847

G_ds^mC_dsA_esA_ksT_es^mC_ksT_e

1198521
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_ds
44
2848

T_dsG_ds^mC_esA_ksA_esT_ks^mC_e

1198522
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_dsG_dsT_dsA_dsA_dsT_dsA_ds
37
2849

T_dsT_dsG_es^mC_ksA_esA_ksT_e

1198523
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_dsA_dsT_dsG_dsT_dsA_dsA_ds
93
2850

T_dsA_dsT_esT_ksG_es^mC_ksA_e

1198524
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_dsA_dsT_dsG_dsT_ds^mC_dsA_ds
3
2863

G_dsA_dsA_esG_ksA_esG_ksT_e

1198525
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
2
2864

C_dsA_dsG_esA_ksA_esG_ksA_e

1198526
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_ds
2
2865

T_ds^mC_dsA_esG_ksA_esA_ksG_e

1198527
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_ds
5
2866

G_dsT_ds^mC_esA_ksG_esA_ksA_e

1198528
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_ds
14
2867

T_dsG_dsT_es^mC_ksA_esG_ksA_e

1198529
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_ds
17
2868

A_dsT_dsG_esT_ks^mC_esA_ksG_e

1198530
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_ds
29
2869

T_dsA_dsT_esG_ksT_es^mC_ksA_e

1198531
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_dsT_dsA_dsA_dsA_dsG_dsT_ds
21
1634

G_dsT_dsA_esT_ksG_esT_ks^mC_e

1198532
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_dsT_dsT_dsT_dsA_dsA_dsA_ds
36
2870

G_dsT_dsG_esT_ksA_esT_ksG_e

1198533
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_dsG_dsG_dsT_dsT_dsT_ds^mC_ds^m
35
2851

C_ds^mC_dsA_esG_ksA_esT_ksT_e

1198534
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_ds
30
2852

T_ds^mC_ds^mC_es^mC_ksA_esG_ksA_e

1198535
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_ds
35
2853

T_dsT_ds^mC_es^mC_ks^mC_esA_ksG_e

1198536
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_ds
20
2854

T_dsT_dsT_es^mC_ks^mC_es^mC_ksA_e

1198537
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_ds
24
1101

G_dsG_dsT_dsT_esT_ks^mC_es^mC_ks^mC_e

1198538
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_ds
29
2855

A_dsG_dsG_dsT_esT_ksT_es^mC_ks^mC_e

1198539
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_ds
54
2856

A_dsA_dsG_dsG_esT_ksT_esT_ks^mC_e

1198540
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ds^mC_dsT_dsA_dsA_dsG_ds
51
2857

T_dsA_dsA_dsG_esG_ksT_esT_ksT_e

1198541
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_dsG_dsA_ds^mC_dsT_dsA_dsA_ds
34
2858

G_dsT_dsA_esA_ksG_esG_ksT_e

1198890
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ds^mC_dsT_ds^mC_dsA_dsT_ds
19
2803

G_ds^mC_ds^mC_dsT_ksT_dsA_ksT_dsA_k

1198891
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_ds
18
2804

A_dsT_dsG_ds^mC_ks^mC_dsT_ksT_dsA_k

1198892
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^m
24
2805

C_dsA_dsT_dsG_ks^mC_ds^mC_ksT_dsT_k

1198899
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_dsA_dsT_dsG_dsT_dsG_dsG_ds^m
75
2809

C_dsA_dsA_ksT_dsA_ksA_dsT_k

1198900
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_ds
11
2810

G_dsG_ds^mC_ksA_dsA_ksT_dsA_k

1198901
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_ds
28
2811

T_dsG_dsG_ks^mC_dsA_ksA_dsT_k

1198902
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
13
963

G_dsT_dsG_ksG_ds^mC_ksA_dsA_k

1198903
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_ds
24
810

T_dsG_dsT_ksG_dsG_ks^mC_dsA_k

1198904
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_ds
12
2812

A_dsT_dsG_ksT_dsG_ksG_ds^mC_k

1198905
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_ds
5
2813

T_dsA_dsT_ksG_dsT_ksG_dsG_k

1198906
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_dsA_dsT_dsT_dsA_dsG_dsA_ds
56
2814

G_dsT_dsA_ksT_dsG_ksT_dsG_k

1198907
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_dsA_dsT_dsA_dsT_dsT_dsA_ds
74
887

G_dsA_dsG_ksT_dsA_ksT_dsG_k

TABLE 45

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ
SEQ

NO: 1
NO: 1
ID NO:
ID NO:

YAP1
SEQ

Compound
Start
Stop
2 Start
2 Stop

(%
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMISTRY NOTATION
UTC)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
28
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
15
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_ds
9
2800

T_ds^mC_dsA_dsT_dsG_ks^mC_ks^mC_k

1095491
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_dsA_ds
65
392

T_dsA_dsA_ks^mC_dsT_ksG_dsG_k

1095509
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
29
1580

C_dsT_ksG_dsG_ksG_ds^mC_k

1095510
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
35
2801

A_dsA_ds^mC_ksT_dsG_ksG_dsG_k

1095511
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_dsT_dsG_dsA_dsG_dsG_dsT_ds
46
2802

A_dsT_dsA_ksA_ds^mC_ksT_dsG_k

1198893
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
58
443

C_dsA_dsT_ksG_ds^mC_ks^mC_dsT_k

1198894
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
57
2800

T_ds^mC_dsA_ksT_dsG_ks^mC_ds^mC_k

1198895
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
22
2806

C_dsT_ds^mC_ksA_dsT_ksG_ds^mC_k

1198896
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
59
2807

C_dsT_ks^mC_dsA_ksT_dsG_k

1198897
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_ds
61
2808

T_ds^mC_ksT_ds^mC_ksA_dsT_k

1198898
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_dsT_dsG_dsG_dsA_dsA_dsA_dsT_ds
53
656

T_dsG_ksT_ds^mC_ksT_ds^mC_k

1198908
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_dsA_dsA_ds^mC_dsT_dsG_dsG_ds
124
2815

G_ds^mC_dsA_ksA_dsA_ksT_dsT_k

1198909
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
56
1427

G_dsG_dsG_ks^mC_dsA_ksA_dsA_k

1198910
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
40
905

T_dsG_dsG_ksG_ds^mC_ksA_dsA_k

1198911
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
26
1503

C_dsT_dsG_ksG_dsG_ks^mC_dsA_k

1198912
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_dsA_ds^mC_dsT_dsG_dsA_dsG_ds
78
2816

G_dsT_dsA_ksT_dsA_ksA_ds^mC_k

1198913
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ds^mC_dsA_dsT_dsT_dsA_dsG_ds
86
2817

G_dsA_dsA_ks^mC_dsA_ksA_dsG_k

1198914
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
68
2818

G_dsG_ksA_dsA_ks^mC_dsA_k

1198915
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_dsT_dsT_dsA_ds^mC_dsA_dsT_ds
37
1124

T_dsA_dsG_ksG_dsA_ksA_ds^mC_k

1198916
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_ksT_dsT_dsT_dsT_dsA_ds^mC_dsA_ds
59
2819

T_dsT_dsA_ksG_dsG_ksA_dsA_k

1198917
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_ds
21
1200

A_dsT_dsT_ksA_dsG_ksG_dsA_k

1198918
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_dsA_ds^m
27
1276

^mC_dsA_dsT_ksT_dsA_ksG_dsG_k

1198919
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG^mC_dsA_ds^mC_dsT_dsT_dsT_dsT_ds
60
2820

A_ds^mC_dsA_ksT_dsT_ksA_dsG_k

1198920
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ds^mC_dsA_ds^mC_dsT_dsT_dsT_ds
54
2821

T_dsA_ds^mC_ksA_dsT_ksT_dsA_k

1198921
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_dsA_dsG_ds^mC_dsA_ds^mC_dsT_ds
89
2822

T_dsT_dsT_ksA_ds^mC_ksA_dsT_k

1198922
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_dsA_dsG_dsA_dsT_ds^mC_dsT_ds
59
2823

G_dsA_dsA_ksA_ds^mC_ksT_ds^mC_k

1198923
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
73
2824

C_dsT_dsG_ksA_dsA_ksA_ds^mC_k

1198924
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
75
2825

C_dsT_ksG_dsA_ksA_dsA_k

1198925
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
52
2826

A_dsT_ds^mC_ksT_dsG_ksA_dsA_k

1198926
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
45
2044

G_dsA_dsT_ks^mC_dsT_ksG_dsA_k

1198927
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
50
2121

A_dsG_dsA_ksT_ds^mC_ksT_dsG_k

1198928
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
28
2827

A_dsA_dsG_ksA_dsT_ks^mC_dsT_k

1198929
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_dsG_ds^mC_dsT_dsT_dsT_dsG_ds
43
2828

G_dsG_dsA_ksG_dsA_ksT_ds^mC_k

1198930
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_dsG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
68
2829

G_dsG_ksA_dsA_ksG_dsA_k

1198931
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_dsA_dsT_dsG_ds^mC_dsA_dsT_ds
47
2830

G_dsG_dsT_ksT_dsT_ksT_dsT_k

1198932
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
35
2831

A_dsT_dsG_ksG_dsT_ksT_dsT_k

1198933
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
69
2832

C_dsA_dsT_ksG_dsG_ksT_dsT_k

1198934
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
56
2833

C_dsA_ksT_dsG_ksG_dsT_k

1198935
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_dsT_ds
18
2834

G_ds^mC_ksA_dsT_ksG_dsG_k

1198936
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_dsA_ds
38
2835

T_dsG_ks^mC_dsA_ksT_dsG_k

1198937
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
48
2836

G_dsA_dsT_ksG_ds^mC_ksA_dsT_k

1198938
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_dsG_dsA_dsT_dsT_dsT_dsA_ds
59
2837

G_dsG_dsA_ksT_dsG_ks^mC_dsA_k

1198939
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ds^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
102
28388

A_dsG_ksG_dsA_ksT_dsG_k

1198940
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_dsT_dsG_dsG_dsT_dsT_dsT_dsT_ds
51
2881

G_dsT_ksG_dsT_ksG_dsT_k

1198941
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_dsT_ds
35
2840

T_dsT_ksG_dsT_ksG_dsT_k

1198942
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_dsT_ds
42
2788

T_dsT_ksT_dsG_ksT_dsG_k

1198943
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_dsT_dsA_dsT_dsA_dsT_dsG_dsG_ds
31
2841

T_dsT_ksT_dsT_ksG_dsT_k

1198944
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_dsT_ds
34
2842

G_dsG_dsT_ksT_dsT_ksT_dsG_k

1198945
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_dsA_ds
48
2859

T_dsG_dsG_ksT_dsT_ksT_dsT_k

1198946
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_ds
72
2860

A_dsT_dsG_ksG_dsT_ksT_dsT_k

1198947
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ds^mC_dsT_ds^mC_dsT_dsT_dsA_ds
88
2861

T_dsA_dsT_ksG_dsG_ksT_dsT_k

1198948
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_dsA_dsA_ds^mC_dsT_ds^mC_dsT_ds
96
2862

T_dsA_dsT_ksA_dsT_ksG_dsG_k

1198949
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_dsG_ds^mC_dsA_dsA_dsT_ds^mC_ds
61
2843

T_dsG_dsT_ks^mC_dsT_ksG_dsA_k

1198950
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
85
2844

T_ds^mC_dsT_ksG_dsT_ks^mC_dsT_k

1198951
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
81
2845

A_dsT_ds^mC_ksT_dsG_ksT_ds^mC_k

1198952
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
77
2846

A_dsA_ksT_ks^mC_dsT_ksG_dsT_k

1198953
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
58
1404

C_dsA_dsA_ksT_ds^mC_ksT_dsG_k

1198954
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
94
2847

C_dsA_ksA_dsT_ks^mC_dsT_k

1198955
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_dsT_ds
92
2848

G_ds^mC_ksA_dsA_ksT_ds^mC_k

1198956
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_dsG_dsT_dsA_dsA_dsT_dsA_dsT_ds
76
2849

T_dsG_ks^mC_dsA_ksA_dsT_k

1198957
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_dsA_dsT_dsG_dsT_dsA_dsA_dsT_ds
81
2850

A_dsT_ksT_dsG_ks^mC_dsA_k

1198958
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_dsA_dsT_dsG_dsT_ds^mC_dsA_ds
12
2863

G_dsA_dsA_ksG_dsA_ksG_dsT_k

1198959
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
8
2864

C_dsA_dsG_ksA_dsA_ksG_dsA_k

1198960
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
6
2865

C_dsA_ksG_dsA_ksA_dsG_k

1198961
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_dsG_ds
12
2866

T_ds^mC_ksA_dsG_ksA_dsA_k

1198962
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_dsT_ds
52
2867

G_dsT_ks^mC_dsA_ksG_dsA_k

1198963
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_dsA_ds
27
2868

T_dsG_ksT_ds^mC_ksA_dsG_k

1198964
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_dsT_ds
59
2869

A_dsT_ksG_dsT_ks^mC_dsA_k

1198965
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_dsT_dsA_dsA_dsA_dsG_dsT_ds
95
1634

G_dsT_dsA_ksT_dsG_ksT_ds^mC_k

1198967
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_dsG_dsG_dsT_dsT_dsT_ds^mC_ds^m
65
2851

C_ds^mC_dsA_ksG_dsA_ksT_dsT_k

1198968
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
57
2852

C_ds^mC_ks^mC_dsA_ksG_dsA_k

1198969
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_dsT_ds
31
2853

T_ds^mC_ks^mC_ds^mC_ksA_dsG_k

1198970
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_dsT_ds
29
2854

T_dsT_ks^mC_ds^mC_ks^mC_dsA_k

1198971
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_ds
31
1101

G_dsT_dsT_ksT_ds^mC_ks^mC_ds^mC_k

1198972
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_ds
46
2855

G_dsG_dsT_ksT_dsT_ks^mC_ds^mC_k

1198973
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
53
2856

A_dsG_dsG_ksT_dsT_ksT_ds^mC_k

1198974
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ds^mC_dsT_dsA_dsA_dsG_dsT_ds
73
2857

A_dsA_dsG_ksG_dsT_ksT_dsT_k

1198975
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_dsG_dsA_ds^mC_dsT_dsA_dsA_ds
52
2858

G_dsT_dsA_ksA_dsG_ksG_dsT_k

Table 46

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop
Sequence

YAP1
ID

Number
Site
Site
Site
Site
(5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_dsT_ds
25
52

A_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
16
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
14
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1095407
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_dsA_dsT_ds
54
392

A_dsA_ks^mC_esT_ksG_esG_k

1095425
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
57
1580

C_dsT_ksG_esG_ksG_es^mC_k

1095426
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_dsA_ds
54
2801

A_ds^mC_ksT_esG_ksG_esG_k

1095427
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_dsT_dsG_dsA_dsG_dsG_dsT_ds
45
2802

A_dsT_dsA_ksA_es^mC_ksT_esG_k

1198804
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ds^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
22
2803

C_ds^mC_dsT_ksT_esA_ksT_esA_k

1198805
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_dsA_dsT_ds
23
2804

G_ds^mC_ks^mC_esT_ksT_esA_k

1198806
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^mC_ds
33
2805

A_dsT_dsG_ks^mC_es^mC_ksT_esT_k

1198807
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
44
433

C_dsA_dsT_ksG_es^mC_ks^mC_esT_k

1198808
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
40
2800

C_dsA_ksT_esG_ks^mC_es^mC_k

1198809
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
27
2806

T_ds^mC_ksA_esT_ksG_es^mC_k

1198810
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
50
2807

C_dsT_ks^mC_esA_ksT_esG_k

1198811
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_dsG_dsA_dsA_dsA_dsT_dsT_dsG_ds
38
2808

T_ds^mC_ksT_es^mC_ksA_esT_k

1198812
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_dsT_dsG_dsG_dsA_dsA_dsA_dsT_ds
26
656

T_dsG_ksT_es^mC_ksT_es^mC_k

1198813
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_dsA_dsT_dsG_dsT_dsG_dsG_ds^mC_ds
55
2809

A_dsA_ksT_esA_ksA_esT_k

1198814
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_dsG_ds
13
2810

G_ds^mC_ksA_esA_ksT_esA_K

1198815
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_dsT_ds
24
2811

G_dsG_ks^mC_esA_ksA_esT_k

1198816
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_dsG_ds
27
963

T_dsG_ksG_es^mC_ksA_esA_k

1198817
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_dsT_ds43
810

G_dsT_ksG_esG_ks^mC_esA_k

1198818
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_dsA_dsG_dsA_dsG_dsT_dsA_ds
15
2812

T_dsG_ksT_esG_ksG_es^mC_k

1198819
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_dsT_ds
44
2813

A_dsT_ksG_esT_ksG_esG_k

1198820
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_dsA_dsT_dsT_dsA_dsG_dsA_dsG_ds
62
2814

T_dsA_ksT_esG_ksT_esG_k

1198821
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_dsA_dsT_dsA_dsT_dsT_dsA_dsG_ds
62
887

A_dsG_ksT_esA_ksT_esG_k

1198822
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_dsA_dsA_ds^mC_dsT_dsG_dsG_dsG_ds^m
97
2815

C_dsA_ksA_esA_ksT_esT_k

1198823
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_dsG_ds
65
1427

G_dsG_ks^mC_esA_ksA_esA_k

1198824
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
72
905

G_dsG_ksG_es^mC_ksA_esA_k

1198825
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
64
1503

T_dsG_ksG_esG_ks^mC_esA_k

1198826
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_dsA_ds^mC_dsT_dsG_dsA_dsG_ds
64
2816

G_dsT_dsA_ksT_esA_ksA_es^mC_k

1198827
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ds^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
60
2817

A_dsA_ks^mC_esA_ksA_esG_k

1198828
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
59
2818

G_dsG_ksA_esA_ks^mC_esA_k

1198829
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_ds
36
1124

A_dsG_ksG_esA_ksA_es^mC_k

1198830
4599
4614
125624
125639
ACTTTTACATTAGGAA

^mA_ksC_ksT_dsT_dsT_dsT_dsA_ds^mC_dsA_dsT_ds
37
2819

T_dsA_ksG_esG_ksA_esA_k

1198831
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^mC_ds
12
1200

A_dsT_dsT_ksA_esG_ksG_esA_k

1198832
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_dsA_ds^m
20
1276

C_dsA_dsT_ksT_esA_ksG_esG_k

1198833
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_dsT_ds
54
2820

A_ds^mC_dsA_ksT_esT_ksA_esG_k

1198834
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ds^mC_dsA_ds^mC_dsT_dsT_dsT_ds
54
2821

T_dsA_ds^mC_ksA_esT_ksT_esA_k

1198835
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_dsA_dsG_ds^mC_dsA_ds^mC_dsT_ds
85
2822

T_dsT_dsT_ksA_es^mC_ksA_esT_k

1198836
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_dsA_dsG_dsA_dsT_ds^mC_dsT_dsG_ds
43
2823

A_dsA_ksA_es^mC_ksT_es^mC_k

1198837
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^mC_ds
66
2824

T_dsG_ksA_esA_ksA_es^mC_k

1198838
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
66
2825

C_dsT_ksG_esA_ksA_esA_k

1198839
4799
4814
125824
125839
CTTTGGAAGATCTGAA
mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_dsA_ds
36
2826

T_ds^mC_ksT_esG_ksA_esA_k

1198840
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_dsG_ds
26
2044

A_dsT_ks^mC_esT_ksG_esA_k

1198841
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_dsA_ds
116
2121

G_dsA_ksT_es^mC_ksT_esG_k

1198842
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
37
2827

A_dsG_ksA_esT_ks^mC_esT_k

1198843
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_dsG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
45
2828

A_dsA_ksG_esA_ksT_es^mC_k

1198844
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_dsG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
56
2829

G_dsG_ksA_esA_ksG_esA_k

1198845
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_dsA_dsT_dsG_ds^mC_dsA_dsT_dsG_ds
43
2830

G_dsT_ksT_esT_ksT_esT_k

1198846
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_dsA_ds
34
2831

T_dsG_ksG_esT_ksT_esT_k

1198847
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
51
2832

A_dsT_ksG_esG_ksT_esT_k

1198848
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
47
2833

C_dsA_ksT_esG_ksG_esT_k

1198849
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_dsT_ds
42
2834

G_ds^mC_ksA_esT_ksG_esG_k

1198850
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_dsA_ds
33
2835

T_dsG_ks^mC_esA_ksT_esG_k

1198851
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksG_dsA_dsT_dsT_dsT_dsA_dsG_dsG_ds
82
2836

A_dsT_ksG_es^mC_ksA_esT_k

1198852
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_dsG_dsA_dsT_dsT_dsT_dsA_dsG_ds
41
2837

G_dsA_ksT_esG_ks^mC_esA_k

1198853
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ds^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
105
2838

A_dsG_ksG_esA_ksT_esG_k

1198854
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_dsT_dsG_dsG_dsT_dsT_dsT_dsT_ds
56
2839

G_dsT_ksG_esT_ksG_esT_k

1198855
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_dsT_ds
30
2840

T_dsT_ksG_esT_ksG_esT_k

1198856
N/A
N/A
115906
115921
CTTATATGGTTTTGTG
mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_dsT_ds
20
2788

T_dsT_ksT_esG_ksT_esG_k

1198857
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_dsT_dsA_dsT_dsG_dsG_ds
19
2841

T_dsT_ksT_esT_ksG_esT_k

1198863
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_dsG_ds^mC_dsA_dsA_dsT_ds^mC_ds
65
2843

T_dsG_dsT_ks^mC_esT_ksG_esA_k

1198864
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^m
56
2844

C_dsT_ksG_esT_ks^mC_esT_k

1198865
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
38
2845

T_ds^mC_ksT_esG_ksT_es^mC_k

1198866
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
60
2846

A_dsT_ks^mC_esT_ksG_esT_k

1198867
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
25
1404

A_dsA_ksT_es^mC_ksT_esG_k

1198868
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
49
2847

C_dsA_ksA_esT_ks^mC_esT_k

1198869
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_dsT_ds
49
2848

G_ds^mC_ksA_esA_ksT_es^mC_k

1198870
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_dsG_dsT_dsA_dsA_dsT_dsA_dsT_ds
86
2849

T_dsG_ks^mC_esA_ksA_esT_k

1198871
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_dsA_dsT_dsG_dsT_dsA_dsA_dsT_ds
77
2850

A_dsT_ksT_esG_ks^mC_esA_k

1198881
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_dsG_dsG_dsTdsT_dsT_ds^mC_ds^m
36
2851

C_ds^mC_dsA_ksG_esA_ksT_esT_k

1198882
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
56
2852

C_ds^mC_ks^mC_esA_ksG_esA_k

1198883
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_dsT_ds
47
2853

T_ds^mC_ks^mC_es^mC_ksA_esG_k

1198884
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_dsT_ds
28
2854

T_dsT_ks^mC_es^mC_ks^mC_esA_k

1198885
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_dsG_ds
41
1101

T_dsT_ksT_es^mC_ks^mC_es^mC_k

1198886
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_dsG_ds
45
2855

G_dsT_ksT_esT_ks^mC_es^mC_k

1198887
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_dsA_ds
71
2856

G_dsG_ksT_esT_ksT_es^mC_k

1198888
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ds^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
51
2857

A_dsG_ksG_esT_ksT_esT_k

1198889
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_dsG_dsA_ds^mC_dsT_dsA_dsA_dsG_ds
27
2858

T_dsA_ksA_esG_ksG_esT_k

1198966
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_dsT_dsT_dsT_dsA_dsA_dsA_dsG_ds
78
2870

T_dsG_ksT_dsA_ksT_dsG_k

Table 47

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop

YAP1
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
39
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

716444
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^m
46
443

C_dsA_dsT_dsG_ds^mC_ks^mC_ksT_k

958497
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_ksT_dsG_dsG_dsA_dsA_dsA_dsT_ds
20
656

T_dsG_dsT_ds^mC_ksT_ks^mC_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_sT_dsA_dsT_ds
17
810

G_dsT_dsG_dsG_ks^mC_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
10
810

G_dsT_dsG_dsG_ks^mC_ksA_k

958500
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_ksA_dsT_dsA_dsT_dsT_dsA_dsG_ds
53
887

A_dsG_dsT_dsA_ksT_ksG_k

1009324
2560
2575
36419
36434
AGTATGTGGCAATAAT
A_ksG_ksT_ksA_dsT_dsG_dsT_dsG_dsG_ds^mC_ds
27
2809

63341
63356

A_dsA_dsT_dsA_ksA_ksT_k

123585
123600

1009325
2562
2577
63343
63358
AGAGTATGTGGCAATA
A_ksG_ksA_ksG_dsT_dsA_dsT_dsG_dsT_dsG_ds
16
2810

71690
71705

G_ds^mC_dsA_dsA_ksT_ksA_k

123587
123602

1009326
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_ds
10
2812

T_dsG_dsT_dsG_ksG_ks^mC_k

1009327
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_ds
27
2813

A_dsT_dsG_dsT_ksG_ksG_k

1009328
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_ds
67
2814

T_dsA_dsT_dsG_ksT_ksG_k

1009394
2223
2238
123248
123263
TATAACTGGGCAAATT
T_ksA_ksT_ksA_dsA_ds^mC_dsT_dsG_dsG_dsG_ds^m
73
2815

4436
4451
125461
125476

C_dsA_dsA_dsA_ksT_ksT_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
5
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1074462
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
7
2806

T_ds^mC_dsA_dsT_ksG_ks^mC_k

1074463
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_ds
20
2811

G_dsG_ds^mC_dsA_ksA_ksT_k

1074464
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_ds
5
963

T_dsG_sG_ds^mC_ksA_ksA_k

1074754
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_ds
69
1124

A_dsG_dsG_dsA_ksA_ks^mC_k

1074755
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mT_dsT_dsT_dsT_dsA_ds^mC_ds
23
1200

A_dsT_dsT_dsA_dsG_ksG_ksA_k

1074756
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^m
8
1276

C_dsA_dsT_dsT_dsA_ksG_ksG_k

1074798
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
19
2044

A_dsT_ds^mC_dsT_ksG_ksA_k

1074799
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
21
2121

G_dsA_dsT_ds^mC_ksT_ksG_k

1076186
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
31
2833

C_dsA_dsT_dsG_ksG_ksT_k

1076187
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_ds
17
2834

G_ds^mC_dsA_dsT_ksG_ksG_k

1076453
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
7
1404

A_dsA_dsT_ds^mC_ksT_ksG_k

1076481
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_ds13
1101

T_dsT_dsT_ds^mC_ks^mC_ks^mC_k

1096369
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
45
2827

A_dsG_dsA_dsT_ks^mC_ksT_k

1097037
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_ds
38
2835

T_dsG_ds^mC_dsA_ksT_ksG_k

1097238
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_ksG_ds^mC_dsA_dsA_dsT_ds^mC_ds
77
2843

T_dsG_dsT_ds^mC_dsT_ksG_ksA_k

1197176
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ks^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
17
2803

C_ds^mC_dsT_dsT_dsA_ksT_ksA_k

1197177
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_ksG_dsT_ds^mC_dsT_ds^mC_dsA_ds
15
2804

T_dsG_ds^mC_ds^mC_dsT_ksT_ksA_k

1197178
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_ds
12
2805

A_dsT_dsG_ds^mC_ds^mC_ksT_ksT_k

1197179
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
16
2807

C_dsT_ds^mC_dsA_ksT_ksG_k

1197180
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_ds
47
2808

T_ds^mC_dsT_ds^mC_ksA_ksT_k

1197181
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ks^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
87
2817

A_dsA_ds^mC_dsA_ksA_ksG_k

1197182
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_ksT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
115
2818

G_dsG_dsA_dsA_ks^mC_ksA_k

1197183
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_ksT_ksT_dsT_dsT_dsA_ds^mC_dsA_ds
41
2819

T_dsT_dsA_dsG_dsG_ksA_ksA_k

1197184
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_ds
20
2820

A_ds^mC_dsA_dsT_dsT_ksA_ksG_k

1197185
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_ds
55
2821

T_dsA_ds^mC_dsA_dsT_ksT_ksA_k

1197186
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_ksA_dsG_ds^mC_dsA_ds^mC_dsT_ds
65
2822

T_dsT_dsT_dsA_ds^mC_ksA_ksT_k

1197187
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_ksA_dsG_dsA_dsT_ds^mC_dsT_dsG_ds
24
2823

A_dsA_dsA_ds^mC_ksT_ks^mC_k

1197188
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_ksG_dsA_dsA_dsG_dsA_dsT_ds^mC_ds
96
2824

T_dsG_dsA_dsA_ksA_ks^mC_k

1197189
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
71
2825

C_dsT_dsG_dsA_ksA_ksA_k

1197190
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ks+lTksT_dsG_dsG_dsA_dsA_dsG_dsA_ds
57
2826

T_ds^mC_dsT_dsG_ksA_ksA_k

1197191
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
40
2828

A_dsA_dsG_dsA_ksT_ks^mC_k

1197192
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_ksG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
39
2829

G_dsG_dsA_dsA_ksG_ksA_k

1197193
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksA_dsT_dsG_ds^mC_dsA_dsT_dsG_ds
15
2830

G_dsT_dsT_dsT_ksT_ksT_k

1197194
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_ksG_dsG_dsA_dsT_dsG_ds^mC_dsA_ds
37
2831

T_dsG_dsG_dsT_ksT_ksT_k

1197195
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
38
2832

A_dsT_dsG_dsG_ksT_ksT_k

1197196
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsC_ds
27
2836

A_dsT_dsG_ds^mC_ksA_ksT_k

1197197
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
20
2837

G_dsA_dsT_dsG_ks^mC_ksA_k

1197198
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ks^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds+l
139
2838

A_dsG_dsG_dsA_ksT_ksG_k

1197206
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_ksT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^m
63
2844

C_dsT_dsG_dsT_ks^mC_ksT_k

1197207
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
51
2845

T_ds^mC_dsT_dsG_ksT_ks^mC_k

1197208
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
66
2846

A_dsT_ds^mC_dsT_ksG_ksT_k

1197209
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
33
2847

C_dsA_dsA_dsT_ks^mC_ksT_k

1197210
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_ds
105
2848

G_ds^mC_dsA_dsA_ksT_ks^mC_k

1197211
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_ds
80
2849

T_dsG_ds^mC_dsA_ksA_ksT_k

1197212
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_ksA_dsT_dsG_dsT_dsA_dsA_dsT_ds
55
2850

A_dsT_dsT_dsG_ks^mC_ksA_k

1197220
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_ksG_dsG_dsT_dsT_dsT_ds^mC_ds^m
32
2851

C_ds^mC_dsA_dsG_dsA_ksT_ksT_k

1197221
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_ksA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
42
2852

C_ds^mC_ds^mC_dsA_ksG_ksA_k

1197222
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_ds
40
2853

T_ds^mC_ds^mC_ds^mC_ksA_ksG_k

1197223
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_ds
11
2854

T_dsT_ds^mC_ds^mC_ks^mC_ksA_k

1197224
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_ds
24
2855

G_dsT_dsT_dsT_ks^mC_ks^mC_k

1197225
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_ds
46
2856

G_dsG_dsT_dsT_ksT_ks^mC_k

1197226
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
67
2857

A_dsG_dsG_dsT_ksT_ksT_k

1197227
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_ksG_dsA_ds^mC_dsT_dsA_dsA_dsG_ds
64
2858

T_dsA_dsA_dsG_ksG_ksT_k

1198858
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_dsT_ds
29
2842

G_dsG_dsT_ksT_esT_ksT_esG_k

1198859
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_dsA_ds
33
2859

T_dsG_dsG_ksT_esT_ksT_esT_k

1198860
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_dsT_ds
82
2860

A_dsT_dsG_ksG_esT_ksT_esT_k

1198861
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ds^mC_dsT_ds^mC_dsT_dsT_dsA_ds
100
2861

T_dsA_dsT_ksG_esG_ksT_esT_k

1198862
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_dsA_dsA_ds^mC_dsT_ds^mC_dsT_ds
72
2862

T_dsA_dsT_ksA_esT_ksG_esG_k

1198872
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_dsA_dsT_dsG_dsT_ds^mC_dsA_dsG_ds
8
2863

A_dsA_ksG_esA_ksG_esT_k

1198873
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
4
2864

A_dsG_ksA_esA_ksG_esA_k

1198874
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_dsT_dsG_dsT_daA_dsT_dsG_dsT_ds^m
2
2865

C_dsA_ksG_esA_ksA_esG_k

1198875
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_dsG_ds
5
2866

T_ds^mC_ksA_esG_ksA_esA_k

1198876
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_dsT_ds
31
2867

G_dsT_ks^mC_esA_ksG_esA_k

1198877
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_dsA_ds
11
2868

T_dsG_ksT_es^mC_ksA_esG_k

1198878
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_dsT_ds
42
2869

A_dsT_ksG_esT_ks^mC_esA_k

1198879
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_dsT_dsA_dsA_dsA_dsG_dsT_dsG_ds
29
1634

T_dsA_ksT_esG_ksT_es^mC_k

1198880
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_dsT_dsT_dsT_dsA_dsA_dsA_dsG_ds
98
2870

T_dsG_ksT_esA_ksT_esG_k

Table 48

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop

YAP1
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
34
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

716524
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
59
392

A_dsA_ds^mC_dsT_ksG_ksG_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
15
810

G_dsT_dsG_dsG_ks^mC_ksA_k

958590
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
18
905

G_dsG_dsG_ds^mC_ksA_ksA_k

1009395
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_ds
43
2801

A_ds^mC_dsT_dsG_ksG_ksG_k

1009396
4444
4459
106028
106043
CACTGAGGTATAACTG

^mC_ksA_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_ds
41
2802

125469
125484

A_dsT_dsA_dsA_ds^mC_ksT_ksG_k

1009397
4446
4461
106030
106045
AACACTGAGGTATAAC
A_ksA_ks^mC_ksA_ds^mC_dsT_dsG_dsA_dsG_ds
44
2816

125471
125486

G_dsT_dsA_dsT_dsA_ksA_ks^mC_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
20
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1074726
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_ksA_dsT_dsA_dsA_ds^mC_dsT_dsG_ds
23
1427

G_dsG_ds^mC_dsA_ksA_ksA_k

1074727
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
51
1503

T_dsG_dsG_dsG_ks^mC_ksA_k

1074728
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
14
1580

C_dsT_dsG_dsG_ksG_ks^mC_k

1076439
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_ds
31
2788

T_dsT_dsT_dsG_ksT_ksG_k

1076456
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_ds
44
1634

T_dsA_dsT_dsG_ksT_ks^mC_k

1097224
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_ksT_dsT_dsA_dsT_dsA_dsT_ds
22
2842

G_dsG_dsT_dsT_dsT_ksT_ksG_k

1097247
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_ds
9
2867

G_dsT_ds^mC_dsA_ksG_ksA_k

1197199
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_ksT_dsG_dsG_dsT_dsT_dsT_dsT_ds
75
2839

G_dsT_dsG_dsT_ksG_ksT_k

1197200
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_ksT_dsA_dsT_dsG_dsG_dsT_dsT_ds
49
2840

T_dsT_dsG_dsT_ksG_ksT_k

1197201
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_ds
46
2841

T_dsT_dsT_dsT_ksG_ksT_k

1197202
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_ds
27
2859

T_dsG_dsG_dsT_dsT_ksT_ksT_k

1197203
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_ds
68
2860

A_dsT_dsG_dsG_dsT_ksT_ksT_k

1197204
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_ds
89
2861

T_dsA_dsT_dsG_dsG_ksT_ksT_k

1197205
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_ksA_dsA_ds^mC_dsT_ds^mC_dsT_ds
67
2862

T_dsA_dsT_dsA_dsT_ksG_ksG_k

1197213
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_ksA_dsT_dsG_dsT_ds^mC_dsA_dsG_ds
5
2863

A_dsA_dsG_dsA_ksG_ksT_k

1197214
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_ksG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
5
2864

A_dsG_dsA_dsA_ksG_ksA_k

1197215
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
13
2865

C_dsA_dsG_dsA_ksA_ksG_k

1197216
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_ds
12
2866

T_ds^mC_dsA_dsG_ksA_ksA_k

1197217
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_ksA_dsA_dsG_dsG_dsT_dsA_ds
8
2868

T_dsG_dsT_ds^mC_ksA_ksG_k

1197218
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_ds
29
2869

A_dsT_dsG_dsT_ks^mC_ksA_k

1197219
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_ksT_dsT_dsT_dsA_dsA_dsA_dsG_ds
71
2870

T_dsG_dsT_dsA_ksT_ksG_k

1198284
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ks^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
27
2803

C_ds^mC_dsT_dsT_ksA_esT_ksA_e

1198285
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_ksG_dsT_ds^mC_dsT_ds^mC_dsA_ds
13
2804

T_dsG_ds^mC_ds^mC_ksT_esT_ksA_e

1198286
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_ds
17
2805

A_dsT_dsG_ds^mC_ks^mC_esT_ksT_e

1198287
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^m
13
443

C_dsA_dsT_dsG_ks^mC_es^mC_ksT_e

1198288
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
10
2800

C_dsA_dsT_ksG_es^mC_ks^mC_e

1198289
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
12
2806

T_ds^mC_dsA_ksT_esG_ks^mC_e

1198290
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
15
2807

C_dsT_ds^mC_ksA_esT_ksG_e

1198291
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_ds
58
2808

T_ds^mC_dsT_ks^mC_esA_ksT_e

1198292
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_ksT_dsG_dsG_dsA_dsA_dsA_dsT_ds
58
656

T_dsG_dsT_ks^mC_esT_ks^mC_e

1198293
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_ksA_dsT_dsG_dsT_dsG_dsG_ds^mC_ds
25
2809

A_dsA_dsT_ksA_esA_ksT_e

1198294
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_ksG_dsT_dsA_dsT_dsG_dsT_dsG_ds
13
2810

G_ds^mC_dsA_ksA_esT_ksA_e

1198295
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_ds
15
2811

G_dsG_ds^mC_ksA_esA_ksT_e

1198296
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_ds
29
963

T_dsG_dsG_ks^mC_esA_ksA_e

1198297
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
8
810

G_dsT_dsG_ksG_es^mC_ksA_e

1198298
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_ds
23
2812

T_dsG_dsT_ksG_esG_ks^mC_e

1198299
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_ds
27
2813

A_dsT_dsG_ksT_esG_ksG_e

1198300
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_ds
60
2814

T_dsA_dsT_ksG_esT_ksG_e

1198301
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_ksA_dsT_dsA_dsT_dsT_dsA_dsG_ds
43
887

A_dsG_dsT_ksA_esT_ksG_e

1198307
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ks^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
49
2817

A_dsA_ds^mC_ksA_esA_ksG_e

1198308
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_ksT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
68
2818

G_dsG_dsA_ksA_es^mC_ksA_e

1198309
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_ds
85
1124

A_dsG_dsG_ksA_esA_ks^mC_e

1198310
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_ksT_ksT_dsT_dsT_dsA_ds^mC_dsA_ds
28
2819

T_dsT_dsA_dsG_ksG_esA_ksA_e

1198311
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_ksT_dsT_dsT_dsT_dsA_ds^mC_ds
39
1200

A_dsT_dsT_dsA_ksG_esG_ksA_e

1198312
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^m
7
1276

C_dsA_dsT_dsT_ksA_esG_ksG_e

1198313
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_ds
31
2820

A_ds^mC_dsA_dsT_ksT_esA_ksG_e

1198314
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_ds
82
2821

T_dsA_ds^mC_dsA_ksT_esT_ksA_e

1198315
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_ksA_dsG_ds^mC_dsA_ds^mC_dsT_ds
85
2822

T_dsT_dsT_dsA_ks^mC_esA_ksT_e

1198316
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_ksA_dsG_dsA_dsT_ds^mC_dsT_dsG_ds
49
2823

A_dsA_dsA_ks^mC_esT_ks^mC_e

1198317
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_ksG_dsA_dsA_dsG_dsA_dsT_ds^mC_ds
74
2824

T_dsG_dsA_ksA_esA_ks^mC_e

1198318
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
120
2825

C_dsT_dsG_ksA_esA_ksA_e

1198319
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_ds
47
2826

T_ds^mC_dsT_ksG_esA_ksA_e

1198320
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_ksT_dsT_dsG_dsG_dsA_dsA_dsG_ds
26
2044

A_dsT_ds^mC_ksT_esG_ksA_e

1198321
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
45
2121

G_dsA_dsT_ks^mC_esT_ksG_e

1198322
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
48
2827

A_dsG_dsA_ksT_es^mC_ksT_e

1198323
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
32
2828

A_dsA_dsG_ksA_esT_ks^mC_e

1198324
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_ksG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
53
2829

G_dsG_dsA_ksA_esG_ksA_e

1198325
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_ksA_dsT_dsG_ds^mC_dsA_dsT_dsG_ds
34
2830

G_dsT_dsT_ksT_esT_ksT_e

1198326
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_ksG_dsG_dsA_dsT_dsG_ds^mC_dsA_ds
84
2831

T_dsG_dsG_ksT_esT_ksT_e

1198327
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
29
2832

A_dsT_dsG_ksG_esT_ksT_e

1198328
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
42
2833

C_dsA_dsT_ksG_esG_ksT_e

1198329
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_ds
36
2834

G_ds^mC_dsA_ksT_esG_ksG_e

1198330
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_ds
27
2934

T_dsG_ds^mC_ksA_esT_ksG_e

1198331
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_ds
26
2836

A_dsT_dsG_ks^mC_esA_ksT_e

1198332
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
58
2837

G_dsA_dsT_ksG_es^mC_ksA_e

1198333
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ks^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
77
2838

A_dsG_dsG_ksA_esT_ksG_e

1198343
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_ksG_ds^mC_dsA_dsA_dsT_ds^mC_ds
39
2843

T_dsG_dsT_ds^mC_ksT_esG_ksA_e

1198344
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_ksT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^m
55
2844

C_dsT_dsG_ksT_es^mC_ksT_e

1198345
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
75
2845

T_ds^mC_dsT_ksG_esT_ks^mC_e

1198346
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
40
2846

A_dsT_ds^mC_ksT_esG_ksT_e

1198347
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
14
1404

A_dsA_dsT_ks^mC_esT_ksG_e

1198348
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
40
2847

C_dsA_dsA_ksT_es^mC_ksT_e

TABLE 49

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop

YAP1
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
30
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_ks

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
13
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
10
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1095547
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
42
392

A_dsA_ds^mC_ksT_esG_ksG_e

1095565
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
25
1580

C_dsT_dsG_ksG_esG_ks^mC_e

1095566
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_ksA_dsG_dsG_dsT_dsA_dsA_ds^m
47
2801

A_ds^mC_dsT_ksG_esG_ksG_e

1095567
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_ksT_dsG_dsA_dsG_dsG_dsT_ds
92
2802

A_dsT_dsA_dsA_ks^mC_esT_ksG_e

1198302
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_ksA_dsA_ds^mC_dsT_dsG_dsG_dsG_ds^m
67
2815

C_dsA_dsA_ksA_esT_ksT_e

1198303
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_ksA_dsT_dsA_dsA_ds^mC_dsT_dsG_ds
27
1427

G_dsG_ds^mC_ksA_esA_ksA_e

1198304
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
33
905

G_dsG_dsG_ks^mC_esA_ksA_e

1198305
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
78
1503

T_dsG_dsG_ksG_es^mC_ksA_e

1198306
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_ksA_ds^mC_dsT_dsG_dsA_dsG_ds
64
2816

G_dsT_dsA_dsT_ksA_esA_ks^mC_e

1198334
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_ksT_dsG_dsG_dsT_dsT_dsT_dsT_ds
57
2839

G_dsT_dsG_ksT_esG_ksT_e

1198335
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_ksT_dsA_dsT_dsG_dsG_dsT_dsT_ds
26
2840

T_dsT_dsG_ksT_esG_ksT_e

1198336
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_ds
31
2788

T_dsT_dsT_ksG_esT_ksG_e

1198337
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_ds
26
2841

T_dsT_dsT_ksT_esG_ksT_e

1198338
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_ksT_dsT_dsA_dsT_dsA_dsT_ds
24
2842

G_dsG_dsT_dsT_ksT_esT_ksG_e

1198339
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_ds
25
2859

T_dsG_dsG_dsT_ksT_esT_ksT_e

1198340
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_ds
123
2860

A_dsT_dsG_dsG_ksT_esT_ksT_e

1198341
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_ds
90
2861

T_dsA_dsT_dsG_ksG_esT_ksT_e

1198342
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_ksA_dsA_ds^mC_dsT_ds^mC_dsT_ds
101
2862

T_dsA_dsT_dsA_ksT_esG_ksG_e

1198349
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_ksT_dsA_dsA_dsT_ds+ AdsT_dsT_ds
85
2848

G_ds^mC_dsA_ksA_esT_ks^mC_e

1198350
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_ds
83
2849

T_dsG_ds^mC_ksA_esA_ksT_e

1198351
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_ksA_dsT_dsG_dsT_dsA_dsA_dsT_ds
40
2850

A_dsT_dsT_ksG_es^mC_ksA_e

1198352
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_ksA_dsT_dsG_dsT_ds^mC_dsA_dsG_ds
7
2863

A_dsA_dsG_ksA_esG_ksT_e

1198353
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_ksG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
8
2864

A_dsG_dsA_ksA_esG_ksA_e

1198354
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
6
2865

C_dsA_dsG_ksA_esA_ksG_e

1198355
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_ds
6
2866

T_ds^mC_dsA_ksG_esA_ksA_e

1198356
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_ds
5
2867

G_dsT_ds^mC_ksA_esG_ksA_e

1198357
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_ds
21
2868

T_dsG_dsT_ks^mC_esA_ksG_e

1198358
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_ds
15
2869

A_dsT_dsG_ksT_es^mC_ksA_e

1198359
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_ds
28
1634

T_dsA_dsT_ksG_esT_ks^mC_e

1198360
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_ksT_dsT_dsT_dsA_dsA_dsA_dsG_ds
74
2870

T_dsG_dsT_ksA_esT_ksG_e

1198361
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_ksG_dsG_dsT_dsT_dsT_ds^mC_ds^m
39
2851

C_ds^mC_dsA_dsG_ksA_esT_ksT_e

1198362
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_ksA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
24
2852

C_ds^mC_ds^mC_ksA_esG_ksA_e

1198363
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_ds
55
2853

T_ds^mC_ds^mC_ks^mC_esA_ksG_e

1198364
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_ds
29
2854

T_dsT_ds^mC_ks^mC_es^mC_ksA_e

1198365
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_ds
13
1101

T_dsT_dsT_ks^mC_es^mC_ks^mC_e

1198366
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_ds
45
2855

G_dsT_dsT_ksT_es^mC_ks^mC_e

1198367
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_ds
58
2856

G_dsG_dsT_ksT_esT_ks^mC_e

1198368
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
79
2857

A_dsG_dsG_ksT_esT_ksT_e

1198369
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_ksG_dsA_ds^mC_dsT_dsA_dsA_dsG_ds
51
2858

T_dsA_dsA_ksG_esG_ksT_e

1198542
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ks^mC_dsT_ds^mC_dsA_dsT_dsG_ds^m
23
2803

C_ds^mC_dsT_dsT_ksA_ksT_ksA_e

1198543
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_ksG_dsT_ds^mC_dsT_ds^mC_dsA_ds
15
2804

T_dsG_ds^mC_ds^mC_ksT_ksT_ksA_e

1198544
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_ksT_dsG_dsT_ds^mC_dsT_ds^mC_ds
21
2805

A_dsT_dsG_ds^mC_ks^mC_ksT_ksT_e

1198545
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_ksT_dsT_dsG_dsT_ds^mC_dsT_ds^m
32
443

C_dsA_dsT_dsG_ks^mC_ks^mC_ksT_e

1198546
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
11
2800

C_dsA_dsT_ksG_ks^mC_ks^mC_e

1198547
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_ksA_dsA_dsT_dsT_dsG_dsT_ds^mC_ds
27
2806

T_ds^mC_dsA_ksT_ksG_ks^mC_e

1198548
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_ksA_dsA_dsA_dsT_dsT_dsG_dsT_ds^m
26
2807

C_dsT_ds^mC_ksA_ksT_ksG_e

1198549
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_ksG_dsA_dsA_dsA_dsT_dsT_dsG_ds
84
2808

T_ds^mC_dsT_ks^mC_ksA_ksT_e

1198550
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_ksTasG_dsG_dsA_dsA_dsA_dsT_ds
17
656

T_dsG_dsT_ks^mC_ksT_ks^mC_e

1198551
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_ksA_dsT_dsG_dsT_dsG_dsG_ds^mC_ds
34
2809

A_dsA_dsT_ksA_ksA_ksT_e

1198552
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_ksG_dsT_dsA_dsT_dsG_dsT_dsG_ds
17
2810

G_ds^mC_dsA_ksA_ksT_ksA_e

1198553
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_ksA_dsG_dsT_dsA_dsT_dsG_dsT_ds
13
2811

G_dsG_ds^mC_ksA_ksA_ksT_e

1198554
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_ksG_dsA_dsG_dsT_dsA_dsT_dsG_ds
16
963

T_dsG_dsG_ks^mC_ksA_ksA_e

1198555
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
11
810

G_dsT_dsG_ksG_ks^mC_ksA_e

1198556
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_ksT_dsA_dsG_dsA_dsG_dsT_dsA_ds
25
2812

T_dsG_dsT_ksG_ksG_ks^mC_e

1198557
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_ksT_dsT_dsA_dsG_dsA_dsG_dsT_ds
16
2813

A_dsT_dsG_ksT_ksG_ksG_e

1198558
2568
2583
123593
123608
TATATTAGAGTATGTG
T_ksA_ksT_ksA_dsT_dsT_dsA_dsG_dsA_dsG_ds
46
2814

T_dsA_dsT_ksG_ksT_ksG_e

1198559
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_ksA_dsT_dsA_dsT_dsT_dsA_dsG_ds
55
887

A_dsG_dsT_ksA_ksT_ksG_e

1198565
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ks^mC_dsA_dsT_dsT_dsA_dsG_dsG_ds
53
2817

A_dsA_ds^mC_ksA_ksA_ksG_e

1198566
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_ksT_dsA_ds^mC_dsA_dsT_dsT_dsA_ds
83
2818

G_dsG_dsA_ksA_ks^mC_ksA_e

1198567
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_ksT_dsT_dsA_ds^mC_dsA_dsT_dsT_ds
54
1124

A_dsG_dsG_ksA_ksA_ks^mC_e

1198568
4599
4614
125624
125639
ACTTTTACATTAGGAA
A_ks^mC_ksT_ksT_dsT_dsT_dsA_ds^mC_dsA_ds
31
2819

T_dsT_dsA_dsG_ksG_ksA_ksA_e

1198569
4600
4615
125625
125640
CACTTTTACATTAGGA

^mC_ksA_ks^mC_ksT_dsT_dsT_dsA_ds^mC_ds
14
1200

A_dsT_dsT_dsA_ksG_ksG_ksA_e

1198570
4601
4616
125626
125641
GCACTTTTACATTAGG
G_ks^mC_ksA_ks^mC_dsT_dsT_dsT_dsT_dsA_ds^m
15
1276

C_dsA_dsT_dsT_ksA_ksG_ksG_e

1198571
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_ksA_ds^mC_dsT_dsT_dsT_dsT_ds
32
2820

A_ds^mC_dsA_dsT_ksT_ksA_ksG_e

1198572
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ks^mC_dsA_ds^mC_dsT_dsT_dsT_ds
53
2821

T_dsA_ds^mC_dsA_ksT_ksT_ksA_e

1198573
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_ksA_dsG_ds^mC_dsA_ds^mC_dsT_ds
76
2822

T_dsT_dsT_dsA_ks^mC_ksA_ksT_e

1198574
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_ksA_dsG_dsA_dsT_ds^mC_dsT_dsG_ds
37
2823

A_dsA_dsA_ks^mC_ksT_ks^mC_e

1198575
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_ksG_dsA_dsA_dsG_dsA_dsT_ds^mC_ds
94
2824

T_dsG_dsA_ksA_ksA_ks^mC_e

1198576
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_ksG_dsG_dsA_dsA_dsG_dsA_dsT_ds^m
92
2825

C_dsT_dsG_ksA_ksA_ksA_e

1198577
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_ds
40
2826

T_ds^mC_dsT_ksG_ksA_ksA_e

1198578
4800
4815
125825
125840
GCTTTGGAAGATCTGA

^mC_ksT_ksT_dsG_dsG_dsA_dsA_dsG_dsA_ds
18
2044

A_dsT_ds^mC_ksT_ksG_ksA_e

1198579
4801
4816
125826
125841
TGCTTTGGAAGATCTG
T_ksG_ks^mC_ksT_dsT_dsT_dsG_dsG_dsA_dsA_ds
34
2121

G_dsA_dsT_ks^mC_ksT_ksG_e

1198580
4802
4817
125827
125842
GTGCTTTGGAAGATCT
G_ksT_ksG_ks^mC_dsT_dsT_dsT_dsG_dsG_dsA_ds
43
2827

A_dsG_dsA_ksT_ks^mC_ksT_e

1198581
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_ksG_ds^mC_dsT_dsT_dsT_dsG_dsG_ds
42
2828

A_dsA_dsG_ksA_ksT_ks^mC_e

1198582
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_ksG_dsT_dsG_ds^mC_dsT_dsT_dsT_ds
63
2829

G_dsG_dsA_ksA_ksG_ksA_e

1198583
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_ksA_dsT_dsG_ds^mC_dsA_dsT_dsG_ds
27
2830

G_dsT_dsT_ksT_ksT_ksT_e

1198584
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_ksG_dsG_dsA_dsT_dsG_ds^mC_ds
37
2831

T_dsG_dsG_ksT_ksT_ksT_e

TABLE 50

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop

YAP1
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
31
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
12
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
16
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1095435
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_ksG_dsA_dsG_dsG_dsT_dsA_dsT_ds
39
392

A_dsA_ds^mC_ksT_ksG_ksG_e

1095453
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_ksG_dsG_dsT_dsA_dsT_dsA_dsA_ds^m
32
1580

C_dsT_dsG_ksG_ksG_ks^mC_e

1095454
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_ksA_dsG_dsG_dsT_dsA_dsT_dsA_ds
47
2801

A_ds^mC_dsT_ksG_ksG_ksG_e

1197228
2527
2542
123552
123567
AATTGTCTCATGCCTT
A_ksA_ksT_ksT_dsG_ysT_ds^mC_dsT_ds^mC_ds
25
2805

A_dsT_dsG_ds^mC_ds^mC_ksT_ksT_k

1197229
2530
2545
123555
123570
GGAAATTGTCTCATGC
G_ksG_ksA_ksA_dsA_ysT_dsT_dsG_dsT_ds^mC_ds
21
2806

T_ds^mC_dsA_dsT_ksG_ks^mC_k

1197230
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_ksA_dsA_ysA_dsT_dsT_dsG_dsT_ds^m
29
2807

C_dsT_ds^mC_dsA_ksT_ksG_k

1197231
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_ksG_dsA_ysA_dsA_dsT_dsT_dsG_ds
50
2808

T_ds^mC_dsT_ds^mC_ksA_ksT_k

1197232
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_ksT_dsG_ysG_dsA_dsA_dsA_dsT_ds
55
656

T_dsG_dsT_ds^mC_ksT_ks^mC_k

1197233
2563
2578
123588
123603
TAGAGTATGTGGCAAT
T_ksA_ksG_ksA_dsG_ysT_dsA_dsT_dsG_dsT_ds
36
2811

G_dsG_ds^mC_dsA_ksA_ksT_k

1197234
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_ksG_dsA_ysG_dsT_dsA_dsT_dsG_ds
24
963

T_dsG_dsG_ds^mC_ksA_ksA_k

1197235
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_ysA_dsG_dsT_dsA_dsT_ds
16
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1197236
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_ksT_dsA_ysG_dsA_dsG_dsT_dsA_ds
17
2812

T_dsG_dsT_dsG_ksG_ks^mC_k

1197244
4595
4610
125620
125635
TTACATTAGGAACAAG
T_ksT_ksA_ks^mC_dsA_ysT_dsT_dsA_dsG_dsG_ds
60
2817

A_dsA_ds^mC_dsA_ksA_ksG_k

1197245
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_ksT_dsA_ys^mC_dsA_dsT_dsT_dsA_ds
60
2818

G_dsG_dsA_dsA_ks^mC_ksA_k

1197246
4602
4617
125627
125642
AGCACTTTTACATTAG
A_ksG_ks^mC_ksA_dsC_ysT_dsT_dsT_dsT_dsA_ds^m
33
2820

C_dsA_dsT_dsT_ksA_ksG_k

1197247
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ks^mC_dsA_ys^mC_dsT_dsT_dsT_ds
47
2821

T_dsA_ds^mC_dsA_dsT_ksT_ksA_k

1197280
2524
2539
123549
123564
TGTCUCATGCCTTATA
T_ksG_ksT_ks^mC_dsU_ys^mC_dsA_dsT_dsG_ds^m
53
2871

C_ds^mC_dsT_dsT_dsA_ksT_ksA_k

1197281
2526
2541
123551
123566
ATTGUCTCATGCCTTA
A_ksT_ksT_ksG_dsU_ys^mC_dsT_dsC_dsA_ds
42
2872

T_dsG_ds^mC_ds^mC_dsT_ksT_ksA_k

1197282
2528
2543
123553
123568
AAATUGTCTCATGCCT
A_ksA_ksA_ksT_dsU_ysG_ds^mC_dsT_ds^m
40
2873

C_dsA_dsT_dsG_ds^mC_ks^mC_ksT_k

1197283
2529
2544
123554
123569
GAAAUTGTCTCATGCC
G_ksA_ksA_ksA_dsU_ysT_dsG_dsT_ds^mC_dsT_ds^m
29
2874

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1197284
2560
2575
123585
123600
AGTAUGTGGCAATAAT
A_ksG_ksT_ksA_dsU_ysG_dsT_dsG_dsG_ds^mC_ds
35
2875

A_dsA_dsT_dsA_ksA_ksT_k

1197285
2562
2577
123587
123602
AGAGUATGTGGCAATA
A_ksG_ksA_ksG_dsU_ysA_dsT_dsG_dsT_dsG_ds
28
2876

G_ds^mC_dsA_dsA_ksT_ksA_k

1197286
2567
2582
123592
123607
ATATUAGAGTATGTGG
A_ksT_ksA_ksT_dsU_ysA_dsG_dsA_dsG_dsT_ds
43
2877

A_dsT_dsG_dsT_ksG_ksG_k

1197287
2568
2583
123593
123608
TATAUTAGAGTATGTG
T_ksA_ksT_ksA_dsU_ysT_dsA_dsG_dsA_dsG_ds
108
2878

T_dsA_dsT_dsG_ksT_ksG_k

1197288
2570
2585
123595
123610
TCTAUATTAGAGTATG
T_ks^mC_ksT_ksA_dsU_ysA_dsT_dsT_dsA_dsG_ds
94
2879

A_dsG_dsT_dsA_ksT_ksG_k

1197291
4598
4613
125623
125638
CTTTUACATTAGGAAC

^mC_ksT_ksT_ksT_dsU_ysA_ds^mC_dsA_dsT_ds
83
2880

T_dsA_dsG_dsG_dsA_ksA_ks^mC_k

1197292
4599
4614
125624
125639
ACTTUTACATTAGGAA
A_ks^mC_ksT_ksT_dsU_ysT_dsA_ds^mC_dsA_ds
84
2881

T_dsT_dsA_dsG_dsG_ksA_ksA_k

1197293
4600
4615
125625
125640
CACTUTTACATTAGGA

^mC_ksA_ks^mC_ksT_dsU_ysT_dsT_dsA_ds^mC_ds
94
2882

A_dsT_dsT_dsA_dsG_ksG_ksA_k

1197294
4601
4616
125626
125641
GCACUTTTACATTAGG
G_ks^mC_ksA_ks^mC_dsU_ysT_dsT_dsT_dsA_ds^m
25
2883

C_dsA_dsT_dsT_dsA_ksG_ksG_k

1198560
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_ksA_dsA_ds^mC_dsT_dsG_dsG_dsG_ds^m
53
2815

C_dsA_dsA_ksA_ksT_ksT_e

1198561
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_ksA_dsT_dsA_dsA_ds^mC_dsT_dsG_ds
29
1427

G_dsG_ds^mC_ksA_ksA_ksA_e

1198562
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_ksT_dsA_dsT_dsA_dsA_ds^mC_dsT_ds
30
905

G_dsG_dsG_ks^mC_ksA_ksA_e

1198563
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_ksG_dsT_dsA_dsT_dsA_dsA_ds^mC_ds
53
1503

T_dsG_dsG_ksG_ks^mC_ksA_e

1198564
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_ksA_ds^mC_dsT_dsG
44
2816

G_dsT_dsA_dsT_ksA_ksA_ks^mC_e

1198585
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_ksA_dsG_dsG_dsA_dsT_dsG_ds^mC_ds
22
2832

A_dsT_dsG_ksG_ksT_ksT_e

1198586
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_ksT_dsA_dsG_dsG_dsA_dsT_dsG_ds^m
96
2833

C_dsA_dsT_ksG_ksG_ksT_e

1198587
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_ksT_dsT_dsA_dsG_dsG_dsA_dsT_ds
41
2834

G_ds^mC_dsA_ksT_ksG_ksG_e

1198588
N/A
N/A
94735
94750
AGATTTAGGATGCATG
A_ksG_ksA_ksT_dsT_dsT_dsA_dsG_dsG_dsA_ds
32
2835

T_dsG_ds^mC_ksA_ksT_ksG_e

1198589
N/A
N/A
94736
94751
CAGATTTAGGATGCAT

^mC_ksA_ksG_ksA_dsT_dsT_dsT_dsA_dsG_dsG_ds
24
2836

A_dsT_dsG_ks^mC_ksA_ksT_e

1198590
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_ksG_dsA_dsT_dsT_dsT_dsA_dsG_ds
46
2837

G_dsA_dsT_ksG_ks^mC_ksA_e

1198591
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ks^mC_dsA_dsG_dsA_dsT_dsT_dsT_ds
106
2838

A_dsG_dsG_ksA_ksT_ksG_e

1198592
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_ksT_dsG_dsG_dsT_dsT_dsT_dsT_ds
50
2839

G_dsT_dsG_ksT_ksG_ksT_e

1198593
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_ksT_dsA_dsT_dsG_dsG_dsT_dsT_ds
45
2840

T_dsT_dsG_ksT_ksG_ksT_e

1198594
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_ksA_dsT_dsA_dsT_dsG_dsG_dsT_ds
23
2788

T_dsT_dsT_ksG_ksT_ksG_e

1198595
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_ksT_dsA_dsT_dsA_dsT_dsG_dsG_ds
27
2841

T_dsT_dsT_ksT_ksG_ksT_e

1198596
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_ksT_dsT_dsA_dsT_dsA_dsT_ds
16
2842

G_dsG_dsT_dsT_ksT_ksT_ksG_e

1198597
N/A
N/A
115909
115924
ACTCTTATATGGTTTT
A_ks^mC_ksT_ks^mC_dsT_dsT_dsA_dsT_dsA_ds
27
2859

T_dsG_dsG_dsT_ksT_ksT_ksT_e

1198598
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_ksT_ds^mC_dsT_dsT_dsA_dsT_ds
76
2860

A_dsT_dsG_dsG_ksT_ksT_ksT_e

1198599
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ks^mC_dsT_ds^mC_dsT_dsT_dsA_ds
90
2861

T_dsA_dsT_dsG_ksG_ksT_ksT_e

1198600
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_ksA_dsA_ds^mC_dsT_ds^mC_dsT_ds
72
2862

T_dsA_dsT_dsA_ksT_ksG_ksG_e

1198601
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_ksG_ds^mC_dsA_dsA_dsT_ds^mC_ds
50
2843

T_dsG_dsT_ds^mC_ksT_ksG_ksA_e

1198602
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_ksT_dsT_dsG_ds^mC_dsA_dsA_dsT_ds^m
29
2844

C_dsT_dsG_ksT_ks^mC_ksT_e

1198603
N/A
N/A
117328
117343
AATATTGCAATCTGTC
A_ksA_ksT_ksA_dsT_dsT_dsG_ds^mC_dsA_dsA_ds
51
2845

T_ds^mC_dsT_ksG_ksT_ks^mC_e

1198604
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_ksT_dsA_dsT_dsT_dsG_ds^mC_dsA_ds
48
2846

A_dsT_ds^mC_ksT_ksG_ksT_e

1198605
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_ksA_dsT_dsA_dsT_dsT_dsG_ds^mC_ds
7
1404

A_dsA_dsT_ks^mC_ksT_ksG_e

1198606
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_ksA_dsA_dsT_dsA_dsT_dsT_dsG_ds^m
25
2847

C_dsA_dsA_ksT_ks^mC_ksT_e

1198607
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_ksT_dsA_dsA_dsT_dsA_dsT_dsT_ds
77
2848

G_ds^mC_dsA_ksA_ksT_ksmC_e

1198608
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_ksG_dsT_dsA_dsA_dsT_dsA_dsT_ds
83
2849

T_dsG_ds^mC_ksA_ksA_ksT_e

1198609
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_ksA_dsT_dsG_dsT_dsA_dsA_dsT_ds
52
2850

A_dsT_dsT_ksG_ks^mC_ksA_e

1198610
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_ksA_dsT_dsG_dsT_ds^mC_dsA_dsG_ds4
2863

A_dsA_dsG_ksA_ksG_ksT_e

1198611
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_ksG_dsT_dsA_dsT_dsG_dsT_ds^mC_ds
7
2864

A_dsG_dsA_ksA_ksG_ksA_e

1198612
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_ksT_dsG_dsT_dsA_dsT_dsG_dsT_ds^m
5
2865

C_dsA_dsG_ksA_ksA_ksG_e

1198613
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_ksG_dsT_dsG_dsT_dsA_dsT_dsG_ds
3
2866

T_ds^mC_dsA_ksG_ksA_ksA_e

1198614
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_ksA_dsG_dsT_dsG_dsT_dsA_dsT_ds
4
2867

G_dsT_ds^mC_ksA_ksG_ksA_e

1198615
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ks+lTksA_ksA_dsA_dsG_dsT_dsG_dsT_dsA_ds
10
2868

T_dsG_dsT_ks^mC_ksA_ksG_e

1198616
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_ksA_dsA_dsA_dsG_dsT_dsG_dsT_ds
16
2869

A_dsT_dsG_ksT_ks^mC_ksA_e

1198617
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_ksT_dsA_dsA_dsA_dsG_dsT_dsG_ds
34
1634

T_dsA_dsT_ksG_ksT_ks^mC_e

1198618
N/A
N/A
117765
117780
AACTTTAAAGTGTATG
A_ksA_ks^mC_ksT_dsT_dsT_dsA_dsA_dsA_dsG_ds
74
2870

T_dsG_dsT_ksA_ksT_ksG_e

1198619
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_ksG_dsG_dsT_dsT_dsT_ds^mC_ds^m
53
2851

C_ds^mC_dsA_dsG_ksA_ksT_ksT_e

1198620
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_ksA_dsA_dsG_dsG_dsT_dsT_dsT_ds^m
26
2852

C_ds^mC_ds^mC_ksA_ksG_ksA_e

1198621
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_ksT_dsA_dsA_dsG_dsG_dsT_dsT_ds
80
2853

T_ds^mC_ds^mC_ks^mC_ksA_ksG_e

1198622
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_ksG_dsT_dsA_dsA_dsG_dsG_dsT_ds
26
2854

T_dsT_ds^mC_ks^mC_ks^mC_ksA_e

1198623
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_ksA_dsG_dsT_dsA_dsA_dsG_dsG_ds
9
1101

T_dsT_dsT_ks^mC_ks^mC_ks^mC_e

1198624
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_ksA_dsA_dsG_dsT_dsA_dsA_dsG_ds
20
2855

G_dsT_dsT_ksT_ks^mC_ks^mC_e

1198625
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_ksT_dsA_dsA_dsG_dsT_dsA_dsA_ds
64
2856

G_dsG_dsT_ksT_ksT_ks^mC_e

1198626
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ks^mC_dsT_dsA_dsA_dsG_dsT_dsA_ds
99
2857

A_dsG_dsG_ksT_ksT_ksT_e

1198627
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_ksG_dsA_ds^mC_dsT_dsA_dsA_dsG_ds
39
2858

T_dsA_dsA_ksG_ksG_ksT_e

TABLE 51

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop

YAP1
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
24
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
9
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
5
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1197237
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_ksA_dsA_ys^mC_dsT_dsG_dsG_dsG_ds^m
74
2815

C_dsA_dsA_dsA_ksT_ksT_k

1197238
4439
4454
125464
125479
AGGTATAACTGGGCAA
A_ksG_ksG_ksT_dsA_ysT_dsA_dsA_ds^mC_dsT_ds
43
905

G_dsG_dsG_ds^mC_ksA_ksA_k

1197239
4441
4456
125466
125481
TGAGGTATAACTGGGC
T_ksG_ksA_ksG_dsG_ysT_dsA_dsT_dsA_dsA_ds^m
47
1580

C_dsT_dsG_dsG_ksG_ks^mC_k

1197240
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_ksA_dsG_ysG_dsT_dsA_dsT_dsA_ds
58
2801

A_ds^mC_dsT_dsG_ksG_ksG_k

1197241
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_ksG_dsA_ysG_dsG_dsT_dsA_dsT_ds+l
19
392

A_dsA_ds^mC_dsT_ksG_ksG_k

1197242
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_ksT_dsG_ysA_dsG_dsG_dsT_ds
46
2802

A_dsT_dsA_dsA_ds^mC_ksT_ksG_k

1197243
4446
4461
125471
125486
AACACTGAGGTATAAC
A_ksA_ks^mC_ksA_dsC_ysT_dsG_dsA_dsG_ds
81
2816

G_dsT_dsA_dsT_dsA_ksA_ks^mC_k

1197248
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_ksA_dsG_ys^mC_dsA_ds^mC_dsT_ds
75
2822

T_dsT_dsT_dsA_ds^mC_ksA_ksT_k

1197249
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_ksA_dsG_ysA_dsT_ds^mC_dsT_dsG_ds28
2823

A_dsA_dsA_ds^mC_ksT_ks^mC_k

1197250
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_ksG_dsA_ysA_dsG_dsA_dsT_ds^mC_ds
60
2824

T_dsG_dsA_dsA_ksA_ks^mC_k

1197251
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_ksG_dsG_ysA_dsA_dsG_dsA_dsT_ds^m
74
2825

C_dsT_dsG_dsA_ksA_ksA_k

1197252
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_ksT_dsG_ysG_dsA_dsA_dsG_dsA_ds
53
2826

T_ds^mC_dsT_dsG_ksA_ksA_k

1197253
4803
4818
125828
125843
AGTGCTTTGGAAGATC
A_ksG_ksT_ksG_dsC_ysT_dsT_dsT_dsG_dsG_ds
58
2828

A_dsA_dsG_dsA_ksT_ks^mC_k

1197254
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_ksG_dsG_ysA_dsT_dsG_ds^mC_dsA_ds
51
2831

T_dsG_dsG_dsT_ksT_ksT_k

1197255
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_ksA_dsG_ysG_dsA_dsT_dsG_ds^mC_ds
38
2832

A_dsT_dsG_dsG_ksT_ksT_k

1197256
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_ksT_dsA_ysG_dsG_dsA_dsT_dsG_ds^m
31
2833

C_dsA_dsT_dsG_ksG_ksT_k

1197257
N/A
N/A
94737
94752
TCAGATTTAGGATGCA
T_ks^mC_ksA_ksG_dsA_ysT_dsT_dsT_dsA_dsG_ds
20
2837

G_dsA_dsT_dsG_ks^mC_ksA_k

1197258
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ks+lTksT_ks^mC_dsA_ysG_dsA_dsT_dsT_dsT_ds
57
2838

A_dsG_dsG_dsA_ksT_ksG_k

1197259
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_ksT_dsG_ysG_dsT_dsT_dsT_dsT_ds
59
2839

G_dsT_dsG_dsT_ksG_ksT_k

1197260
N/A
N/A
115905
115920
TTATATGGTTTTGTGT
T_ksT_ksA_ksT_dsA_ysT_dsG_dsG_dsT_dsT_ds
65
2840

T_dsT_dsG_dsT_ksG_ksT_k

1197261
N/A
N/A
115907
115922
TCTTATATGGTTTTGT
T_ks^mC_ksT_ksT_dsA_ysT_dsA_dsT_dsG_dsG_ds
91
2841

T_dsT_dsT_dsT_ksG_ksT_k

1197262
N/A
N/A
115910
115925
AACTCTTATATGGTTT
A_ksA_ks^mC_ksT_dsC_ysT_dsT_dsA_dsT_dsA_ds
89
2860

T_dsG_dsG_dsT_ksT_ksT_k

1197263
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ks^mA_ks^mC_ksA_dsA_ys^mC_dsT_ds^mC_dsT_ds
91
2862

T_dsA_dsT_dsA_dsT_ksG_ksG_k

1197264
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_ksG_dsC_ysA_dsA_dsT_ds^mC_dsT_ds
33
2843

G_dsT_ds^mC_dsT_ksG_ksA_k

1197265
N/A
N/A
117329
117344
TAATATTGCAATCTGT
T_ksA_ksA_ksT_dsA_ysT_dsT_dsG_ds^mC_dsA_ds
103
2846

A_dsT_ds^mC_dsT_ksG_ksT_k

1197266
N/A
N/A
117331
117346
TGTAATATTGCAATCT
T_ksG_ksT_ksA_dsA_ysT_dsA_dsT_dsT_dsG_ds^m
31
2847

C_dsA_dsA_dsT_ks^mC_ksT_k

1197267
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_ksT_dsA_ysA_dsT_dsA_dsT_dsT_ds
62
2848

G_ds^mC_dsA_dsA_ksT_ks^mC_k

1197268
N/A
N/A
117758
117773
AAGTGTATGTCAGAAG
A_ksA_ksG_ksT_dsG_ysT_dsA_dsT_dsG_dsT_ds^m
25
2865

C_dsA_dsG_dsA_ksA_ksG_k

1197269
N/A
N/A
117760
117775
TAAAGTGTATGTCAGA
T_ksA_ksA_ksA_dsG_ysT_dsG_dsT_dsA_dsT_ds
3
2867

G_dsT_ds^mC_dsA_ksG_ksA_k

1197270
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_ksA_dsA_ysG_dsT_dsG_dsT_dsA_ds
2
2868

T_dsG_dsT_ds^mC_ksA_ksG_k

1197271
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_ksA_dsA_ysA_dsG_dsT_dsG_dsT_ds
12
2869

A_dsT_dsG_dsT_ks^mC_ksA_k

1197272
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_ksT_dsA_ysA_dsA_dsG_dsT_dsG_ds
32
1634

T_dsA_dsT_dsG_ksT_ks^mC_k

1197273
N/A
N/A
119667
119682
TAAGGTTTCCCAGATT
T_ksA_ksA_ksG_dsG_ysT_dsT_dsT_ds^mC_ds^m
68
2851

C_ds^mC_dsA_dsG_dsA_ksT_ksT_k

1197274
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_ksA_dsA_ysG_dsG_dsT_dsT_dsT_ds^m
31
2852

C_ds^mC_ds^mC_dsA_ksG_ksA_k

1197275
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_ksT_dsA_ysA_dsG_dsG_dsT_dsT_ds
30
2853

T_ds^mC_ds^mC_ds^mC_ksA_ksG_k

1197276
N/A
N/A
119672
119687
CTAAGTAAGGTTTCCC

^mC_ksT_ksA_ksA_dsG_ysT_dsA_dsA_dsG_dsG_ds
44
1101

T_dsT_dsT_ds^mC_ks^mC_ks^mC_k

1197277
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_ksA_dsA_ysG_dsT_dsA_dsA_dsG_ds
23
2855

G_dsT_dsT_dsT_ks^mC_ks^mC_k

1197278
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_ksT_dsA_ysA_dsG_dsT_dsA_dsA_ds
36
2856

G_dsG_dsT_dsT_ksT_ks^mC_k

1197279
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_ksG_dsA_ys^mC_dsT_dsA_dsA_dsG_ds
54
2858

T_dsA_dsA_dsG_ksG_ksT_k

1197289
4438
4453
125463
125478
GGTAUAACTGGGCAAA
G_ksG_ksT_ksA_dsU_ysA_dsA_ds^mC_dsT_dsG_ds
48
2884

G_dsG_ds^mC_dsA_ksA_ksA_k

1197290
4440
4455
125465
125480
GAGGUATAACTGGGCA
G_ksA_ksG_ksG_dsU_ysA_dsT_dsA_dsA_ds^m
37
2885

C_dsT_dsG_dsG_dsG_ks^mC_ksA_k

1197295
4800
4815
125825
125840
GCTTUGGAAGATCTGA
G_ks^mC_ksT_ksT_dsU_ysG_dsG_dsA_dsA_dsG_ds
24
2886

A_dsT_dsC_dsT_ksG_ksA_k

1197296
4801
4816
125826
125841
TGCTUTGGAAGATCTG
T_ksG_ks^mC_ksT_dsU_ysT_dsG_dsG_dsA_dsA_ds
36
2887

G_dsA_dsT_ds^mC_ksT_ksG_k

1197297
4802
4817
125827
125842
GTGCUTTGGAAGATCT
G_ksT_ksG_ks^mC_dsU_ysT_dsT_dsG_dsT_dsA_ds
25
2888

A_dsG_dsA_dsT_ks^mC_ksT_k

1197298
4805
4820
125830
125845
ATAGUGCTTTGGAAGA
A_ksT_ksA_ksG_dsU_ysG_ds^mC_dsT_dsT_dsT_ds
46
2889

G_dsG_dsA_dsA_ksG_ksA_k

1197299
N/A
N/A
94729
94744
AGGAUGCATGGTTTTT
A_ksG_ksG_ksA_dsU_ysG_ds^mC_dsA_dsT_ds
41
2890

G_dsG_dsT_dsT_dsT_ksT_ksT_k

1197300
N/A
N/A
94734
94749
GATTUAGGATGCATGG
G_ksA_ksT_ksT_dsU_ysA_dsG_dsG_dsA_dsT_ds
42
2891

G_ds^mC_dsA_dsT_ksG_ksG_k

1197301
N/A
N/A
94735
94750
AGATUTAGGATGCATG
A_ksA_ksT_dsU_ysT_dsA_dsG_dsG_dsA_ds
71
2892

T_dsG_ds^mC_dsA_ksT_ksG_k

1197302
N/A
N/A
94736
94751
CAGAUTTAGGATGCAT

^mC_ksA_ksG_ksA_dsU_ysT_dsT_dsA_dsG_dsG_ds
54
2893

A_dsT_dsG_ds^mC_ksA_ksT_k

1197303
N/A
N/A
115906
115921
CTTAUATGGTTTTGTG

^mC_ksT_ksT_ksA_dsU_ysA_dsT_dsG_dsG_dsT_ds
72
2894

T_dsT_dsT_dsG_ksT_ksG_k

1197304
N/A
N/A
115908
115923
CTCTUATATGGTTTTG

^mC_ksT_ks^mC_ksT_dsU_ysA_dsT_dsA_dsT_ds
45
2895

G_dsG_dsT_dsT_dsT_ksT_ksG_k

1197305
N/A
N/A
115909
115924
ACTCUTATATGGTTTT
A_ks^mC_ksT_ks^mC_dsU_ysT_dsA_dsT_dsA_ds
30
2896

T_dsG_dsG_dsT_dsT_ksT_ksT_k

1197306
N/A
N/A
115911
115926
CAACUCTTATATGGTT

^mC_ksA_ksA_ks^mC_dsU_ys^mC_dsT_dsT_dsA_ds
77
2897

T_dsA_dsT_dsG_dsG_ksT_ksT_k

1197307
N/A
N/A
117327
117342
ATATUGCAATCTGTCT
A_ksT_ksA_ksT_dsU_ysG_ds^mC_dsA_dsA_dsT_ds^m
88
2898

C_dsT_dsG_dsT_ks^mC_ksT_k

1197308
N/A
N/A
117328
117343
AATAUTGCAATCTGTC
A_ksA_ksT_ksA_dsU_ysT_dsG_ds^mC_dsA_dsA_ds
49
2899

T_ds^mC_dsT_dsG_ksT_ks^mC_k

1197309
N/A
N/A
117330
117345
GTAAUATTGCAATCTG
G_ksT_ksA_ksA_dsU_ysA_dsT_dsT_dsG_ds^mC_ds
11
2900

A_dsA_dsT_ds^mC_ksT_ksG_k

1197310
N/A
N/A
117333
117348
TATGUAATATTGCAAT
T_ksA_ksT_ksG_dsU_ysA_dsA_dsT_dsA_dsT_ds
109
2901

T_dsG_ds^mC_dsA_ksA_ksT_k

1197311
N/A
N/A
117335
117350
TTTAUGTAATATTGCA
T_ksT_ksT_ksA_dsU_ysG_dsT_dsA_dsA_dsT_ds
27
2902

A_dsT_dsT_dsG_ks^mC_ksA_k

1197312
N/A
N/A
117755
117770
TGTAUGTCAGAAGAGT
T_ksG_ksT_ksA_dsU_ysG_dsT_ds^mC_dsA_dsG_ds
10
2903

A_dsA_dsG_dsA_ksG_ksT_k

1197313
N/A
N/A
117757
117772
AGTGUATGTCAGAAGA
A_ksG_ksT_ksG_dsU_ysA_dsT_dsG_dsT_ds^mC_ds
8
2904

A_dsG_dsA_dsA_ksG_ksA_k

1197314
N/A
N/A
117759
117774
AAAGUGTATGTCAGAA
A_ksA_ksA_ksG_dsU_ysG_dsT_dsA_dsT_dsG_ds
22
2905

T_ds^mC_dsA_dsG_ksA_ksA_k

1197315
N/A
N/A
117765
117780
AACTUTAAAGTGTATG
A_ksA_ks^mC_ksT_dsU_ysT_dsA_dsA_dsA_dsG_ds
116
2906

T_dsG_dsT_dsA_ksT_ksG_k

1197316
N/A
N/A
119671
119686
TAAGUAAGGTTTCCCA
T_ksA_ksA_ksG_dsU_ysA_dsA_dsG_dsG_dsT_ds
46
2907

T_dsT_ds^mC_ds^mC_ks^mC_ksA_k

1197317
N/A
N/A
119675
119690
AGACUAAGTAAGGTTT
A_ksG_ksA_ks^mC_dsU_ysA_dsA_dsG_dsT_ds
78
2908

A_dsA_dsG_dsG_dsT_ksT_ksT_k

1200784
2524
2539
123549
123564
TGTCTCATGCCTTATA
T_ksG_ksT_ks^mC_dsT_dsC_ysA_dsT_dsG_ds^m
19
2803

C_ds^mC_dsT_dsT_dsA_ksT_ksA_k

1200785
2526
2541
123551
123566
ATTGTCTCATGCCTTA
A_ksT_ksT_ksG_dsT_dsC_ysT_ds^mC_dsA_dsT_ds
15
2804

G_ds^mC_ds^mC_dsT_ksT_ksA_k

1200786
2527
2542
123552
123567
AATTGUCTCATGCCTT
A_ksA_ksT_ksT_dsG_dsU_ys^mC_dsT_ds^mC_ds
21
2909

A_dsT_dsG_ds^mC_ds^mC_ksT_ksT_k

1200787
2528
2543
123553
123568
AAATTGTCTCATGCCT
A_ksA_ksA_ksT_dsT_dsG_ysT_ds^mC_dsT_ds^m
38
443

C_dsA_dsT_dsG_ds^mC_ks^mC_ksT_k

1200793
2560
2575
123585
123600
AGTATGTGGCAATAAT
A_ksG_ksT_ksA_dsT_dsG_ysT_dsG_dsG_ds^mC_ds
31
2809

A_dsA_dsT_dsA_ksA_ksT_k

1200794
2562
2577
123587
123602
AGAGTATGTGGCAATA
A_ksG_ksA_ksG_dsT_dsA_ysT_dsG_dsT_dsG_ds
18
2810

G_ds^mC_dsA_dsA_ksT_ksA_k

1200795
2563
2578
123588
123603
TAGAGUATGTGGCAAT
T_ksA_ksG_ksA_dsG_dsU_ysA_dsT_dsG_dsT_ds
30
2910

G_dsG_ds^mC_dsA_ksA_ksT_k

1200796
2564
2579
123589
123604
TTAGAGTATGTGGCAA
T_ksT_ksA_ksG_dsA_dsG_ysT_dsA_dsT_dsG_ds
15
963

T_dsG_dsG_ds^mC_ksA_ksA_k

1200797
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_ysG_dsT_dsA_dsT_ds
11
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1200798
2566
2581
123591
123606
TATTAGAGTATGTGGC
T_ksA_ksT_ksT_dsA_dsG_ysA_dsG_dsT_dsA_ds
7
2812

T_dsG_dsT_dsG_ksG_ks^mC_k

1200799
2567
2582
123592
123607
ATATTAGAGTATGTGG
A_ksT_ksA_ksT_dsT_dsA_ysG_dsA_dsG_dsT_ds
27
2813

A_dsT_dsG_dsT_ksG_ksG_k

1200800
2568
2583
123593
123608
TATATUAGAGTATGTG
T_ksA_ksT_ksA_dsT_dsU_ysA_dsG_dsA_dsG_ds
61
2911

T_dsA_dsT_dsG_ksT_ksG_k

1200801
2570
2585
123595
123610
TCTATATTAGAGTATG
T_ks^mC_ksT_ksA_dsT_dsA_ysT_dsT_dsA_dsG_ds
77
887

A_dsG_dsT_dsA_ksT_ksG_k

TABLE 52

Inhibition of Yap1 mRNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2

SEQ
SEQ

ID
ID
SEQ ID
SEQ ID

YAP1

NO: 1
NO: 1
NO: 2
NO: 2

SEQ
SEQ

Compound
Start
Stop
Start
Stop

YAP1
ID

Number
Site
Site
Site
Site
Sequence (5' to 3')
CHEMSITRY NOTATION
(% UT)
NO

715487
3630
3645
124655
124670
ATTACTTCATAGCTTA
A_ksT_ksT_ksA_ds^mC_dsT_dsT_ds^mC_dsA_ds
29
52

T_dsA_dsG_ds^mC_dsT_ksT_ksA_k

958499
2565
2580
123590
123605
ATTAGAGTATGTGGCA
A_ksT_ksT_ksA_dsG_dsA_dsG_dsT_dsA_dsT_ds
14
810

G_dsT_dsG_dsG_ks^mC_ksA_k

1074461
2529
2544
123554
123569
GAAATTGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsT_dsG_dsT_ds^mC_dsT_ds^m
15
2800

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1200788
2529
2544
123554
123569
GAAATUGTCTCATGCC
G_ksA_ksA_ksA_dsT_dsU_ysG_dsT_ds^mC_dsT_ds^m
19
2912

C_dsA_dsT_dsG_ks^mC_ks^mC_k

1200789
2530
2545
123555
123570
GGAAAUTGTCTCATGC
G_ksG_ksA_ksA_dsA_dsU_ysT_dsG_dsT_ds^mC_ds
12
2913

T_ds^mC_dsA_dsT_ksG_ks^mC_k

1200790
2531
2546
123556
123571
TGGAAATTGTCTCATG
T_ksG_ksG_ksA_dsA_dsA_ysT_dsT_dsG_dsT_ds^m
33
2807

C_dsT_ds^mC_dsA_ksT_ksG_k

1200791
2532
2547
123557
123572
ATGGAAATTGTCTCAT
A_ksT_ksG_ksG_dsA_dsA_ysA_dsT_dsT_dsG_ds
46
2808

T_ds^mC_dsT_ds^mC_ksA_ksT_k

1200792
2534
2549
123559
123574
ATATGGAAATTGTCTC
A_ksT_ksA_ksT_dsG_dsG_ysA_dsA_dsA_dsT_ds
52
656

T_dsG_dsT_ds^mC_ksT_ks^mC_k

1200802
4436
4451
125461
125476
TATAACTGGGCAAATT
T_ksA_ksT_ksA_dsA_dsC_ysT_dsG_dsG_dsG_ds^m
89
2815

C_dsA_dsA_dsA_ksT_k

1200803
4438
4453
125463
125478
GGTATAACTGGGCAAA
G_ksG_ksT_ksA_dsT_dsA_ysA_ds^mC_dsT_dsG_ds
22
1427

G_dsG_ds^mC_dsA_ksA_ksA_k

1200804
4439
4454
125464
125479
AGGTAUAACTGGGCAA
A_ksG_ksG_ksT_dsA_dsU_ysA_dsA_ds^mC_dsT_ds
44
2914

G_dsG_dsG_ds^mC_ksA_ksA_k

1200805
4440
4455
125465
125480
GAGGTATAACTGGGCA
G_ksA_ksG_ksG_dsT_dsA_ysT_dsA_dsA_ds^mC_ds
50
1503

T_dsG_dsG_dsG_ks^mC_ksA_k

1200806
4441
4456
125466
125481
TGAGGUATAACTGGGC
T_ksG_ksA_ksG_dsG_dsU_ysA_dsT_dsA_dsA_ds^m
24
2915

C_dsT_dsG_dsG_ksG_ks^mC_k

1200807
4442
4457
125467
125482
CTGAGGTATAACTGGG

^mC_ksT_ksG_ksA_dsG_dsG_ysT_dsA_dsT_ds
69
2801

A_dsA_ds^mC_dsT_dsG_ksG_ksG_k

1200808
4443
4458
125468
125483
ACTGAGGTATAACTGG
A_ks^mC_ksT_ksG_dsA_dsG_ysG_dsT_dsA_dsT_ds
45
392

A_dsA_ds^mC_dsT_ksG_ksG_k

1200809
4444
4459
125469
125484
CACTGAGGTATAACTG

^mC_ksA_ks^mC_ksT_dsG_dsA_ysG_dsG_dsT_ds
69
2802

A_dsT_dsA_dsA_ds^mC_ksT_ksG_k

1200810
4446
4461
125471
125486
AACACUGAGGTATAAC
A_ksA_ks^mC_ksA_ds^mC_dsU_ysG_dsA_dsG_ds
94
2916

G_dsT_dsA_dsT_dsA_ksA_ks^mC_k

1200811
4595
4610
125620
125635
TTACAUTAGGAACAAG
T_ksT_ksA_ks^mC_dsA_dsU_ysT_dsA_dsG_dsG_ds
62
2917

A_dsA_ds^mC_dsA_ksA_ksG_k

1200812
4597
4612
125622
125637
TTTTACATTAGGAACA
T_ksT_ksT_ksT_dsA_dsC_ysA_dsT_dsT_dsA_ds
59
2928

G_dsG_dsA_dsA_ks^mC_ksA_k

1200813
4598
4613
125623
125638
CTTTTACATTAGGAAC

^mC_ksT_ksT_ksT_dsT_dsA_ys^mC_dsA_dsT_ds
58
1124

T_dsA_dsG_dsG_dsA_ksA_ks^mC_k

1200814
4599
4614
125624
125639
ACTTTUACATTAGGAA
A_ks^mC_ksT_ksT_dsT_dsU_ysA_ds^mC_dsA_ds
73
2918

T_dsT_dsA_dsG_dsG_ksA_ksA_k

1200815
4600
4615
125625
125640
CACTTUTACATTAGGA

^mC_ksA_ks^mC_ksT_dsT_dsU_ysT_dsA_ds^mC_ds
55
2919

A_dsT_dsT_dsA_dsG_ksG_ksA_k

1200816
4601
4616
125626
125641
GCACTUTTACATTAGG
G_ks^mC_ksA_ks^mC_dsT_dsU_ysT_dsT_dsA_ds^m
37
2920

C_dsA_dsT_dsT_dsA_ksG_ksG_k

1200817
4602
4617
125627
125642
AGCACUTTTACATTAG
A_ksG_ks^mC_ksA_ds^mC_dsU_ysT_dsT_dsT_ds
38
2921

A_ds^mC_dsA_dsT_dsT_ksA_ksG_k

1200818
4603
4618
125628
125643
AAGCACTTTTACATTA
A_ksA_ksG_ks^mC_dsA_dsC_ysT_dsT_dsT_dsT_ds
31
2821

A_ds^mC_dsA_dsT_ksT_ksA_k

1200819
4605
4620
125630
125645
TTAAGCACTTTTACAT
T_ksT_ksA_ksA_dsG_dsC_ysA_ds^mC_dsT_dsT_ds
101
2822

T_dsT_dsA_ds^mC_ksA_ksT_k

1200820
4795
4810
125820
125835
GGAAGATCTGAAACTC
G_ksG_ksA_ksA_dsG_dsA_ysT_ds^mC_dsT_dsG_ds
24
2823

A_dsA_dsA_ds^mC_ksT_ks^mC_k

1200821
4797
4812
125822
125837
TTGGAAGATCTGAAAC
T_ksT_ksG_ksG_dsA_dsA_ysG_dsA_dsT_ds^mC_ds
59
2824

T_dsG_dsA_dsA_ksA_ks^mC_k

1200822
4798
4813
125823
125838
TTTGGAAGATCTGAAA
T_ksT_ksT_ksG_dsG_dsA_ysA_dsG_dsA_dsT_ds^m
55
2938

C_dsT_dsG_dsA_ksA_ksA_k

1200823
4799
4814
125824
125839
CTTTGGAAGATCTGAA

^mC_ksT_ksT_ksT_dsG_dsG_ysA_dsA_dsG_ds
46
2826

A_dsT_ds^mC_dsT_dsG_ksA_ksA_k

1200824
4800
4815
125825
125840
GCTTTGGAAGATCTGA
G_ks^mC_ksT_ksT_dsT_dsG_ysG_dsA_dsA_dsG_ds
43
2044

A_dsT_ds^mC_dsT_ksG_ksA_k

1200825
4801
4816
125826
125841
TGCTTUGGAAGATCTG
T_ksG_ks^mC_ksT_dsT_dsU_ysG_dsG_dsA_dsA_ds
39
2922

G_dsA_dsT_ds^mC_ksT_ksG_k

1200826
4802
4817
125827
125842
GTGCTUTGGAAGATCT
G_ksT_ksG_ks^mC_dsT_dsU_ysT_dsG_dsG_dsA_ds
26
2923

A_dsG_dsA_dsT_ks^mC_ksT_k

1200827
4803
4818
125828
125843
AGTGCUTTGGAAGATC
A_ksG_ksT_ksG_ds^mC_dsU_ysT_dsT_dsG_dsG_ds
67
2924

A_dsA_dsG_dsA_ksT_ks^mC_k

1200828
4805
4820
125830
125845
ATAGTGCTTTGGAAGA
A_ksT_ksA_ksG_dsT_dsG_ys^mC_dsT_dsT_dsT_ds
54
2829

G_dsG_dsA_dsA_ksG_ksA_k

1200829
N/A
N/A
94729
94744
AGGATGCATGGTTTTT
A_ksG_ksG_ksA_dsT_dsG_ys^mC_dsA_dsT_dsG_ds
49
2830

G_dsT_dsT_dsT_ksT_ksT_k

1200830
N/A
N/A
94731
94746
TTAGGATGCATGGTTT
T_ksT_ksA_ksG_dsG_dsA_ysT_dsG_ds^mC_dsA_ds
50
2831

T_dsG_dsG_dsT_ksT_ksT_k

1200831
N/A
N/A
94732
94747
TTTAGGATGCATGGTT
T_ksT_ksT_ksA_dsG_dsG_ysA_dsT_dsG_ds^mC_ds
42
2832

A_dsT_dsG_dsG_ksT_ksT_k

1200832
N/A
N/A
94733
94748
ATTTAGGATGCATGGT
A_ksT_ksT_ksT_dsA_dsG_ysG_dsA_dsT_dsG_ds^m
61
2833

C_dsA_dsT_dsG_ksG_ksT_k

1200833
N/A
N/A
94734
94749
GATTTAGGATGCATGG
G_ksA_ksT_ksT_dsT_dsA_ysG_dsG_dsA_dsT_ds
31
2834

G_ds^mC_dsA_dsT_ksG_ksG_k

1200834
N/A
N/A
94735
94750
AGATTUAGGATGCATG
A_ksG_ksA_ksT_dsT_dsU_ysA_dsG_dsG_dsA_ds
37
2925

T_dsG_ds^mC_dsA_ksT_ksG_k

1200835
N/A
N/A
94736
94751
CAGATUTAGGATGCAT

^mC_ksA_ksG_ksA_dsT_dsU_ysT_dsA_dsG_ds
82
2926

G_dsA_dsT_dsG_ds^mC_ksA_ksT_k

1200836
N/A
N/A
94737
94752
TCAGAUTTAGGATGCA
T_ks^mC_ksA_ksG_dsA_dsU_ysT_dsT_dsA_dsG_ds
72
2927

G_dsA_dsT_dsG_ks^mC_ksA_k

1200837
N/A
N/A
94739
94754
ATTCAGATTTAGGATG
A_ksT_ksT_ks^mC_dsA_dsG_ysA_dsT_dsT_dsT_ds
82
2838

A_dsG_dsG_dsA_ksT_ksG_k

1200838
N/A
N/A
115903
115918
ATATGGTTTTGTGTGT
A_ksT_ksA_ksT_dsG_dsG_ysT_dsT_dsT_dsT_ds
65
2839

G_dsT_dsG_dsT_ksG_ksT_k

1200839
N/A
N/A
115905
115920
TTATAUGGTTTTGTGT
T_ksT_ksA_ksT_dsA_dsU_ysG_dsG_dsT_dsT_ds
44
2928

T_dsT_dsG_dsT_ksG_ksT_k

1200840
N/A
N/A
115906
115921
CTTATATGGTTTTGTG

^mC_ksT_ksT_ksA_dsT_dsA_ysT_dsG_dsG_dsT_ds
48
2788

T_dsT_dsT_dsG_ksT_ksG_k

1200841
N/A
N/A
115907
115922
TCTTAUATGGTTTTGT
T_ks^mC_ksT_ksT_dsA_dsU_ysA_dsT_dsG_dsG_ds
76
2929

T_dsT_dsT_dsT_ksG_ksT_k

1200842
N/A
N/A
115908
115923
CTCTTATATGGTTTTG

^mC_ksT_ks^mC_ksT_dsT_dsA_ysT_dsA_dsT_ds
168
2842

G_dsG_dsT_dsT_dsT_ksT_ksG_k

1200843
N/A
N/A
115909
115924
ACTCTUATATGGTTTT
A_ks^mC_ksT_ks^mC_dsT_dsU_ysA_dsT_dsA_ds
46
2930

T_dsG_dsG_dsT_dsT_ksT_ksT_k

1200844
N/A
N/A
115910
115925
AACTCUTATATGGTTT
A_ksA_ks^mC_ksT_ds^mC_dsU_ysT_dsA_dsT_ds
132
2931

A_dsT_dsG_dsG_dsT_ksT_ksT_k

1200845
N/A
N/A
115911
115926
CAACTCTTATATGGTT

^mC_ksA_ksA_ks^mC_dsT_dsC_ysT_dsT_dsA_ds
100
2861

T_dsA_dsT_dsG_dsG_ksT_ksT_k

1200846
N/A
N/A
115913
115928
GACAACTCTTATATGG
G_ksA_ks^mC_ksA_dsA_dsC_ysT_ds^mC_dsT_ds
38
2862

T_dsA_dsT_dsA_dsT_ksG_ksG_k

1200847
N/A
N/A
117325
117340
ATTGCAATCTGTCTGA
A_ksT_ksT_ksG_ds^mC_dsA_ysA_dsT_ds^mC_ds
54
2843

T_dsG_dsT_ds^mC_dsT_ksG_ksA_k

1200848
N/A
N/A
117327
117342
ATATTGCAATCTGTCT
A_ksT_ksA_ksT_dsT_dsG_ys^mC_dsA_dsA_dsT_ds^m
58
2844

C_dsT_dsG_dsT_ks^mC_ksT_k

1200849
N/A
N/A
117328
117343
AATATUGCAATCTGTC
A_ksA_ksT_ksA_dsT_dsU_ysG_ds^mC_dsA_dsA_ds
53
2932

T_ds^mC_dsT_dsG_ksT_ks^mC_k

1200850
N/A
N/A
117329
117344
TAATAUTGCAATCTGT
T_ksA_ksA_ksT_dsA_dsU_ysT_dsG_ds^mC_dsA_ds
83
2933

A_dsT_ds^mC_dsT_ksG_ksT_k

1200851
N/A
N/A
117330
117345
GTAATATTGCAATCTG
G_ksT_ksA_ksA_dsT_dsA_ysT_dsT_dsG_ds^mC_ds
25
1404

A_dsA_dsT_ds^mC_ksT_ksG_k

1200852
N/A
N/A
117331
117346
TGTAAUATTGCAATCT
T_ksG_ksT_ksA_dsA_dsU_ysA_dsT_dsT_dsG_ds^m
32
2934

C_dsA_dsA_dsT_ks^mC_ksT_k

1200853
N/A
N/A
117332
117347
ATGTAATATTGCAATC
A_ksT_ksG_ksT_dsA_dsA_ysT_dsA_dsT_dsT_ds
69
2848

G_ds^mC_dsA_dsA_ksT_ks^mC_k

1200854
N/A
N/A
117333
117348
TATGTAATATTGCAAT
T_ksA_ksT_ksG_dsT_dsA_ysA_dsT_dsA_dsT_ds
91
2849

T_dsG_ds^mC_dsA_ksA_ksT_k

1200855
N/A
N/A
117335
117350
TTTATGTAATATTGCA
T_ksT_ksT_ksA_dsT_dsG_ysT_dsA_dsA_dsT_ds
56
2850

A_dsT_dsT_dsG_ks^mC_ksA_k

1200856
N/A
N/A
117755
117770
TGTATGTCAGAAGAGT
T_ksG_ksT_ksA_dsT_dsG_ysT_ds^mC_dsA_dsG_ds
29
2863

A_dsA_dsG_dsA_ksG_ksT_k

1200857
N/A
N/A
117757
117772
AGTGTATGTCAGAAGA
A_ksG_ksT_ksG_dsT_dsA_ysT_dsG_dsT_ds^mC_ds
4
2864

A_dsG_dsA_dsA_ksG_ksA_k

1200858
N/A
N/A
117758
117773
AAGTGUATGTCAGAAG
A_ksA_ksG_ksT_dsG_dsU_ysA_dsT_dsG_dsT_ds^m
10
2935

C_dsA_dsG_dsA_ksA_ksG_k

1200859
N/A
N/A
117759
117774
AAAGTGTATGTCAGAA
A_ksA_ksA_ksG_dsT_dsG_ysT_dsA_dsT_dsG_ds
28
2866

T_ds^mC_dsA_dsG_ksA_ksA_k

1200860
N/A
N/A
117760
117775
TAAAGUGTATGTCAGA
T_ksA_ksA_ksA_dsG_dsU_ysG_dsT_dsA_dsT_ds
16
2936

G_dsT_ds^mC_dsA_ksG_ksA_k

1200861
N/A
N/A
117761
117776
TTAAAGTGTATGTCAG
T_ksT_ksA_ksA_dsA_dsG_ysT_dsG_dsT_dsA_ds
10
2868

T_dsG_dsT_ds^mC_ksA_ksG_k

1200862
N/A
N/A
117762
117777
TTTAAAGTGTATGTCA
T_ksT_ksT_ksA_dsA_dsA_ysG_dsT_dsG_dsT_ds
17
2869

A_dsT_dsG_dsT_ks^mC_ksA_k

1200863
N/A
N/A
117763
117778
CTTTAAAGTGTATGTC

^mC_ksT_ksT_ksT_dsA_dsA_ysA_dsG_dsT_ds
41
1634

G_dsT_dsA_dsT_dsG_ksT_ks^mC_k

1200864
N/A
N/A
117765
117780
AACTTUAAAGTGTATG
A_ksA_ks^mC_ksT_dsT_dsU_ysA_dsA_dsA_dsG_ds
84
2937

T_dsG_dsT_dsA_ksT_ksG_k

1200865
N/A
N/A
119667
119682
TAAGGUTTCCCAGATT
T_ksA_ksA_ksG_dsG_dsU_ysT_dsT_ds^mC_ds^m
54
2938

C_ds^mC_dsA_dsG_dsA_ksT_ksT_k

1200866
N/A
N/A
119669
119684
AGTAAGGTTTCCCAGA
A_ksG_ksT_ksA_dsA_dsG_ysG_dsT_dsT_dsT_ds^m
41
2852

C_ds^mC_ds^mC_dsA_ksG_ksA_k

1200867
N/A
N/A
119670
119685
AAGTAAGGTTTCCCAG
A_ksA_ksG_ksT_dsA_dsA_ysG_dsG_dsT_dsT_ds
38
2853

T_ds^mC_ds^mC_ds^mC_ksA_ksG_k

1200868
N/A
N/A
119671
119686
TAAGTAAGGTTTCCCA
T_ksA_ksA_ksG_dsT_dsA_ysA_dsG_dsG_dsT_ds
36
2854

T_dsT_ds^mC_ds^mC_ks^mC_ksA_k

1200869
N/A
N/A
119672
119687
CTAAGUAAGGTTTCCC

^mC_ksT_ksA_ksA_dsG_dsU_ysA_dsA_dsG_ds
25
2939

G_dsT_dsT_dsT_ds^mC_ks^mC_ks^mC_k

1200870
N/A
N/A
119673
119688
ACTAAGTAAGGTTTCC
A_ks^mC_ksT_ksA_dsA_dsG_ysT_dsA_dsA_dsG_ds
73
2855

G_dsT_dsT_dsT_ks^mC_ks^mC_k

1200871
N/A
N/A
119674
119689
GACTAAGTAAGGTTTC
G_ksA_ks^mC_ksT_dsA_dsA_ysG_dsT_dsA_dsA_ds
65
2856

G_dsG_dsT_dsT_ksT_ks^mC_k

1200872
N/A
N/A
119675
119690
AGACTAAGTAAGGTTT
A_ksG_ksA_ks^mC_dsT_dsA_ysA_dsG_dsT_dsA_ds
98
2857

A_dsG_dsG_dsT_ksT_ksT_k

1200873
N/A
N/A
119677
119692
TTAGACTAAGTAAGGT
T_ksT_ksA_ksG_dsA_dsC_ysT_dsA_dsA_dsG_ds
55
2858

T_dsA_dsA_dsG_ksG_ksT_k

Example 6
Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides described in the studies above were tested at various doses in A-431 cells. Cultured A-431 cells at a density of 5,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). IC50s were calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 53

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
148 nM
444 nM
1333 nM
4000 nM
(μM)

715415
84
59
55
42
1.8

715423
83
91
80
57
>4.0

715433
87
72
65
40
2.5

715434
84
69
64
43
2.8

715473
89
67
50
30
1.3

715478
70
47
29
16
0.4

715479
98
80
77
64
>4.0

715480
91
79
67
59
>4.0

715483
82
58
43
35
1.1

715486
93
89
81
56
>4.0

715487
87
56
48
29
1.0

715490
98
89
76
43
4.1

715500
97
72
67
48
3.6

715501
82
82
68
56
>4.0

715508
78
70
67
43
3.5

715510
88
67
59
45
2.4

715523
100
62
75
44
3.2

715555
93
71
63
42
2.5

715577
87
76
73
45
>4.0

TABLE 54

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
148 nM
444 nM
1333 nM
4000 nM
(μM)

715414
91
91
102
67
>4.0

715435
80
67
61
48
3.4

715471
82
103
105
79
>4.0

715478
72
59
31
18
0.6

715558
94
112
80
66
>4.0

715582
98
63
93
70
>4.0

716370
81
79
69
49
>4.0

716376
103
94
79
50
>4.0

716424
76
69
51
44
2.0

716445
89
82
56
44
2.6

716454
91
71
54
48
2.6

716469
71
78
89
39
>4.0

716481
89
90
58
32
2.0

716484
88
78
80
55
>4.0

716493
95
97
86
72
>4.0

716496
74
87
64
49
>4.0

716502
73
57
45
30
0.8

716505
83
103
82
66
>4.0

716577
109
93
79
60
>4.0

TABLE 55

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
148 nM
444 nM
1333 nM
4000 nM
(μM)

715478
76
56
32
18
0.6

716381
106
90
80
44
4.2

716387
94
94
80
67
>4.0

716407
84
75
72
39
3.0

716419
89
84
49
47
2.5

716438
93
75
62
49
3.4

716455
95
70
49
25
1.2

716479
88
78
55
57
>4.0

716480
80
56
38
39
1.0

716489
84
83
69
61
>4.0

716500
88
96
79
46
>4.0

716501
91
69
66
55
>4.0

716503
91
80
67
64
>4.0

716513
82
73
39
39
1.4

716524
103
92
96
62
>4.0

716537
120
96
88
63
>4.0

716543
62
99
79
64
>4.0

716548
99
89
79
67
>4.0

716554
87
90
76
50
>4.0

Example 7
Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides described in the studies above were tested at various doses in A-431 cells. Cultured A-431 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS36584. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). IC50s were calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 56

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
78
38
15
6
0.05

715491
92
83
48
28
0.27

958356
84
79
39
21
0.18

958361
100
80
42
22
0.22

958369
107
68
34
17
0.17

958370
98
74
41
22
0.20

958371
89
57
27
11
0.10

958373
72
45
21
17
0.05

958375
74
35
11
5
0.04

958377
90
60
38
17
0.13

958403
94
63
30
12
0.12

958476
71
30
13
6
0.03

958496
86
53
27
9
0.09

958536
94
67
30
16
0.14

958596
69
38
14
7
0.04

958721
72
32
9
3
0.03

958726
99
70
40
16
0.17

958736
83
38
14
7
0.06

958796
91
62
32
15
0.13

TABLE 57

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
79
45
15
4
0.1

958451
98
74
51
23
0.2

958466
84
81
49
30
0.3

958481
86
62
28
14
0.1

958486
87
73
45
22
0.2

958491
94
65
27
10
0.1

958506
80
55
24
10
0.1

958526
118
83
40
17
0.2

958531
92
63
26
13
0.1

958541
81
51
18
9
0.1

958546
91
72
45
22
0.2

958551
95
73
34
14
0.2

958556
103
95
63
34
0.5

958616
78
49
29
17
0.1

958686
75
69
38
18
0.1

958731
85
64
39
19
0.1

958761
84
73
41
24
0.2

958781
77
45
20
10
0.1

958786
106
84
51
25
0.3

TABLE 58

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
84
44
15
5
0.1

958457
91
50
24
13
0.1

958472
92
63
39
23
0.2

958477
83
37
14
6
0.1

958497
82
35
11
3
0.1

958527
89
74
35
13
0.1

958532
88
44
16
7
0.1

958537
100
56
21
11
0.1

958542
90
70
35
17
0.1

958547
98
74
43
22
0.2

958567
99
80
44
16
0.2

958577
81
51
22
11
0.1

958587
94
49
18
7
0.1

958622
79
50
18
7
0.1

958727
90
42
25
8
0.1

958742
105
70
39
20
0.2

958752
102
66
26
9
0.1

958757
110
89
43
27
0.3

958807
92
65
30
10
0.1

TABLE 59

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
83
44
16
4
0.1

958498
70
21
5
2
0.02

958507
93
69
38
19
0.2

958518
95
55
18
4
0.1

958533
99
61
27
12
0.1

958553
68
23
12
5
0.03

958562
105
95
59
28
0.4

958563
94
54
22
10
0.1

958572
83
77
31
22
0.2

958573
81
56
23
8
0.1

958597
104
46
45
20
0.2

958603
70
27
11
4
0.03

958623
100
62
29
10
0.1

958668
81
38
12
5
0.1

958737
104
92
57
29
0.4

958758
83
66
33
12
0.1

958763
98
60
22
8
0.1

958767
101
57
20
10
0.1

958798
101
61
26
12
0.1

TABLE 60

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
79
40
13
3
0.1

958473
85
60
29
17
0.1

958508
65
64
32
13
0.1

958523
86
64
31
12
0.1

958538
101
77
52
30
0.3

958543
84
63
36
18
0.1

958554
70
34
11
4
0.03

958558
84
83
67
35
0.5

958568
88
65
37
21
0.1

958578
78
52
23
10
0.1

958588
93
73
46
27
0.2

958593
99
60
27
15
0.1

958598
93
58
36
19
0.1

958648
80
65
48
24
0.2

958658
90
88
59
29
0.4

958718
104
80
44
24
0.2

958753
72
48
20
11
0.1

958793
88
61
42
25
0.2

958813
81
79
47
29
0.2

TABLE 61

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
80
38
13
4
0.1

958454
72
40
12
4
0.04

958474
63
37
18
11
0.03

958484
77
38
10
4
0.05

958499
54
12
3
1
<0.01

958509
66
37
15
7
0.03

958529
103
64
27
11
0.1

958534
85
48
21
9
0.1

958569
82
49
24
7
0.1

958579
85
52
24
12
0.1

958589
75
50
19
8
0.1

958599
100
74
44
16
0.2

958614
84
49
22
13
0.1

958644
97
85
50
24
0.3

958659
91
68
28
9
0.1

958724
89
55
20
6
0.1

958729
73
44
13
4
0.05

958739
77
46
19
7
0.1

958799
88
53
25
10
0.1

TABLE 62

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
88
40
12
4
0.1

958485
68
38
13
8
0.04

958525
94
57
26
8
0.1

958544
65
77
40
17
0.1

958545
75
50
19
8
0.1

958549
98
78
47
28
0.3

958550
91
60
26
10
0.1

958555
99
73
34
13
0.2

958565
83
62
30
13
0.1

958580
95
59
24
9
0.1

958590
71
33
9
4
0.03

958594
91
70
42
20
0.2

958615
91
60
34
18
0.1

958650
82
51
17
7
0.1

958725
65
36
7
1
0.03

958730
88
48
19
7
0.1

958734
87
65
35
15
0.1

958785
78
52
18
6
0.1

958819
79
63
34
19
0.1

TABLE 63

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
15.6 nM
62.5 nM
250.0 nM
4000.00 nM
(μM)

715483
87
45
15
4
0.1

715483
77
36
10
3
0.04

715487
77
44
13
4
0.1

716454
84
39
12
6
0.1

958490
81
54
26
13
0.1

958500
91
63
32
16
0.1

958505
81
72
53
21
0.2

958535
98
64
38
19
0.2

958540
62
28
14
8
0.02

958570
93
60
33
17
0.1

958575
89
58
34
20
0.1

958585
95
71
40
17
0.2

958595
83
57
37
16
0.1

958600
69
44
23
14
0.05

958605
76
63
34
9
0.1

958625
86
59
35
17
0.1

958735
116
69
37
23
0.2

958795
90
69
38
20
0.2

958805
90
89
56
28
0.3

Example 8
Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by cEt Gapmers

Modified oligonucleotides described in the studies above were tested at various doses in A-431 cells. Cultured A-431 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). IC50s were calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 64

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
27
4
3
2
<0.02

1074368
67
34
15
10
0.1

1074464
25
6
3
3
<0.02

1074560
50
16
6
4
<0.02

1074753
42
10
6
4
<0.02

1075137
70
22
8
4
0.1

1075233
45
12
5
3
<0.02

1075712
69
38
13
7
0.1

1075744
55
22
9
7
<0.02

1075808
38
9
4
4
<0.02

1075968
74
37
11
5
0.1

1076000
71
31
10
5
0.1

1076064
68
26
10
5
0.1

1076256
68
33
11
6
0.1

1076288
31
7
3
4
<0.02

1076416
67
33
13
7
0.1

1076448
61
19
4
3
<0.02

1076449
44
8
3
2
<0.02

1076481
21
4
2
3
<0.02

TABLE 65

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
24
4
2
2
<0.02

1074274
42
14
7
5
<0.02

1074593
50
20
9
8
<0.02

1074594
53
23
10
5
<0.02

1074595
67
21
8
4
0.04

1074626
54
18
8
5
<0.02

1074627
17
5
3
3
<0.02

1074755
28
9
5
3
<0.02

1074817
50
22
13
11
<0.02

1074850
63
20
7
5
0.04

1075041
62
31
11
7
0.05

1075138
66
27
8
5
0.05

1075457
52
21
8
6
<0.02

1075458
74
43
17
6
0.1

1075778
56
29
10
5
0.03

1075810
67
28
12
7
0.1

1075842
27
7
3
3
<0.02

1076067
45
13
5
4
<0.02

1076386
61
30
11
5
0.04

TABLE 66

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
28
4
2
2
<0.02

1074563
80
31
7
5
0.1

1074564
40
14
7
4
<0.02

1074628
29
13
7
6
<0.02

1074723
56
24
11
8
<0.02

1074756
22
7
4
4
<0.02

1074851
51
19
9
7
<0.02

1074852
36
11
4
4
<0.02

1075395
60
18
7
5
<0.02

1075748
81
36
12
7
0.1

1075876
47
20
7
5
<0.02

1075939
46
19
10
8
<0.02

1076003
60
28
17
11
0.04

1076004
27
7
3
2
<0.02

1076260
61
30
12
5
0.05

1076291
75
26
8
5
0.1

1076323
41
35
13
5
<0.02

1076388
87
40
13
6
0.1

1076483
63
27
11
6
0.04

TABLE 67

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
23
4
2
2
<0.02

1074245
47
21
8
5
<0.02

1074565
47
20
9
6
<0.02

1074566
41
12
5
3
<0.02

1074597
35
15
8
7
<0.02

1074629
21
5
3
3
<0.02

1074630
57
23
10
6
<0.02

1074726
26
8
4
3
<0.02

1074758
74
23
8
5
0.1

1075078
65
32
12
4
0.1

1075749
46
22
7
4
<0.02

1075781
52
15
4
3
<0.02

1075813
57
31
11
5
0.04

1076293
49
18
6
5
<0.02

1076326
53
20
6
3
<0.02

1076453
11
2
1
2
<0.02

1076486
84
45
16
6
0.1

1076516
64
39
18
13
0.1

1076549
53
24
10
6
<0.02

TABLE 68

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
31
5
2
2
<0.02

1074407
55
27
13
8
<0.02

1074535
57
21
7
5
<0.02

1074536
64
24
9
6
0.04

1074728
28
7
4
4
<0.02

1074792
48
17
7
5
<0.02

1075047
80
63
27
10
0.2

1075048
76
42
13
5
0.1

1075111
42
11
6
5
<0.02

1075112
87
36
13
7
0.1

1075143
59
21
5
3
<0.02

1075207
82
51
17
7
0.1

1075686
72
44
18
14
0.1

1075784
54
18
5
3
<0.02

1076070
55
17
8
6
<0.02

1076294
76
50
21
11
0.1

1076295
55
17
5
3
<0.02

1076327
73
38
17
9
0.1

1076456
43
14
5
3
<0.02

TABLE 69

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
36
5
2
2
<0.02

1074250
67
35
15
9
0.1

1074313
56
21
9
5
<0.02

1074409
60
30
13
7
0.04

1074537
47
21
6
4
<0.02

1074762
74
32
14
8
0.1

1074794
56
23
10
6
<0.02

1075081
76
50
22
9
0.1

1075401
62
26
11
7
0.04

1075465
75
35
14
9
0.1

1075689
97
59
19
8
0.2

1075785
29
7
3
3
<0.02

1075816
66
29
12
8
0.1

1076330
57
31
9
4
0.04

1076393
54
20
8
5
<0.02

1076458
88
52
23
10
0.2

1076489
43
13
4
3
<0.02

1076490
36
9
4
3
<0.02

1076552
73
40
17
12
0.1

TABLE 70

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
27
4
2
2
<0.02

1074251
73
33
16
10
0.1

1074315
57
26
9
5
0.03

1074411
47
20
8
6
<0.02

1074443
69
35
14
8
0.1

1074795
38
14
7
5
<0.02

1075115
57
41
17
9
0.1

1075146
67
38
16
8
0.1

1075242
71
39
18
12
0.1

1075243
50
18
7
5
<0.02

1075498
82
40
21
16
0.1

1075819
48
18
7
5
<0.02

1076298
92
58
29
18
0.2

1076299
68
38
13
5
0.1

1076426
68
46
24
18
0.1

1076427
75
30
9
4
0.1

1076459
67
32
13
7
0.1

1076491
81
45
21
10
0.1

1076523
67
38
18
7
0.1

TABLE 71

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
29
5
2
2
<0.02

1074221
75
38
14
7
0.1

1074413
50
19
6
3
<0.02

1074444
49
21
7
4
<0.02

1074508
62
30
14
8
0.05

1074509
44
12
6
5
<0.02

1075052
40
10
4
4
<0.02

1075053
61
24
8
5
0.04

1075084
103
72
37
14
0.3

1075757
43
14
5
2
<0.02

1075916
73
34
14
8
0.1

1076077
53
19
9
5
<0.02

1076396
64
22
5
3
0.04

1076397
43
14
5
4
<0.02

1076460
79
53
25
12
0.2

1076461
65
24
7
3
0.04

1076524
71
30
12
7
0.1

1076525
43
14
5
2
<0.02

1076556
72
46
19
11
0.1

TABLE 72

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
95
89
82
81
>2.0

1074222
59
21
8
5
<0.02

1074318
48
12
6
4
<0.02

1074414
64
34
14
7
0.1

1074445
57
19
8
6
<0.02

1074446
39
11
5
3
<0.02

1074477
77
48
20
12
0.1

1074606
31
10
6
4
<0.02

1074638
14
4
3
3
<0.02

1074766
72
32
14
7
0.1

1074798
34
12
5
6
<0.02

1075118
85
36
8
4
0.1

1075246
70
34
12
6
0.1

1076174
58
21
7
4
<0.02

1076366
63
25
8
4
0.04

1076430
42
14
6
4
<0.02

1076462
61
22
8
5
0.03

1076494
34
7
3
2
<0.02

1076526
44
9
3
2
<0.02

TABLE 73

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
103
89
85
87
>2.0

1074351
69
33
13
7
0.1

1074447
47
20
8
5
<0.02

1074448
54
13
4
3
<0.02

1074479
23
8
4
4
<0.02

1074480
33
9
5
3
<0.02

1074607
45
22
10
5
<0.02

1074639
46
18
7
5
<0.02

1075055
60
20
6
4
0.03

1075088
37
9
4
2
<0.02

1075824
33
10
5
3
<0.02

1075855
65
30
12
8
0.1

1075983
81
46
17
6
0.1

1076015
70
37
15
9
0.1

1076143
81
48
20
9
0.1

1076367
31
10
4
3
<0.02

1076399
60
29
11
6
0.04

1076464
36
10
3
2
<0.02

1076527
81
41
16
8
0.1

TABLE 74

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
33
5
3
2
<0.02

1074417
68
26
7
3
0.1

1074576
69
41
14
9
0.1

1074577
33
10
4
3
<0.02

1074608
49
20
9
7
<0.02

1074609
65
29
15
11
0.1

1074672
34
18
10
7
<0.02

1074736
34
12
7
7
<0.02

1074737
50
21
8
6
<0.02

1074800
48
21
10
7
<0.02

1074801
76
41
19
12
0.1

1075089
45
9
3
3
<0.02

1075249
77
37
16
8
0.1

1075792
79
41
15
10
0.1

1076017
59
25
9
5
0.03

1076049
61
16
13
6
<0.02

1076369
60
20
6
3
<0.02

1076370
46
12
4
2
<0.02

1076465
72
32
14
7
0.1

TABLE 75

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
27
5
2
2
<0.02

1074290
49
17
9
7
<0.02

1074418
55
26
9
4
<0.02

1074419
48
15
5
3
<0.02

1074420
38
8
3
2
<0.02

1074450
54
22
7
5
<0.02

1074451
63
26
8
4
0.04

1074484
43
12
5
3
<0.02

1074578
66
30
18
11
0.1

1074579
54
22
8
5
<0.02

1074610
57
20
10
7
<0.02

1074675
47
18
6
3
<0.02

1075155
51
15
6
4
<0.02

1075699
26
6
3
2
<0.02

1076114
34
11
6
5
<0.02

1076115
47
17
9
6
<0.02

1076466
43
18
8
6
<0.02

1076467
24
6
3
2
<0.02

1076530
53
26
11
7
<0.02

TABLE 76

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
36
5
2
2
<0.02

1074229
58
24
9
5
<0.02

1074421
61
29
8
5
0.04

1074452
88
28
9
5
0.1

1074453
51
18
9
5
<0.02

1074485
47
14
5
3
<0.02

1074548
50
15
7
8
<0.02

1074549
67
31
12
7
0.1

1074580
55
18
8
5
<0.02

1074613
63
23
9
6
0.04

1074676
54
16
6
5
<0.02

1075061
58
23
9
6
<0.02

1075093
74
26
7
4
0.1

1075701
84
34
11
6
0.1

1075797
43
11
4
3
<0.02

1075893
80
29
11
8
0.1

1076084
69
34
12
8
0.1

1076085
70
34
14
9
0.1

1076340
79
42
17
11
0.1

TABLE 77

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

958499
37
4
2
2
<0.02

1074230
62
30
12
8
0.05

1074454
39
9
3
3
<0.02

1074486
55
26
10
6
<0.02

1074487
73
28
11
6
0.1

1074678
73
37
16
10
0.1

1074679
52
16
6
5
<0.02

1074775
26
5
2
2
<0.02

1075222
75
30
8
5
0.1

1075766
56
21
11
8
<0.02

1075990
28
6
3
3
<0.02

1076022
63
28
8
5
0.04

1076023
60
18
5
3
<0.02

1076119
82
35
12
6
0.1

1076183
65
22
9
6
0.04

1076406
51
20
9
7
<0.02

1076439
48
13
6
5
<0.02

1076471
64
29
9
5
0.05

1076534
88
48
20
10
0.2

Example 9
Dose-Dependent Inhibition of Human Yap1 in SNU-449 Cells by Modified Oligonucleotides

Modified oligonucleotides described in the studies above were tested at various doses in SNU-449 cells. Cultured SNU-449 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS36584. Yap1 mRNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). IC50s were calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 78

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
94
47
23
8
0.2

1198371
85
66
46
21
0.3

1198380
72
55
27
11
0.1

1198382
77
56
36
18
0.2

1198384
76
50
24
17
0.1

1198397
70
53
28
14
0.1

1198398
73
55
33
18
0.2

1198406
70
57
31
16
0.2

1198409
100
68
45
27
0.4

1198412
73
54
33
15
0.2

1198422
88
60
30
19
0.2

1198423
58
35
15
6
0.05

1198424
64
44
24
9
0.1

1198438
62
28
7
2
0.04

1198439
44
21
5
2
<0.03

1198440
55
23
6
2
<0.03

1198718
87
37
14
4
0.1

1198719
67
30
9
3
0.1

1198746
49
24
9
3
<0.03

TABLE 79

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
90
44
15
5
0.1

1198202
83
46
16
5
0.1

1198212
74
35
10
2
0.1

1198213
91
33
11
3
0.1

1198638
70
42
13
4
0.1

1198641
55
29
11
3
0.03

1198642
79
48
15
4
0.1

1198656
55
22
8
3
<0.03

1198664
52
33
14
5
<0.03

1198673
51
26
8
3
<0.03

1198696
58
31
11
2
0.04

1198697
60
29
7
1
0.04

1198698
55
29
8
2
0.03

1198724
56
25
8
3
<0.03

1198728
51
28
9
3
<0.03

1198786
63
32
11
2
0.1

1198787
68
21
6
1
0.05

1198788
64
30
7
2
0.1

1198799
62
35
13
4
0.1

TABLE 80

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
98
56
25
10
0.2

958590
69
52
29
12
0.1

1074728
69
45
19
8
0.1

1097247
58
28
8
2
0.04

1197215
56
31
7
2
0.04

1197216
66
39
15
4
0.1

1197217
66
39
14
4
0.1

1198285
67
41
16
5
0.1

1198286
64
45
22
8
0.1

1198287
95
68
36
16
0.3

1198288
77
43
17
7
0.1

1198289
72
41
18
9
0.1

1198290
60
39
20
10
0.1

1198294
59
33
14
5
0.05

1198295
82
47
19
8
0.1

1198297
67
42
16
7
0.1

1198347
67
54
24
8
0.1

1198354
66
24
5
1
0.05

1198356
85
30
7
1
0.1

TABLE 81

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
109
53
28
12
0.3

1198352
58
29
10
3
0.04

1198353
60
30
10
4
0.04

1198355
63
34
10
4
0.1

1198358
68
39
20
8
0.1

1198365
59
38
15
5
0.1

1198543
75
42
19
6
0.1

1198546
70
42
18
6
0.1

1198550
73
56
30
13
0.2

1198552
72
46
23
9
0.1

1198553
65
38
19
6
0.1

1198554
72
46
22
8
0.1

1198555
73
40
19
9
0.1

1198557
81
52
26
11
0.2

1198569
71
45
22
14
0.1

1198570
58
33
16
9
0.04

1198578
73
45
25
12
0.1

1198610
69
29
7
2
0.1

1198613
80
25
7
2
0.1

TABLE 82

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
125
73
35
15
0.4

1197229
54
32
16
7
0.03

1197235
64
36
16
5
0.1

1197236
64
46
25
14
0.1

1197269
48
21
7
1
<0.03

1197270
43
23
8
2
<0.03

1197312
101
58
34
11
0.3

1197313
71
38
16
6
0.1

1198596
73
40
14
4
0.1

1198605
57
27
7
1
0.03

1198611
37
19
4
1
<0.03

1198612
44
12
2
0
<0.03

1198614
69
26
3
1
0.1

1198615
52
23
5
2
<0.03

1198616
78
46
18
5
0.1

1198623
48
24
5
1
<0.03

1198624
62
37
21
9
0.1

1200797
84
52
23
11
0.2

1200798
77
44
17
7
0.1

TABLE 83

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
136
70
35
10
0.4

958499
93
47
19
7
0.2

1074461
76
37
15
5
0.1

1197271
70
47
19
8
0.1

1197309
91
63
30
9
0.2

1200784
70
51
26
12
0.1

1200785
98
73
42
24
0.4

1200788
61
38
19
9
0.1

1200789
60
32
15
5
0.05

1200794
85
59
31
13
0.2

1200796
69
47
25
12
0.1

1200803
72
52
34
18
0.2

1200806
91
54
34
18
0.2

1200820
104
69
36
17
0.3

1200857
66
30
8
2
0.1

1200858
71
39
14
4
0.1

1200860
59
35
15
5
0.05

1200861
74
43
17
4
0.1

1200862
88
64
35
13
0.2

TABLE 84

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
100
62
29
12
0.3

1074462
90
38
13
3
0.1

1074464
109
50
19
6
0.2

1198804
71
48
19
5
0.1

1198805
61
42
20
7
0.1

1198814
63
25
6
3
0.04

1198815
84
64
34
15
0.2

1198818
68
33
15
5
0.1

1198831
74
33
10
4
0.1

1198832
77
53
23
13
0.1

1198856
72
55
24
7
0.1

1198857
78
44
13
4
0.1

1198873
38
12
2
0
<0.03

1198874
36
8
1
0
<0.03

1198875
61
23
4
1
0.04

1198895
62
37
16
9
0.1

1198911
62
31
12
7
0.05

1198917
81
37
12
6
0.1

1198918
60
33
13
9
0.05

TABLE 85

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
103
56
25
10
0.2

1009325
59
36
16
4
0.1

1009326
59
35
14
4
0.05

1074756
42
20
6
3
<0.03

1074798
62
38
17
8
0.1

1076187
68
46
24
12
0.1

1076453
67
29
8
1
0.1

1076481
86
40
15
3
0.1

1197176
66
37
19
6
0.1

1197177
56
29
8
2
0.03

1197178
64
36
14
4
0.1

1197179
58
38
17
7
0.1

1197193
85
52
24
11
0.2

1197213
87
46
14
2
0.1

1197214
88
31
7
1
0.1

1197223
88
55
25
8
0.2

1198312
76
34
10
5
0.1

1198872
49
21
6
1
<0.03

1198877
62
32
13
5
0.05

TABLE 86

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
92
53
22
12
0.2

1095481
73
47
16
8
0.1

1095593
73
44
27
10
0.1

1198203
71
51
25
11
0.1

1198211
72
37
23
12
0.1

1198243
55
28
10
5
<0.03

1198267
78
44
15
3
0.1

1198268
83
52
17
5
0.1

1198457
82
56
31
12
0.2

1198460
60
49
28
11
0.1

1198466
68
44
18
6
0.1

1198470
73
41
18
9
0.1

1198484
80
45
24
12
0.1

1198501
65
36
17
11
0.1

1198524
50
32
9
3
<0.03

1198525
62
26
8
1
0.04

1198526
61
30
8
2
0.04

1198527
63
35
12
3
0.1

1198905
75
43
21
6
0.1

TABLE 87

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-449 cells

% UTC
IC50

ION No.
31.3 nM
125.0 nM
500.0 nM
2000.00 nM
(μM)

715487
89
48
23
10
0.2

1198492
67
39
19
10
0.1

1198494
59
37
24
13
0.1

1198499
89
42
30
12
0.2

1198500
72
51
34
15
0.2

1198502
76
50
29
15
0.2

1198504
77
46
27
24
0.1

1198507
83
57
29
13
0.2

1198510
71
44
18
6
0.1

1198528
87
54
30
11
0.2

1198529
86
69
37
16
0.3

1198900
69
36
18
7
0.1

1198902
74
46
22
10
0.1

1198904
78
36
23
10
0.1

1198935
50
46
23
11
0.04

1198958
68
39
16
5
0.1

1198959
62
28
8
2
0.04

1198960
77
35
8
2
0.1

1198961
77
35
11
3
0.1

Example 10
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 4-6 weeks of age (obtained from Taconic) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male Balb/c mice was injected with PBS. Mice were euthanized on day 26 post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 88

Plasma chemistry markers in Balb/c mice

ALT
AST
TBIL

ION No.
(U/L)
(U/L)
(mg/dL)

PBS
35
56
0.18

715480
791
439
0.15

715484
116
110
0.15

715487
79
96
0.13

715491
33
48
0.11

715557
1755
2377
0.28

715558
65
91
0.16

715582
2460
2320
2.09

715593
628
610
0.11

715609
1120
2941
0.67

715659
332
431
0.23

715744
164
138
0.15

715763
522
316
0.18

715766
182
191
0.12

715784
47
47
0.13

715797
188
222
0.15

715859
306
133
0.17

715863
2090
903
0.54

Body and Organ Weights

Body weights of Balb/c mice were measured at the end of the study, and the average body weight for each group is presented in the table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 89

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
22
1.05
0.37
0.09

715480
22
1.64
0.34
0.12

715484
22
1.47
0.37
0.13

715487
23
1.24
0.36
0.14

715491
22
1.03
0.32
0.12

715557
21
1.96
0.31
0.12

715558
22
1.33
0.38
0.12

715582
22
1.46
0.38
0.16

715593
19
1.12
0.30
0.13

715609
21
2.64
0.33
0.10

715659
20
1.21
0.31
0.11

715744
22
1.18
0.32
0.17

715763
23
1.71
0.36
0.13

715766
21
1.40
0.30
0.12

715784
23
1.15
0.39
0.12

715797
22
1.39
0.36
0.16

715859
22
1.32
0.36
0.14

715863
21
1.79
0.33
0.12

Example 11
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 90

Plasma chemistry markers in Balb/c mice

ALT
AST
BUN
TBIL

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
18
54
14
0.18

715415
1075
701
17
0.14

715473
3046
2861
20
2.77

715483
62
70
16
0.17

715487
59
81
16
0.18

716424
2077
1422
20
0.22

716454
39
60
14
0.18

716455
1089
1193
22
0.25

716480
2156
844
19
0.14

716481
1935
2248
21
0.46

716502
2920
1329
17
0.27

716513
325
229
17
0.14

Body and Organ Weights

TABLE 91

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
24
1.09
0.40
0.11

715415
25
1.79
0.40
0.17

715473
20
1.46
0.31
0.09

715483
25
1.56
0.43
0.12

715487
27
1.46
0.42
0.15

716424
23
2.08
0.36
0.15

716454
25
1.48
0.42
0.14

716455
21
2.66
0.32
0.14

716480
21
2.58
0.34
0.10

716481
22
1.99
0.36
0.13

716502
23
2.18
0.42
0.10

716513
25
1.59
0.41
0.18

Example 12
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 6-7 weeks of age (obtained from Taconic) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male Balb/c mice was injected with PBS. Mice were euthanized on day 26 post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

TABLE 92

Plasma chemistry markers in Balb/c mice

ALT
AST
TBIL
BUN

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
22
63
0.16
22

958375
2736
3013
0.43
22

958454
1183
2162
6.53
45

958498
1441
3197
0.74
12

958499
142
146
0.17
26

958509
1483
1627
0.31
26

958540
4127
3940
0.44
25

958553
174
227
0.20
29

958554
583
1051
0.28
17

958590
374
360
0.16
25

958603
1103
927
0.35
27

958721
57
114
0.17
28

958725
3758
3758
0.91
31

958729
4368
4503
2.15
30

958736
2439
1450
0.31
20

Body and Organ Weights

TABLE 93

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
24
1.28
0.37
0.09

958375
23
2.00
0.39
0.12

958454
14
0.68
0.25
0.03

958498
20
1.51
0.45
0.19

958499
23
1.44
0.32
0.14

958509
20
1.50
0.27
0.13

958540
19
1.53
0.33
0.09

958553
21
1.01
0.29
0.11

958554
22
1.05
0.28
0.15

958590
25
1.76
0.40
0.13

958603
21
1.80
0.36
0.20

958721
24
1.45
0.33
0.12

958725
15
1.23
0.21
0.04

958729
15
1.32
0.24
0.05

958736
24
1.95
0.39
0.18

Example 13
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 4-6 weeks of age (obtained from Taconic) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male Balb/c mice was injected with PBS. Mice were euthanized on day 25 post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

TABLE 94

Plasma chemistry markers in Balb/c mice

ALT
AST
TBIL
BUN

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
26*
65*
0.18
22

958371
249
199
0.24
30

958914
1855
1837
0.68
29

958933
63
122
0.22
33

958939
2236
1863
0.38
23

958941
772
500
0.23
30

958961
66
106
0.19
28

958973
93
126
0.20
22

959022
13242
8058
1.12
25

959030
1160
1328
0.21
29

959155
2146
1686
0.22
26

959167
1556
2096
0.56
24

959196
1169
785
0.31
27

959197
753
493
0.29
23

*Average of 3 values

Body and Organ Weights

TABLE 95

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
25
1.29
0.39
0.09

958371
23
1.31
0.32
0.15

958914
19
1.22
0.32
0.12

958933
27
1.86
0.37
0.15

958939
24
1.67
0.40
0.23

958941
26
1.81
0.37
0.15

958961
26
1.47
0.39
0.15

958973
26
1.71
0.40
0.19

959022
19
1.76
0.34
0.11

959030
25
1.73
0.38
0.14

959155
21
1.53
0.34
0.25

959167
22
0.96
0.37
0.10

959196
23
1.22
0.34
0.11

959197
23
1.37
0.34
0.14

Example 14
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Balb/c Mice

Balb/c mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of male Balb/c mice at 5-6 weeks of age (obtained from Taconic) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male Balb/c mice was injected with PBS. Mice were euthanized on day 27 post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

TABLE 96

Plasma chemistry markers in Balb/c mice

ALT
AST
TBIL
BUN

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
33
123
0.25
22

958497
46
151
0.24
26

958534
1962
1617
0.33
26

958589
35
66
0.21
24

958596
207
162
0.23
24

958622
224
254
0.24
23

958739
145
186
0.21
21

Body and Organ Weights

Body weights of Balb/c mice were measured on day 25, and the average body weight for each group is presented in the table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 97

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
23
1.14
0.35
0.08

958497
23
1.31
0.35
0.11

958534
22
1.81
0.32
0.09

958589
25
1.40
0.37
0.10

958596
25
2.11
0.36
0.13

958622
23
0.92
0.33
0.12

958739
24
1.58
0.36
0.13

Example 15
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-5 weeks of age (obtained from Charles River) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized on day 26 post start of treatment (24 hrs following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 98

Plasma chemistry markers in CD-1 mice

ALT
AST
TBIL
BUN
ALB

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)
(g/dL)

PBS
32
47
19
0.2
2.5

1074234
81
187
23
0.2
2.3

1074461
1563
865
22
0.6
2.2

1074554
32
49
22
0.2
2.5

1074557
32
65
23
0.2
2.3

1074587
163
131
25
0.2
2.4

1074588
38
67
22
0.2
2.3

1074622
34
59
20
0.2
2.5

1074655
1360
978
19
0.3
2.0

1074680
78
125
19
0.1
2.0

1075067
28
59
23
6.4
2.5

1075068
43
81
19
0.2
2.2

1075741
114
113
20
0.2
2.3

1075768
48
65
19
0.2
2.3

1075769
74
103
18
0.2
2.5

1075774
45
71
20
0.2
2.5

1075838
97
131
22
0.2
2.2

715483
79
125
21
0.2
2.2

715487
66
113
21
0.1
1.9

716454
44
56
20
0.2
2.3

Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and the average body weight for each group is presented in the table below. Kidney, spleen, and liver weights were measured at the end of the study and are presented in the table below. Modified oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 99

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
44
2.51
0.61
0.12

1074234
37
2.26
0.55
0.12

1074554
38
2.09
0.52
0.11

1074557
38
1.87
0.61
0.15

1074587
39
2.33
0.58
0.16

1074588
40
2.40
0.69
0.20

1074622
38
2.16
0.64
0.21

1074655
39
3.40
0.69
0.30

1074680
42
2.52
0.65
0.24

1075067
40
2.12
0.65
0.17

1075068
38
2.15
0.64
0.20

1075741
39
2.21
0.62
0.23

1075768
37
1.86
0.54
0.13

1075769
35
1.76
0.47
0.10

1075774
37
2.23
0.59
0.14

1075838
41
2.28
0.57
0.25

715483
40
2.26
0.64
0.21

715487
41
2.24
0.59
0.21

716454
38
2.31
0.55
0.20

Example 16
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-5 weeks of age (obtained from Charles River) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized on day 27 post start of treatment (24 hrs following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 100

Plasma chemistry markers in CD-1 mice

ALT
AST
TBIL
BUN
Albumin

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)
(g/dL)

PBS
21
45
0.19
22
2.5

1076024
41
88
0.19
19
2.3

1076157
55
105
0.19
19
2.1

1076186
74
97
0.16
23
2.5

1076187
57
90
0.18
20
2.3

1076190
48
63
0.17
20
2.2

1076287
53
98
0.20
21
2.1

1076379
37
89
0.15
20
2.1

1076382
52
87
0.14
19
1.9

1076475
38
62
0.15
18
2.0

1095493
1623
1449
0.69
18
1.8

Body and Organ Weights

TABLE 101

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
35
1.78
0.56
0.12

1076024
40
2.28
0.66
0.15

1076157
38
2.48
0.58
0.23

1076186
37
2.42
0.58
0.16

1076187
34
1.95
0.56
0.14

1076190
38
2.28
0.56
0.15

1076287
36
2.36
0.63
0.36

1076379
38
2.21
0.57
0.18

1076382
36
2.22
0.62
0.21

1076475
37
2.16
0.64
0.17

1095493
28
1.94
0.50
0.17

Example 17
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-5 weeks of age (obtained from Charles River) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized on day 27 post start of treatment (24 hrs following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 102

Plasma chemistry markers in CD-1 mice

ALT
AST
BUN
TBIL

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
22
100
24
0.16

1095404
1282
503
22
0.14

1095515
1041
951
19
1.12

1095632
92
126
26
0.15

1096947
46
116
23
0.17

1096450
1104
635
25
2.19

1096973
35
59
20
0.22

1097037
73
97
23
0.12

1096522
652
397
21
0.16

1075395
38
51
21
0.18

1097183
834
738
16
0.39

1097224
39
78
21
0.09

1097231
85
112
21
0.13

Body and Organ Weights

TABLE 103

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
34
1.92
0.55
0.11

1095404
33
2.09
0.58
0.15

1095515
26
1.52
0.47
0.20

1095632
33
2.04
0.48
0.17

1096947
33
1.91
0.51
0.21

1096450
35
2.59
0.42
0.19

1096973
35
2.21
0.48
0.18

1097037
33
2.33
0.52
0.21

1096522
31
2.04
0.45
0.18

1075395
34
2.30
0.49
0.20

1097183
28
1.23
0.46
0.20

1097224
37
1.93
0.54
0.16

1097231
34
2.37
0.47
0.24

Example 18
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 5-6 weeks of age (obtained from Charles River) were injected subcutaneously twice a week for four weeks (for a total of 9 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized on day 34 post start of treatment (24 hours following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 104

Plasma chemistry markers in CD-1 mice

ALT
AST
BUN
TBIL

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
24
53
20
0.27

958499
79
88
24
0.18

1074755
88
104
22
0.21

1076453
56
113
20
0.24

1076481
71
121
23
0.23

Body and Organ Weights

TABLE 105

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
39
1.84
0.59
0.17

958499
39
2.20
0.57
0.22

1074755
39
2.27
0.61
0.19

1076453
38
1.91
0.56
0.20

1076481
39
2.06
0.57
0.23

Example 19
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Groups of four male CD-1 mice at 4-6 weeks of age (obtained from Charles River) were injected subcutaneously twice a week for four weeks (for a total of 8 treatments) with 50 mg/kg of modified oligonucleotides. One group of male CD-1 mice was injected with PBS. Mice were euthanized on day 26 post start of treatment (24 hrs following the final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function, plasma levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and total bilirubin (TBIL) were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The results are presented in the table below. Modified oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 106

Plasma chemistry markers in CD-1 mice

ALT
AST
TBIL
BUN

ION No.
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
32
48
0.25
20

1198439
210
219
0.25
18

1198440
121
140
0.22
19

1198872
192
207
0.25
22

1157929
39
50
0.22
19

1157034
210
165
0.19
17

1157111
48
74
0.22
17

Body and Organ Weights

TABLE 107

Body and organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
36
2.04
0.59
0.12

1198439
36
2.03
0.51
0.25

1198440
35
1.97
0.46
0.18

1198872
34
1.84
0.40
0.16

1157929
34
1.98
0.43
0.13

1157034
35
2.43
0.53
0.17

1157111
36
2.53
0.50
0.21

Example 20
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety and efficacy evaluations. The rats were treated with Ionis modified oligonucleotides from the studies described in the Examples above and evaluated for changes in the levels of various plasma chemistry markers.

Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow. Groups of 4 Sprague-Dawley rats each were weekly injected subcutaneously with 50 mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Forty-eight hours after the last dose, the rats were euthanized; and organs, urine and plasma were harvested for further analysis.

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the table below expressed in IU/L. Plasma levels of total bilirubin (TBIL), albumin (ALB), and blood urea nitrogen (BUN) were also measured using the same clinical chemistry analyzer and the results are also presented in the table below. Ionis modified oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 108

Plasma chemistry markers in Sprague-Dawley rats

Plasma clinical chemistry

ALT
AST
TBIL
BUN
ALB

ASO
(U/L)
(U/L)
(mg/dL)
(mg/dL)
(g/dL)

PBS
31*
67*
0.17*
16
1.61

958499
61
109
0.18
24
2.78

1074755
57
97
0.12
29
2.99

1076187
54
113
0.10
21
2.91

1076453
47
77
0.13
23
3.14

1076481
50
91
0.13
49
2.74

1097224
31
51
0.07
86
1.61

*Refers to groups with only 3 data points

Kidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function, urinary levels of total protein and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The ratios of total protein to creatinine (P/C ratio) are presented in the Table below. Ionis oligonucleotides that caused changes in the levels of the ratio outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 109

Total protein to creatinine ratio in Sprague-Dawley rats

URINE

P/C

ION NO.
ratio

PBS
1

958499
5

1074755
5

1076187
5

1076453
5

1076481
5

1097224
87

Body and Organ Weights

Liver, spleen and kidney weights were measured at the end of the study and are presented in the table below. Terminal body weight was measured prior to necropsy. Ionis oligonucleotides that caused any changes in organ weights outside the expected range for modified oligonucleotides were excluded from further studies.

TABLE 110

Body and Organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
423
16
3.1
0.9

958499
333
14
3.1
2.8

1074755
357
16
3.3
2.1

1076187
344
17
3.0
1.7

1076453
371
16
3.2
2.1

1076481
367
14
2.6
2.1

1097224
316
13
4.5
1.4

Example 21
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Sprague-Dawley Rats

Treatment

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. Plasma levels of total bilirubin (TBIL) and blood urea nitrogen (BUN) were also measured using the same clinical chemistry analyzer and the results are also presented in the Table below. Ionis modified oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 111

Plasma chemistry markers in Sprague-Dawley rats

Plasma clinical chemistry

ALT
AST
TBIL
BUN

ASO
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
64
98
0.19
19

1198874
73
102
0.16
22

1200857
183
318
4.93
56

1074756
114*
79*
0.10*
0.57*

1198873
78*
79*
0.17*
24*

1198439
54*
94*
0.15*
22*

1198615
38
71
0.13
21

1198440
58**
108**
0.17**
20**

1198612
74
91
0.12
31

1198312
132
108
0.14
25

*Refers to groups with 3 samples

**Refers to groups with 2 samples

Body and Organ Weights

TABLE 112

Body and Organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
453
17
3.64
0.91

1198874
372
20
3.67
2.61

1200857
307
19
6.97
2.55

1074756
349
21*
4.71*
1.99*

1198873
408
19
3.65
2.42

1198439
319*
17*
3.68*
2.28*

1198615
369
16
3.01
2.35

1198440
373
18
3.29
2.78

1198612
345
17
3.60
2.33

1198312
365
19
4.26
2.19

*Refers to groups with 3 samples

Kidney Function

TABLE 113

Total protein to creatinine ratio in Sprague-Dawley rats

URINE

P/C

ION NO.
ratio

PBS
1

1198874
9

1200857
52

1074756
167

1198873
9

1198439
8*

1198615
8

1198440
9

1198612
11

1198312
60

*Refers to groups with 3 samples

Example 22
Tolerability of Modified Oligonucleotides Targeting Human Yap1 in Sprague-Dawley Rats

Treatment

Plasma Chemistry Markers

To evaluate the effect of Ionis oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in the Table below expressed in IU/L. Plasma levels of total bilirubin (TBIL) and blood urea nitrogen (BUN) were also measured using the same clinical chemistry analyzer and the results are also presented in the Table below. Ionis modified oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for modified oligonucleotides were excluded in further studies.

TABLE 114

Plasma chemistry markers in Sprague-Dawley rats

Plasma clinical chemistry

ALT
AST
TBIL
BUN

ASO
(U/L)
(U/L)
(mg/dL)
(mg/dL)

PBS
80
105
0.22
19

1197270
84
120
0.19
24

1198872
109
134
0.20
18

1198728
54
71
0.18
22

1198831
54
69
0.20
23

1198623
96
87
0.24
21

1198605
46
76
0.33
18

Kidney Function

TABLE 115

Total protein to creatinine ratio in Sprague-Dawley rats

URINE

P/C

ION NO.
ratio

PBS
1

1197270
14

1198872
8

1198728
7

1198831
17

1198623
5

1198605
28

Body and Organ Weights

TABLE 116

Body and Organ weights

body

weight
Liver
Kidney
Spleen

ION No.
(g)
(g)
(g)
(g)

PBS
476
18
3.4
0.9

1197270
374
15
3.6
2.0

1198872
417
17
3.4
1.3

1198728
381
15
2.9
1.4

1198831
426
19
3.3
2.0

1198623
472
20
3.6
1.9

1198605
372
18
3.6
2.1

Example 23
Measurement of Viscosity of Modified Oligonucleotides Targeting Human Yap1

The viscosity of select modified oligonucleotides from the studies described above was measured with the aim of screening out modified oligonucleotides which have a viscosity of more than 40 centipoise (cP). Modified oligonucleotides having a viscosity greater than 40 cP would have less than optimal viscosity.

Oligonucleotides (32-38 mg) were weighed into a glass vial; approximately 100 μL of water was added, and the modified oligonucleotide was dissolved into solution by heating the vial to 55° C. Part (75 μL) of the pre-heated sample was pipetted to a micro-viscometer (PAC Cambridge Viscosity Viscometer). The temperature of the micro-viscometer was set to 25° C. and the viscosity of the sample was measured. The entire 75 uL of sample was them combined with the remaining portion of the sample was diluted appropriately for UV reading at 260 nM (Cary UV instrument). Modified oligonucleotides solutions that were not optimal in their viscosity under the criterion stated above were excluded in further studies.

TABLE 117

Viscosity of modified oligonucleotides

Concentration
Concentration

Compound
by weight
by UV
Viscocity

ID
(mg/mL)
(mg/mL)
(cP)

958499
300
220.7
84.5

1074755
300
217.2
7.2

1074756
300
232.8
17.4

1076187
300
237.4
40.6

1076453
300
229.1
46.4

1076481
300
213.0
6.4

1097224
300
230.7
8.1

1197269
300
211.4
10.7

1197270
300
241.6
15.1

1198243
300
234.0
13.4

1198312
300
233.1
17.5

1198439
300
233.8
14

1198440
300
219.7
8.6

1198501
300
220.0
14.5

1198605
300
220.7
59.6

1198611
300
228.3
8.6

1198612
300
230.1
10.2

1198615
300
223.1
23

1198623
300
215.4
20.8

1198641
300
223.2
16.4

1198656
300
227.6
26.1

1198673
300
237.2
15.3

1198728
300
241.8
30.9

1198746
300
232.7
13.4

1198831
300
204.0
5.8

1198872
300
220.7
5.5

1198873
300
229.1
7.6

1198874
300
222.0
12.5

1200857
300
226.4
13.1

Example 24
Dose-Dependent Inhibition of Human Yap1 in A-431 Cells by Modified Oligonucleotides

Modified oligonucleotides described in the studies above were tested at various doses in A-431 cells. Cultured A-431 cells at a density of 11,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS36584. Yap1 mRNA levels were normalized to GAPDH content, as measured by primer probe set RTS104 (forward sequence GAAGGTGAAGGTCGGAGTC, designated herein as SEQ ID NO.: 17; reverse sequence GAAGATGGTGATGGGATTTC, designated herein as SEQ ID NO.: 18; probe sequence CAAGCTTCCCGTTCTCAGCC, designated herein as SEQ ID NO.: 19). Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC). IC50s were calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 118

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 cells

% UTC
IC50

ION No.
0.002 μM
0.008 μM
0.04 μM
0.2 μM
1 μM
(μM)

958499
1
3
28
91
117
0.03

1076453
0
1
23
74
89
0.01

1197270
0
2
26
80
99
0.02

1198439
0
1
11
65
93
0.02

1198440
0
1
14
69
96
0.02

1198605
0
2
26
57
96
0.02

1198623
2
5
28
72
96
0.01

1198728
1
4
27
85
87
0.02

1198831
2
6
28
72
83
0.01

1198872
1
3
19
70
94
0.01

Example 25
Activity of Modified Oligonucleotides Targeting Human Yap1 in SCC25 Cells

Modified oligonucleotides described in the studies above were tested at various doses in squamous cell carcinoma cell SCC25. A control oligonucleotide 792169 (a 3-10-3 cET gapmer with a full phosphorothioate backbone, CGCCGATAAGGTACAC, designated herein as SEQ ID No.: 2940; is not complementary to any known human gene) was also tested.

RNA Analysis

Cultured SCC25 cells at a density of 5,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002 (forward sequence CGGACTATGACTTAGTTGCGTTACA, designated herein as SEQ ID NO.: 20; reverse sequence GCCATGCCAATCTCATCTTGT, designated herein as SEQ ID NO.: 21; probe sequence CCTTTCTTGACAAAACCTAACTTGCGCAGA, designated herein as SEQ ID NO.: 22). Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 119

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SCC25 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
96
89
93
98

958499
47
22
10
4

1076453
59
21
7
3

1197270
48
24
12
7

1198439
35
12
5
3

1198440
39
14
5
3

1198605
48
23
10
5

1198623
61
31
15
10

1198728
71
31
15
7

1198831
63
36
16
14

1198872
54
22
9
7

Cell Proliferation Assay

Cultured SCC25 cells at a density of 1,000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 120

Antiproliferative effect of modified

oligonucleotides in SCC25 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
103
104
100
88

958499
76
42
25
14

1076453
81
40
23
15

1197270
75
40
22
14

1198439
62
30
22
16

1198440
73
33
22
16

1198605
77
39
23
13

1198623
84
55
36
29

1198728
88
61
30
20

1198831
88
54
25
21

1198872
82
37
22
18

Example 26
Dose Dependent Inhibition of Human Yap1 by Modified Oligonucleotides in a Human Hepatocellular Carcinoma SNU449 Xenograft Tumor Model

A SNU449 hepatocellular carcinoma xenograft tumor model was used to evaluate activity of modified oligonucleotides targeted to human Yap1. Ten million SNU449 cells in 30% matrigel were implanted subcutaneously into the flanks of female NOD Cg-Prkdcscid ll2rgtm1Wjl/SzJ (NSG) mice (from Jackson Laboratory) at 4-6 weeks of age. When tumors reached an average volume of 100 mm³, approximately two weeks post-implantation, groups of four mice each were administered at 50 mg/kg twice weekly with modified oligonucleotides for five days. Tumors were collected and tested for Yap1 mRNA knockdown by RT-qPCR. Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to PBS treated animals (% control).

TABLE 121

Inhibition of human Yap1 mRNA expression by modified

oligonucleotides in SNU449 xenografts

ION No.
% control

PBS
100

958499
54

1074755
70

1076453
56

1197269
57

1197270
54

1198439
51

1198440
51

1198501
54

1198605
55

1198615
62

1198623
60

1198641
68

1198673
52

1198728
64

1198831
67

1198872
52

715487
61

Example 27
Dose Dependent Inhibition of Human Yap1 by Modified Oligonucleotides in a Human Epidermoid Carcinoma A-431 Xenograft Tumor Model

An epidermoid carcinoma A-431 xenograft tumor model was used to evaluate activity of modified oligonucleotides targeted to human Yap1. Five million A-431 cells in 30% matrigel were implanted subcutaneously into the flanks of female NCr-Foxn1nu mice (from Taconic) at 4-6 weeks of age. When tumors reached an average volume of 40 mm³, approximately two weeks post-implantation, groups of four mice each were administered at either 25 mg/kg or 50 mg/kg daily with modified oligonucleotides for four days (5 doses). Tumors were collected 6-8 hours post final dose and tested for Yap1 mRNA knockdown by RT-qPCR. Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to PBS treated animals (% control).

TABLE 122

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in A-431 xenografts

% control

ION No.
25 mpk
50 mpk

PBS
100
100

958499
49
29

1076453
55
25

1197270
57
38

1198439
37
19

1198440
32
21

1198605
32
30

1198623
43
36

1198728
47
39

1198831
47
37

1198872
34
26

715487
61
57

Example 28
Dose Dependent Inhibition of Human Yap1 by Modified Oligonucleotides in a Human Squamous Cell Carcinoma CAL27 Xenograft Tumor Model

A squamous cell carcinoma CAL27 xenograft tumor model was used to evaluate activity of modified oligonucleotides targeted to human Yap1. Five million CAL27 cells in 30% matrigel were implanted subcutaneously into the flanks of female CrTac:NCr-Foxn1nu mice (from Taconic) at 4-6 weeks of age. Groups of four mice each were administered with either 15 mg/kg or 30 mg/kg of modified oligonucleotides daily for five days after tumor size had reached ˜100 mm³(about 3 weeks post implantation). Tumors were collected and tested for Yap1 mRNA knockdown by RT-qPCR. Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to PBS treated untreated control cells (% UTC).

TABLE 123

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in CAL27 xenografts

% UTC

ION No.
15 mg/kg
30 mg/kg

PBS
100
100

958499
68
53

1076453
69
46

1197270
55
38

1198439
66
38

1198440
67
41

1198605
65
48

1198623
52
44

1198728
77
56

1198831
70
48

1198872
55
38

Example 29
Activity of Modified Oligonucleotides Targeting Human Yap1 in a Human Squamous Cell Carcinoma CAL33 Xenograft Tumor Model

A xenograft tumor model was used to evaluate activity of modified oligonucleotides targeted to human Yap1. One million CAL33 cells in 30% matrigel were implanted subcutaneously into the flanks of female CrTac:NCr-Foxnlnu (Taconic) mice. When tumors reached an average volume of 100 mm³, approximately two weeks post-implantation, groups of eight mice were administered at 50 mg/kg twice weekly with modified oligonucleotides for two weeks. ION 792169 was administered as a control.

Tumor samples were collected for measurement of Yap1 mRNA levels by RT-qPCR. Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to PBS treated animals (% control).

Tumor volume was measured at the indicated days in the table below. Tumor weight was determined at end of study. Mice were sacrificed when tumors from PBS-treated mice reached 2,000 mm3.

TABLE 124

Yap1 mRNA levels in tumors

ION No.
% control

PBS
102

792169
74

1198728
40

1198440
12

TABLE 125

Tumor volume (mm³)

Days post-implantation

10
13
17
21
24
27
31
34
38
40
44

ION Number
Average Tumor Volume(mm³)

PBS
144
254
382
666
855
974
1180
1342
1458
1472
1377

792169
123
262
367
531
774
805
962
1057
1171
1160
1069

1198728
113
253
423
621
835
988
1123
1233
1239
1277
1277

1198440
115
279
376
574
651
818
888
857
770
746
834

TABLE 126

Tumor weight (g)

Average

Tumor

ION No.
weight (g)

PBS
1.02

792169
0.85

1198728
0.88

1198440
0.36

Example 30
Activity of Modified Oligonucleotides Targeting Human Yap1 in a Human Hepatocellular Carcinoma SNU449 Xenograft Tumor Model

Modified oligonucleotides described in the studies above were tested in a hepatocellular carcinoma SNU449 xenograft tumor model. A control oligonucleotide 792169 was also tested.

Five million SNU449 cells in 30% matrigel were implanted subcutaneously into the fatpads of female NOD.Cg-Prkdcscid II2rgtmlWjl/SzJ mice (from Jackson Laboratory) at 4-6 weeks of age. 43 days post implantation (when tumors had reached approximately 100 mm³in size), groups of eight mice each were administered with 50 mg/kg modified oligonucleotide daily for 10 days (loading dose), following which they were administered with 50 mg/kg modified oligonucleotide four times a week for one week, following which they were dosed with 50 mg/kg modified oligonucleotide thrice weekly until the end of the study. Animals were sacrificed and tumors were collected on day 119 post implantation. Yap1 mRNA knockdown in tumors was measured by RT-qPCR as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to PBS treated animals (% control).

Tumor volumes were also measured at the indicated days in the table below

TABLE 127

Yap1 mRNA levels in tumors

Ion No.
% control

PBS
100

792169
90

1198440
34

TABLE 128

Tumor volume (mm³)

Days Post
Average Tumor Volume

Tumor
(mm³)

Implantation
PBS
792169
1198440

43
111
111
111

46
175
162
152

50
208
180
168

53
252
247
201

57
292
280
242

60
362
317
263

64
396
397
338

67
438
466
376

71
463
519
373

75
570
559
401

78
597
634
429

81
657
681
514

85
760
785
606

88
786
889
613

92
955
1170
690

94
1048
1215
773

98
1114
1355
804

101
1175
1417
818

105
1252
1509
894

108
1284
1571
921

119
1431
1697*
978

*Average of 7 samples

Example 31
Activity of Modified Oligonucleotides Targeting Human Yap1 in NCI H747 Cells

Modified oligonucleotides described in the studies above were tested at various doses in colorectal adenocarcinoma cell line NCI H747. A control oligonucleotide 792169 was also tested.

RNA Analysis

Cultured NCI H747 cells at a density of 10,000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 129

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in NCI H747 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
94
83
87
100

715487
83
70
49
30

1198440
73
53
21
9

Cell Proliferation Assay

Cultured NCI H747 cells at a density of 3000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After 7 days, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 130

Antiproliferative effect of modified

oligonucleotides in NCI H747 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
89
97
91
80

715487
91
86
65
42

1198440
87
66
36
18

Example 32
Activity of Modified Oligonucleotides Targeting Human Yap1 in NCI H292 Cells

Modified oligonucleotides described in the studies above were tested at various doses in mucoepidermoid pulmonary carcinoma cell line NCI 1-1292. A control oligonucleotide 792169 was also tested.

RNA Analysis

Cultured NCI H292 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 131

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in NCI H292 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
98
112
111
106

715487
104
83
40
12

1198440
89
53
18
5

Cell Proliferation Assay

Cultured NCI H292 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 132

Antiproliferative effect of modified

oligonucleotides in NCI H292 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
98
97
99
92

715487
87
90
69
20

1198440
100
83
30
15

Example 33
Activity of Modified Oligonucleotides Targeting Human Yap1 in BICR56 Cells

Modified oligonucleotides described in the studies above were tested at various doses in squamous cell carcinoma adherent keratinocyte cell line BICR56. A control oligonucleotide 792169 was also tested.

RNA Analysis

Cultured BICR56 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 133

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in BICR56 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
99
92
85
97

715487
68
28
16
11

1198440
40
10
7
7

Cell Proliferation Assay

Cultured BICR56 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 134

Antiproliferative effect of modified

oligonucleotides in BICR56 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
106
100
92
87

715487
70
26
9
4

1198440
28
10
6
4

Example 34
Effect of Modified Oligonucleotides Targeting Human Yap1 in Cynomolgus Monkeys

Cynomolgus monkeys were treated with Ionis modified oligonucleotides selected from studies described in the Examples above. Modified oligonucleotide tolerability was evaluated.

Treatment

Prior to the study, the monkeys were kept in quarantine during which the animals were observed daily for general health. The monkeys were 2-4 years old and weighed 2-4 kg. Eleven groups of 4 randomly assigned male cynomolgus monkeys each were injected subcutaneously with Ionis oligonucleotide or saline in a clock-wise rotation between four different sites on the back. Following loading doses on days 1, 3, 5 and 7, the monkeys were dosed once per week (on days 14, 21, 28, 35, and 42) with 35 mg/kg of Ionis oligonucleotide. A control group of 4 cynomolgus monkeys was injected with 0.9% saline in a similar manner and served as the control group.

During the study period, the monkeys were observed twice daily for signs of illness or distress. Any animal experiencing more than momentary or slight pain or distress due to the treatment, injury or illness was treated by the veterinary staff with approved analgesics or agents to relieve the pain after consultation with the Study Director. Any animal in poor health or in a possible moribund condition was identified for further monitoring and possible euthanasia. Scheduled euthanasia of the animals was conducted on day 86 approximately 48 hours after the last dose by exsanguination while under deep anesthesia. The protocols described in the Example were approved by the Institutional Animal Care and Use Committee (IACUC).

Body and Organ Weight Measurements

To evaluate the effect of Ionis oligonucleotides on the overall health of the animals, body and organ weights were measured. Terminal body weight was measured prior to necropsy. Organ weights were measured as well, and all weight measurements are presented in the Table below. The results indicate that effect of treatment with modified oligonucleotides on body and organ weights was within the expected range for modified oligonucleotides. Specifically, treatment with ION 1198440 was well tolerated in terms of the body and organ weights of the monkeys.

TABLE 135

Body and Organ weights (g)

Terminal

Body

Liver with

ION No.
Weight
Heart
kidney
spleen
gallbladder

Saline
2855
11
14
3
60

958499
2894
10
15
4
68

1076453
2955
11
16
5
72

1197270
2852
10
17
4
73

1198439
2959
10
15
3
67

1198440
2919
11
15
3
65

1198605
2968
11
15
4
67

1198623
2790
9
13
3
62

1198728
2722
10
15
5
65

1198831
2788
11
14
4
65

1198872
3126
12
15
4
63

Kidney and Liver Function

To evaluate the effect of Ionis oligonucleotides on hepatic and kidney function, blood samples were collected from all the study groups on day 44. The monkeys were fasted overnight prior to blood collection. Blood was collected in tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 minutes and then centrifuged at 3000 rpm for 10 minutes to obtain serum. Levels of various liver function markers were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). Plasma levels of glucose (GLU), blood urea nitrogen (BUN), creatinine (CREA), total protein (TP), albumin (ALB), globulin (GLO), albumin/globulin (A/G) ratio calculated, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL) were measured and the results are presented in the table below. The results indicate that modified oligonucleotides had no effect on liver function outside the expected range for modified oligonucleotides. Specifically, treatment with ION 1198440 was well tolerated in terms of the liver function in monkeys.

TABLE 136

Liver/Kidney function markers in cynomolgus monkey plasma

ALT
AST
TBIL
GGT
ALP
TG
HDL
LDL

ION NO.
(IU/L)
(IU/L)
(mg/dL)
(IU/L)
(IU/L)
(mg/dL)
(mg/dL)
(mg/dL)

Saline
60
50
0.3
91
1539
34
96
68

958499
67
73
0.2
67
1449
41
89
46

1076453
53
76
0.2
78
1173
29
98
66

1197270
84
78
0.2
75
1215
31
102
48

1198439
40
65
0.2
63
1298
28
82
59

1198440
45
75
0.2
80
1412
30
104
54

1198605
40
58
0.2
85
1445
25
115
57

1198623
50
47
0.2
59
916
34
87
50

1198728
58
92
0.3
59
1165
24
95
57

1198831
48
63
0.3
65
1096
22
108
63

1198872
48
94
0.3
79
1098
19
114
60

TABLE 137

Liver/Kidney function markers in cynomolgus monkey plasma

GLU
BUN
CREA
TP
ALB
GLO
A/G

ION NO.
(mg/dL)
(mg/dL)
(mg/dL)
(g/dL)
(g/dL)
(g/dL)
ratio

Saline
84
25
1.0
7.2
4.2
3.0
1.4

958499
83
24
0.9
7.2
4.0
3.2
1.3

1076453
89
27
0.9
7.0
3.9
3.1
1.3

1197270
115
27
0.9
6.8
3.7
3.1
1.2

1198439
115
24
0.9
6.8
4.0
2.8
1.4

1198440
91
26
0.9
7.0
4.1
2.9
1.4

1198605
69
22
0.8
6.7
4.0
2.7
1.5

1198623
70
26
0.8
7.2
4.2
3.0
1.4

1198728
95
26
0.9
7.3
4.1
3.2
1.3

1198831
73
26
0.7
6.7
3.9
2.8
1.4

1198872
80
27
0.9
7.1
4.0
3.1
1.3

Pro-Inflammatory Proteins Analysis

To evaluate any inflammatory effect of Ionis oligonucleotides in cynomolgus monkeys, blood samples were taken for analysis. The monkeys were fasted overnight prior to blood collection. On day 42 (pre-dose and 24 hours post-dose), approximately 0.8 mL of blood was collected from each animal and put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min at room temperature to obtain serum. Complement C3 were measured using a Toshiba 120 FR NEO chemistry analyzer (Toshiba Co., Japan). The results indicate that treatment with ION 1198440 did not cause any inflammation in monkeys. Another marker of inflammation, C-Reactive Protein (CRP) was tested together with the clinical chemistry parameters tested for liver function above.

TABLE 138

Pro-inflammatory protein analysis in cynomolgus monkeys

Complement C3 (mg/dL)

Day 42
day 42
CRP (mg/L)

ION No.
(pre-dose)
(24 hr post-dose)
day 44

Saline
117
106
4.1

958499
112
89
9.9

1076453
101
88
1.5

1197270
103
86
9.8

1198439
99
94
2.9

1198440
95
88
4.8

1198605
105
95
4.2

1198623
105
101
2.0

1198728
93
90
4.0

1198831
81
81
1.1

1198872
103
96
1.1

Hematology

To evaluate any effect of Ionis oligonucleotides in cynomolgus monkeys on hematologic parameters, blood samples of approximately 0.5 mL of blood was collected from each of the available study animals on day 44. The samples were collected in tubes containing K₂-EDTA. Samples were analyzed for red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit (HCT), Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RBC Distribution Width (RCDW), reticulocyte count (Retic), platelet count (PLT), mean platelet volume (MPV), white blood cells (WBC) count, individual white blood cell counts, such as that of monocytes (MON), neutrophils (NEU), lymphocytes (LYM), eosinophils (EOS), basophils (BAS), and large unstained cells (LUC) using an ADVIA2120i hematology analyzer (Siemens, USA).

The data indicate the oligonucleotides did not cause any changes in hematologic parameters outside the expected range for modified oligonucleotides at this dose. Specifically, treatment with ION 1198440 was well tolerated in terms of the hematologic parameters of the monkeys.

TABLE 139

Blood cell counts in cynomolgus monkeys

RBC
HGB
HCT
MCV
MCH
MCHC
RCDW
Retic
PLT

ION NO.
(×10{circumflex over ( )}6/μL)
(g/dL)
(%)
(fL)
(pg)
(g/dL)
(%)
(%)
(10³/μL)

Saline
5.8
13
46
79
23
29
13
1.2
334

958499
5.6
12
43
77
22
29
12
1.5
399

1076453
5.5
13
43
79
23
29
15
1.2
358

1197270
5.6
12
44
79
22
28
12
1.1
452

1198439
6.0
14
48
79
22
28
12
1.2
367

1198440
5.9
14
47
80
23
29
12
1.2
420

1198605
6.1
13
46
75
22
29
13
1.1
385

1198623
5.9
14
46
78
23
30
13
1.0
376

1198728
5.9
14
47
80
23
29
12
1.3
428

1198831
5.6
13
43
76
23
30
12
1.0
377

1198872
5.7
13
44
78
23
30
12
1.2
400

TABLE 140

Blood cell counts in cynomolgus monkeys

WBC
NEU
LYM
MON
EOS
BAS
LUC
MPV

ION NO.
(×10³/μL)
(%)
(%)
(%)
(%)
(%)
(%)
(fL)

ine
9.2
41
55
3.2
1.0
0.3
0.5
8.2

958499
12.0
49
44
3.5
1.1
0.4
1.2
7.6

1076453
10.0
39
54
3.9
1.1
0.4
1.2
8.4

1197270
10.6
38
54
3.5
2.7
0.4
1.2
7.1

1198439
10.3
27
68
2.9
1.5
0.3
0.6
7.6

1198440
10.9
28
65
3.2
2.8
0.4
0.7
7.5

1198605
10.5
44
51
2.8
0.8
0.4
0.5
8.1

1198623
11.7
43
53
2.0
0.8
0.4
0.7
7.8

1198728
10.7
29
64
2.9
2.2
0.5
0.9
8.0

1198831
7.6
44
50
3.3
2.0
0.3
0.8
7.3

1198872
10.4
64
32
2.2
0.6
0.3
0.5
7.1

Coagulation

To evaluate effect of Ionis modified oligonucleotides on coagulation in cynomolgus monkeys, blood samples of approximately 0.9 mL were collected from each of the available study animals on day 44. The samples were collected in tubes containing 3.2% sodium citrate. Coagulation parameters tested include Activated partial thromboplastin time (APTT), prothrombin time (PT) and Figrinogen (FIB).

The data indicate the modified oligonucleotides did not cause any changes in coagulation parameters outside the expected range for modified oligonucleotides at this dose. Specifically, treatment with ION 1198440 was well tolerated in terms of the coagulation parameters of the monkeys.

TABLE 141

Coagulation Parameters in cynomolgus monkeys

PT
FIB
APTT

ION No.
(sec)
(mg/dL)
(sec)

Saline
9
229
18

958499
9
275
18

1076453
9
234
20

1197270
10
257
17

1198439
10
246
19

1198440
10
260
20

1198605
9
236
23

1198623
10
229
17

1198728
9
242
18

1198831
10
209
18

1198872
10
206
21

Urine Analysis

Food was removed overnight the day before fresh urine collection, but water was supplied. Fresh urine samples for urinalysis and urine chemistry were collected from all animals using a clean cage pan on wet ice (first in the morning) on day 44. Urinalysis/Urine Chemistry parameters creatinine (UCRE), microprotein (UTP), urine microalbumin (UALB), and protein/creatinine (P/C) ratio were measured using a Toshiba 120FR automated chemistry analyzer (Toshiba Co., Japan). Specifically, treatment with ION 1198440 was well tolerated in terms urine chemistry markers.

TABLE 142

Urinalysis and Urine Chemistry Markers

UTP
UALB
UCRE
P/C

ION NO.
(mg/dL)
(mg/dL)
(mg/dL)
ratio

Saline
13
0.5
69
0.3

958499
16
0.1
60
0.3

1076453
14
0.1
50
0.3

1197270
18
1.3
56
0.3

1198439
15
0.1
68
0.2

1198440
13
0.2
53
0.3

1198605
12
0.4
69
0.2

1198623
10
0.2
44
0.2

1198728
16
0.3
70
0.2

1198831
13
0.1
46
0.3

1198872
14
0.3
111
0.2

Example 35
Activity of Modified Oligonucleotides Targeting Human Yap1 in BICR-22 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous carcinoma (lymph node metastasis) cell line BICR-22. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured BICR-22 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 144

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in BICR-22 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
99
98
98
98

715487
82
45
23
13

1198440
44
14
4
4

Cell Proliferation Assay

Cultured BICR-22 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 145

Antiproliferative effect of modified

oligonucleotides in BICR-22 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
97
95
82
65

715487
70
56
28
22

1198440
55
37
29
19

Example 36
Activity of Modified Oligonucleotides Targeting Human Yap1 in CAL33 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma line CAL33. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured CAL33 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 146

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in CAL33 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
106
106
91
85

715487
81
41
12
6

1198440
43
14
5
5

Cell Proliferation Assay

Cultured CAL33 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 147

Antiproliferative effect of modified

oligonucleotides in CAL33 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
92
93
81
67

715487
89
79
61
37

1198440
84
67
58
44

Example 37
Activity of Modified Oligonucleotides Targeting Human Yap1 in CAL27 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma line CAL27. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured CAL27 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 148

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in CAL27 cells

% UTC

ION No.
0.08 μM
0.4 μM
2 μM
10 μM

792169
95
90
97
88

715487
35
23
5
3

1198440
23
6
4
4

Cell Proliferation Assay

Cultured CAL27 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 149

Antiproliferative effect of modified

oligonucleotides in CAL27 cells

% UTC

ION No.
0.08 μM
0.4 μM
2 μM
10 μM

792169
96
102
103
90

715487
95
85
67
33

1198440
86
85
83
51

Example 38
Activity of Modified Oligonucleotides Targeting Human Yap1 in Detroit-562 Cells

Modified oligonucleotides described in the studies above were tested at various doses in pharynx carcinoma cell line Detroit-562. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured Detroit-562 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 150

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in Detroit-562 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
102
102
94
99

715487
77
29
10
5

1198440
32
8
3
2

Cell Proliferation Assay

Cultured Detroit-562 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 151

Antiproliferative effect of modified

oligonucleotides in Detroit-562 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
99
106
100
79

715487
92
84
71
52

1198440
84
67
59
45

Example 39
Activity of Modified Oligonucleotides Targeting Human Yap1 in SCC-4 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma cell line SCC 4. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-4 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 152

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SCC-4 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
92
106
105
104

715487
81
46
23
13

1198440
63
27
11
5

Cell Proliferation Assay

Cultured SCC-4 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 153

Antiproliferative effect of modified oligonucleotides in SCC-4 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
125
169
142
136

715487
158
121
106
69

1198440
82
60
21
11

Example 40
Activity of Modified Oligonucleotides Targeting Human Yap1 in SCC-9 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma cell line SCC-9. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-9 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 154

Dose-dependent inhibition of human Yap 1 mRNA expression

by modified oligonucleotides in SCC-9 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
86
94
96
101

715487
74
44
21
11

1198440
53
18
6
2

Cell Proliferation Assay

Cultured SCC-9 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 155

Antiproliferative effect of modified oligonucleotides in SCC-9 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
104
111
102
94

715487
97
73
51
34

1198440
88
46
35
31

Example 41
Activity of Modified Oligonucleotides Targeting Human Yap1 in SCC-15 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma cell line SCC-15. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-15 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 156

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SCC-15 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
91
100
102
105

715487
69
33
12
5

1198440
39
10
4
2

Cell Proliferation Assay

Cultured SCC-15 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 157

Antiproliferative effect of modified

oligonucleotides in SCC-15 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
93
92
89
71

715487
87
66
47
28

1198440
72
54
42
32

Example 42
Activity of Modified Oligonucleotides Targeting Human Yap1 in SCC-25 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma cell line SCC-25. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SCC-25 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 158

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SCC-25 cells

% UTC

ION No.
0.08 μM
0.4 μM
2 μM
10 μM

792169
87
87
89
86

715487
70
32
16
11

1198440
32
12
8
7

Cell Proliferation Assay

Cultured SCC-25 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 159

Antiproliferative effect of modified

oligonucleotides in SCC-25 cells

% UTC

ION No.
0.08 μM
0.4 μM
2 μM
10 μM

792169
97
101
96
92

715487
82
48
25
15

1198440
56
27
20
16

Example 43
Activity of Modified Oligonucleotides Targeting Human Yap1 in SNU-899 Cells

Modified oligonucleotides described in the studies above were tested at various doses in laryngeal squamous cell carcinoma cell line SNU-899. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-899 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 160

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-899 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
106
106
111
102

715487
62
26
9
4

1198440
35
12
3
2

Cell Proliferation Assay

Cultured SNU-899 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 161

Antiproliferative effect of modified

oligonucleotides in SNU-899 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
90
94
96
86

715487
82
78
71
62

1198440
82
75
69
66

Example 44
Activity of Modified Oligonucleotides Targeting Human Yap1 in SNU-1066 Cells

Modified oligonucleotides described in the studies above were tested at various doses in laryngeal squamous cell carcinoma line SNU-1066. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-1066 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 162

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-1066 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
91
94
93
98

715487
77
49
22
7

1198440
70
28
7
2

Cell Proliferation Assay

Cultured SNU-1066 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 163

Antiproliferative effect of modified

oligonucleotides in SNU-1066 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
100
104
102
96

715487
97
86
72
47

1198440
89
66
58
43

Example 45
Activity of Modified Oligonucleotides Targeting Human Yap1 in SNU-1076 Cells

Modified oligonucleotides described in the studies above were tested at various doses in upper aerodigestive tract/laryngeal squamous cell carcinoma line SNU-1076. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-1076 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 164

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-1076 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
89
98
102
107

715487
89
67
31
11

1198440
83
43
11
3

Cell Proliferation Assay

Cultured SNU-1076 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 165

Antiproliferative effect of modified

oligonucleotides in SNU-1076 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
97
104
106
108

715487
91
90
86
79

1198440
99
87
81
81

Example 46
Activity of Modified Oligonucleotides Targeting Human Yap1 in SNU-1214 Cells

Modified oligonucleotides described in the studies above were tested at various doses in laryngeal squamous cell carcinoma cell line SNU-12 4. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured SNU-1214 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 166

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in SNU-1214 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
97
104
106
109

715487
71
36
16
9

1198440
40
11
4
3

Cell Proliferation Assay

Cultured SNU-1214 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 167

Antiproliferative effect of modified

oligonucleotides in SNU-1214 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
105
90
96
72

715487
93
69
52
38

1198440
84
72
53
49

Example 47
Activity of Modified Oligonucleotides Targeting Human Yap1 in UPCI:SCC090 Cells

Modified oligonucleotides described in the studies above were tested at various doses in tongue squamous cell carcinoma cell line UPCI:SCC090. A control oligonucleotide 792169, described herein above, was also tested.

RNA Analysis

Cultured UPCI:SCC090 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to untreated control cells (% UTC).

TABLE 168

Dose-dependent inhibition of human Yap1 mRNA expression

by modified oligonucleotides in UPCI:SCC090 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
100
108
112
84

715487
70
37
26
14

1198440
60
26
10
5

Cell Proliferation Assay

Cultured UPCI:SCC090 cells at a density of 1000 cells/well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below. After approximately 144 hours, cell proliferation was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 169

Antiproliferative effect of modified

oligonucleotides in UPCI:SCC090 cells

% UTC

ION No.
0.04 μM
0.2 μM
1 μM
5 μM

792169
100
104
99
93

715487
92
94
72
68

1198440
101
92
75
70

Example 30
Activity of Modified Oligonucleotides Targeting Human Yap1 in a Human Hepatocellular Carcinoma SNU449 Xenograft Tumor Model (Alone and in Combination with Sorafenib)

Modified oligonucleotides described in the studies above were tested in a hepatocellular carcinoma SNU449 xenograft tumor model. In addition to testing the modified oligonucleotide by itself, combination therapy with sorafenib was also tested. A control oligonucleotide 792169, described herein above, was also tested.

Five million SNU449 cells in 30% matrigel were implanted subcutaneously into the fatpads of female NOD.Cg-Prkdcscid II2rgtmlWjl/SzJ mice (from Jackson Laboratory) at 4-6 weeks of age. 43 days post implantation (when tumors had reached approximately 100 mm³in size), groups of eight mice each were administered with 50 mg/kg modified oligonucleotide daily for 10 days (loading dose), following which they were administered with 50 mg/kg modified oligonucleotide four times a week for one week, following which they were dosed with 50 mg/kg modified oligonucleotide thrice weekly until the end of the study. Another group of 8 animals was treated with 30 mg/kg of sorafenib orally 7 times a week until end of study. A final group of 8 animals were treated with a combination of 30 mg/kg of sorafenib orally 7 times a week for 11 weeks and 50 mg/kg of modified oligonucleotide 1198440 at 50 mg/kg 5 times a week for 3 weeks, 4 times a week for the following week, then 3 times a week for the duration of the study (7 weeks). Animals were sacrificed, and tumors were collected on day 119 post implantation.

Measurement of RNA

Yap1 mRNA knockdown in tumors was measured by RT-qPCR as previously described using the Human Yap1 primer-probe set RTS4814. Yap1 mRNA levels were normalized to actin-beta content, as measured by primer probe set RTS5002. Results are presented in the tables below as percent control of the amount of Yap1 mRNA relative to PBS treated animals (% control).

TABLE 127

Yap1 mRNA levels in tumors

%

Ion No.
control

PBS
100

792169
90

1198440
34

Sorafenib
103

1198440 +
42

Sorafenib

Measurement of Tumor Volume

Tumor volumes were also measured at the indicated days in the table below. Treatment with ION No. 1198440 led to significant reduction in tumor volume. In addition, combination treatment of ION No. 1198440 with sorafenib led to further reduction in tumor volume.

TABLE 128

Tumor volume (mm³)

Days Post
Average Tumor Volume (mm³)

Tumor

1198440 +

Implantation
PBS
792169
1198440
sorafenib
sorafenib

43
111
111
111
112
111

46
175
162
152
145
162

50
208
180
168
159
162

53
252
247
201
173
210

57
292
280
242
200
224

60
362
317
263
234
258

64
396
397
338
217
210

67
438
466
376
277
250

71
463
519
373
249
241

75
570
559
401
283
279

78
597
634
429
322
296

81
657
681
514
391
400

85
760
785
606
416
380

88
786
889
613
451
413

92
955
1170
690
508
421

94
1048
1215
773
581
495

98
1114
1355
804
625
525

101
1175
1417
818
685
541

105
1252
1509
894
671
495

108
1284
1571
921
663
470

119
1431
1697*
978
747
584

*Average of 7 samples

Measurement of ERK Activation

Sorafenib is a RAF inhibitor used for treatment of several cancers including hepatocellular carcinoma. However, it leads to ERK activation in HCCs, which impacts therapeutic efficacy (Chen Y., et al., Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors, Sci Rep. 2017; 7: 44123).

The effect of modified oligonucleotide in mitigating the ERK1/2 activation mediated by sorafenib was tested. Protein analysis was carried out using standard procedures. The primary antibody against Erk1/2 was rabbit mAb 4695, Cell Signaling Technology, and against pERK1/2 was rabbit anti-phospho p44/42 antibody 9101, Cell Signaling Technology. ERK protein levels were compared to internal control GAPDH. GAPDH levels were measured using rabbit mAb 5174, Cell Signaling Technology as the primary antibody. The secondary antibody used was donkey anti-rabbit NA934, GE Healthcare. pERK/ERK levels were calculated relative to PBS control to determine % activation of ERK1/2. Combination therapy of ION No. 1198440 with sorafenib led to a significant decrease in ERK1/2 activation mediated by sorafenib treatment alone.

TABLE 129

Tumor volume (mm³)

%

activation

Ion No.
of ERK1/2

PBS
100

792169
100

1198440
88

Sorafenib
142

1198440 +
68

Sorafenib

Example 48
Activity of Modified Oligonucleotides Targeting Human Yap1 in Combination with Sorafenib in SNU449 Cells

Modified oligonucleotides described in the studies above were tested at various doses in hepatocellular carcinoma cell line SNU449. ION No. 792169, described herein above, was used as a control modified oligonucleotide. ION No. 715487 was used to target Yap1 RNA. Cultured SNU449 cells at a density of 5000 cells per well were treated using free uptake with modified oligonucleotides diluted to concentrations described in the tables below in combination with sorafenib diluted to concentrations described in the tables below. After approximately 48 hours, Yap1 mRNA levels were measured.

Measurement of RNA

TABLE 170

Yap1 mRNA levels

SORAFENIB
YAP1 mRNA (% control)

CONCENTRATION
715487
715487
715487
715487
792169
792169
792169
792169

(uM)
at 0.04 uM
at 0.2 uM
at 1 uM
at 5 uM
at 0.04 uM
at 0.2 uM
at 1 uM
at 5 uM

0
98
54
30
9
115
113
103
103

0.37
97
51
23
8
97
96
99
104

1.11
77
44
22
7
100
97
93
95

3.33
83
45
21
7
99
91
92
97

10
78
46
20
8
102
94
93
97

Cell Proliferation Assay

SNU449 plated at 1000 cells/well were treated with a combination of modified oligonucleotide and sorafenib at concentrations outlined in the table below. 144 hours post treatment, proliferation of SNU449 cells was measured using the luminescent cell viability CellTiter-Glo® 2.0 Assay (Promega). Results are presented in the tables below as percent control of the amount of luminescence in samples treated with modified oligonucleotides relative to untreated control cells (% UTC).

TABLE 171

Antiproliferative effect of modified oligonucleotides in SNU449 cells

SORAFENIB
% UTC

CONCENTRATION
715487
715487
715487
715487
792169
792169
792169
792169

(uM)
at 0.04 uM
at 0.2 uM
at 1 uM
at 5 uM
at 0.04 uM
at 0.2 uM
at 1 uM
at 5 uM

0
98
93
84
64
99
97
97
86

0.37
102
94
83
64
103
100
95
84

1.11
93
77
45
23
97
91
89
68

3.33
27
12
5
3
51
30
27
6

10
2
2
1
1
3
4
3
1

Example 49
Activity of Modified Oligonucleotides Targeting Human Yap1 in Combination with a-PD1 Antibody in DEN-HCC Model

The DEN model is a chemically induced model of hepatocellular carcinoma (HCC). N-nitrosodiethylamine (DEN) is administered at 25 mg/kg into 15 day old C57/BL6 mice. Carcinomas form 6 months post injection. After formation, carcinomas were then dissected from the liver and passaged subcutaneously into C57BL/6 male mice at 4-6 weeks of age to establish a subcutaneous model. For this experiment, mice were passaged with P8 subcutaneously established DEN carcinomas, rendering P9 for the duration of the experiment. Subcutaneous carcinomas are found to form at 4-6 weeks post implantation. Modified oligonucleotides 792169 (control compound) and 715491 (YAP-1 targeting modified oligonucleotide) were treated subcutaneously into groups of 7-8 mice at 10 mg/kg/week 5 times a week for 11 weeks (total of 55 doses). The PBS-only treated group and the control group were treated 5 times a week for 4 weeks (total of 20 doses). α-PD1 antibody (BioXCell) was treated intraperitoneally at 10 mg/kg/week twice a week for 4 weeks (total of 8 doses). Tumor volume was measured over the time points indicated in the table below. F.D. refers to mice that were sacrificed because their tumor volume became too large. As shown in the table below, mice administered PBS, 792169 (control compound), or α-PD1 antibody were sacrificed before the end of the experiment because their tumor volume became too large.

TABLE 172

Tumor volume (mm³)

Average Tumor Volume (mm3)

Days on

715491 +

treatment
PBS
792169
715491
α-PD1
α-PD1

1
373
354
356
546
455

5
553
376
417
673
475

8
688
414
463
782
558

11
729
523
461
910
525

15
856
604
523
911
529

18
968
633
526
1127
524

23
1220
773
658
1134
508

25
1337
864
659
1252
513

28
1355
802
661
1412
489

31
F.D.
F.D.
740
F.D.
516

35
F.D.
F.D.
798
F.D.
519

38
F.D.
F.D.
741
F.D.
491

43
F.D.
F.D.
723
F.D.
440

45
F.D.
F.D.
741
F.D.
457

49
F.D.
F.D.
765
F.D.
474

54
F.D.
F.D.
780
F.D.
552

58
F.D.
F.D.
852
F.D.
544

61
F.D.
F.D.
925
F.D.
592

65
F.D.
F.D.
896
F.D.
590

68
F.D.
F.D.
940
F.D.
604

72
F.D.
F.D.
953
F.D.
577

75
F.D.
F.D.
985
F.D.
675

79
F.D.
F.D.
960
F.D.
590

Number	Date	Country
WO 2009054004	Apr 2009	WO
WO 2011017809	Feb 2011	WO
WO 2013173637	Nov 2013	WO
WO 201705 3722	Mar 2017	WO
WO 2017160990	Sep 2017	WO
WO 2017197104	Nov 2017	WO

	Number	Date	Country
	62845077	May 2019	US
	62799591	Jan 2019	US

Modulators of YAP1 expression

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

Field of Search

CPC

International Classifications

Term Extension

Abstract

Description

Claims

US Referenced Citations (224)

Foreign Referenced Citations (6)

Non-Patent Literature Citations (19)

Related Publications (1)

Provisional Applications (2)

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