Treatment of CDHR3 related diseases and disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets CDHR3. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating conditions associated with CDHR3 variants that include providing an oligonucleotide that targets CDHR3 in a subject.

Description

Attorney Docket No. 54462-768.601 TREATMENT OF CDHR3 RELATED DISEASES AND DISORDERS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 636,622, filed April 19, 2024, which is incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462_768-601_Sequence_Listing.xml, created April 17, 2025, which is 19,476,009 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. BACKGROUND

[0003] Lung disorders are a common problem and may affect a wide variety of persons. Improved therapeutics are needed for treating these disorders. SUMMARY

[0004] Disclosed herein are compositions comprising oligonucleotides targeting CDHR3. Disclosed herein, in some aspects, are methods of treating a subject having a lung disorder or who is at risk for developing the lung disorder, the method comprising evaluating a subject’s risk for developing a lung disorder and administering an effective amount of composition disclosed herein to the subject.

[0005] Disclosed herein, in some aspects, are compositions comprising an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount treats a lung disorder. In some embodiments, the effective amount of the oligonucleotide improves:(a) a lung function measurement; (b) a leukocyte measurement; (c) a viral load measurement; (d) an infection or inflammation measurement; (e) a chronic obstructive pulmonary disease (COPD) symptom or exacerbation measurement; or (f) an asthma symptom or exacerbation measurement. In some embodiments, the lung function measurement comprises a forced expiratory volume in 1 second (FEV1) measurement, a forced expiratory volume in 1 second percent predicted (FEV1pp) measurement, a forced vital capacity (FVC) measurement, a FEV1 / FVC ratio measurement, a forced expiratory volume, or a peak expiratory flow measurement. In some embodiments, the lung function measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the leukocyte measurement comprises a lung leukocyte measurement. In some embodiments, the leukocyte measurement comprises a circulating leukocytemeasurement. In some embodiments, the leukocyte measurement comprises a neutrophil measurement,eosinophil measurement, basophil measurement, monocyte measurement, macrophage measurement, lymphocyte measurement, or neutrophil:lymphocyte ratio measurement, or a combination thereof. In some embodiments, the leukocyte measurement is improved by about 10% or more, as compared to prior to administration. In some embodiment, the viral load measurement comprises a rhinovirus-CAttorney Docket No. 54462-768.601 measurement. In some embodiments, the viral load measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the infection or inflammation measurement comprises a IFN-β, IFN-λ, CXCL10, CCL5, IL8, IL6, IL4, IL13, IL5, MUC5AC or FeNO measurement. In some embodiments, the infection or inflammation measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the COPD symptom or exacerbation measurement or asthma exacerbation or symptom measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the lung disorder comprises COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiment, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’,4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2’-O-alkyl, 2’-C-allyl, 2'-O-allyl, 2'-fluoro, or 2'- deoxy, 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2' O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, α-tocopherol, stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof. In some embodiments, the lipid comprises a lipid moiety depicted in Table 1. In some embodiments, the lipid moiety comprises ETL20. In some embodiments, the oligonucleotidecomprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments,the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, wherein the oligonucleotide comprises an integrin targeting ligand attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the integrin comprises integrin alpha-v-beta-6 or integrin alpha-v-beta-3 (αvβ3) or a combination thereof. In some embodiments, the integrin targetingAttorney Docket No. 54462-768.601 ligand comprises an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length.

[0006] Disclosed herein, in some aspects, are methods of treating a subject having a lung disorder, comprising administering an effective amount of the composition as described herein to the subject.

[0007] Disclosed herein, in some aspects, are methods of treating a subject having a lung disorder or who is at risk for developing the lung disorder, the method comprising evaluating a subject’s risk for developing a lung disorder and administering an effective amount of a composition disclosed herein to the subject. In some embodiments, the subject has a genotype at risk for developing an exacerbation of asthma or COPD related to rhinovirus-C (RVC) infection. In some embodiments, the subject is a heterozygous or homozygous carrier of the CDHR3 rs6967330-A variant.

[0008] Disclosed herein, in some aspects, are composition comprising an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises: an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 12861; an antisense oligonucleotide (ASO) comprising 12- 30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 12861. In some embodiments, the sense sequence comprises a modification pattern selected from the group consisting of 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S. In some embodiments, the antisense sequence comprises a modification pattern selected from the group consisting of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purinesAttorney Docket No. 54462-768.601 comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the composition described herein further comprises a pharmaceutically acceptable carrier. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’- O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’- O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; orAttorney Docket No. 54462-768.601 (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside.

[0009] Disclosed herein, in some aspects, are a method of treating a subject having a lung disorder, comprising administering an effective amount of the composition disclosed herein to the subject. In some embodiments, the lung disorder comprises COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough,dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis.

[0010] Disclosed herein, in some aspects, are a composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a sequence of Table 3.

[0011] Disclosed herein, in some aspects, are a composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 12861; and the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S.

[0012] Disclosed herein, in some aspects, are a composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 12861; and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS,Attorney Docket No. 54462-768.601 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.

[0013] Disclosed herein, in some aspects, are a composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 12861; wherein the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, 155S 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. DETAILED DESCRIPTION

[0014] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of disease and provide applicable treatments. A GWAS can utilize genotyping and / or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease. Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”Attorney Docket No. 54462-768.601

[0015] Functional annotation of variants and / or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of disease-causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gaininsight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0016] Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics. There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These may include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality can depend onseveral factors including the location of a target (for example, intracellular, extracellular, or secreted), arelevant tissue and a relevant indication.

[0017] The CDHR3 (cadherin related family member 3) gene, is located on chromosome 7, and is a protein coding gene, also known as CDH28, Cadherin-Like Protein 28, FLJ44366 and FLJ23834. CDHR3 may include 885 amino acids and have a mass of about 97977 Da. CDHR3 is a protein from the cadherin superfamily of transmembrane calcium-dependent adhesion proteins which are typically involved in cell adhesion, epithelial polarity, cell-cell interactions and cellular differentiation. CDHR3 may be transmembrane. CDHR3 may be intracellular. CDHR3 may be expressed in airway epithelium. CDHR3 may be expressed in airway epithelial cells. CDHR3 may be expressed in ciliated airway epithelial cells. CDHR3 may be expressed in airway epithelium. CDHR3 may be expressed in bronchium epithelium from adults and in fetal lung tissue. An example of an CDHR3 protein amino acid sequence, and further description of CDHR3 protein is included at uniprot.org under accession no. ENST00000317716.14.

[0018] The CDHR3 canonical sequence (885 amino acids) encodes six extracellular domain repeats with the usual, easily defined amino and carboxyl extensions. CDHR3 is the only known receptor for rhinovirus-C (RVC). There are more than 150 known types of rhinoviruses (RVs), which are classified into A, B, and C species of the Enterovirus genus in the Picornaviridae family. All three RV species frequently cause upper respiratory illnesses, and rhinovirus-A (RVA) and RVC infections can also cause more severe respiratory illnesses such as pneumonia, bronchiolitis and chronic rhinosinusitis and exacerbations of asthma, COPD, and cystic fibrosis.

[0019] Here, it is shown that genetic variants that may result in loss of function of the CDHR3 gene in humans are associated with decreased risk of chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD, asthma, and with increased lung function measures. Therefore, inhibition of CDHR3 or CDH28 may serve as a therapeutic strategy for treatment of a lung disorder such as COPD,Attorney Docket No. 54462-768.601 acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, asthma exacerbations, status asthmaticus, asthma-COPD overlap syndrome (ACOS), respiratory tract infections, exacerbations in the context of other chronic respiratory diseases e.g., bronchiectasis, bronchiolitis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. The rs6967330-A single nucleotide polymorphism in CDHR3 results in a substitution at amino acid position 529 (Cys529Tyr). Evidence suggests that the CDHR3 protein has increased surface expression in individuals carrying the rs6967330-A (Tyr) allele, which results in increased RVC binding and increased risk and severity of RVC infections and asthma exacerbations.

[0020] Disclosed herein, are methods or compositions are oligonucleotides that inhibit or target CDHR3 or CDH28. Where inhibition or targeting of CDHR3 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting CDHR3 protein or CDHR3 RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the CDHR3 gene using an oligonucleotide described herein, CDHR3 protein may be inhibited or targeted as a result of there being less production of CDHR3 protein by translation of the CDHR3 RNA; or CDHR3 protein may be targeted or inhibited by an oligonucleotide that binds or interacts with an CDHR3 RNA and reduces production of CDHR3 protein from the CDHR3 RNA. Thus, targeting CDHR3 may refer to binding an CDHR3 RNA and reducing CDHR3 RNA levels or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a lung disorder by providing an oligonucleotide that targets CDHR3 to a subject in need thereof. In certain aspects, disclosed herein is a method of treating a subject having a lung disorder, comprising administering an effective amount of the siRNAs disclosed herein to the subject.

[0021] In some embodiments, the sense strand or the antisense strand comprises any of modification patterns 1S to 155S or 1AS to 69AS. In some embodiments, the sense strand or the antisense strand comprises any of modification patterns 54S, 58S, 7AS, 24AS, or 46AS. In some embodiments, the sense strand comprises modification pattern 54S. In some embodiments, the sense strand comprises modification pattern 58S. In some embodiments, the antisense strand comprises modification pattern 7AS. In some embodiments, the antisense strand comprises modification pattern 46AS. In some embodiments, the sense strand comprises modification pattern 24AS. I. COMPOSITIONS

[0022] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets CDHR3. In some embodiments, the composition consists of an oligonucleotide that targets CDHR3. In some embodiments, the oligonucleotide reduces CDHR3 mRNA expression in the subject. In some embodiments, the oligonucleotide reduces CDHR3 protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used inAttorney Docket No. 54462-768.601 a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein.

[0023] Some embodiments include a composition comprising an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount decreases CDHR3 mRNA or CDHR3 protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount decreases CDHR3 mRNA levels in a cell or tissue. In some embodiments, the cell is a lung cell, airway epithelial cell, ciliated airway epithelial cell, airway epithelium, type I or II alveolar cell, macrophage, alveolar macrophage, goblet cell, club cell, or fibroblast. In some embodiments, the tissue is lung tissue. In some embodiments, the CDHR3 mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CDHR3 mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CDHR3 mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CDHR3 mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CDHR3 mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CDHR3 mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CDHR3 mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0024] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount decreases CDHR3 protein levels in a cell, fluid or tissue. In some embodiments, the cell is a lung cell, lung epithelial cell, ciliated airway epithelial cell, type I or II alveolar cell, macrophage, alveolar macrophage, goblet cell, club cell, or fibroblast. In some embodiments, the tissue is lung tissue. In some embodiments, the fluid is a blood, serum, or plasma sample. In some embodiments, the fluid is a lung fluid such as a bronchoalveolar fluid or sputum. In some embodiments, the CDHR3 protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CDHR3 protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CDHR3 protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CDHR3Attorney Docket No. 54462-768.601 protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CDHR3 protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CDHR3 protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CDHR3 protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0025] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount diminishes an adverse phenotype of lung disorder in the subject. The lung disorder may include chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, asthma exacerbations, status asthmaticus, asthma-COPD overlap syndrome (ACOS), exacerbations in the context of other chronic respiratory diseases e.g., bronchiectasis, bronchiolitis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. In some embodiments, the adverse phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the adverse phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%, or by a range defined by any of the two aforementioned percentages.

[0026] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount enhances a protective phenotype of a lung disorder. The lung disorder may include chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, asthma exacerbations, status asthmaticus, asthma-COPD overlap syndrome (ACOS), respiratory tract infections, exacerbations in the context of other chronic respiratory diseases e.g., bronchiectasis, bronchiolitis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, asAttorney Docket No. 54462-768.601 compared to prior to administration. In some embodiments, the protective phenotype is increased by about 10% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0027] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves (e.g., increases) a lung function measurement. The lung function measurement may include a measurement of forced expiratory volume in 1 second (FEV1), forced expiratory volume in 1 second percent predicted (FEV1pp), forced vital capacity (FVC), FEV1 / FVC ratio, forced expiratory volume, or peak expiratory flow. In some embodiments, the lung function measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the lung function measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the lung function measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the lung function measurement is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the lung function measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the lung function measurement is improved by no more than about 10%, as compared to prior toAttorney Docket No. 54462-768.601 administration. In some embodiments, the lung function measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the lung function measurement is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the lung function measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0028] A leukocyte measurement may be affected by a lung disorder. For example, some inflammatory lung disorders that may include chronic obstructive pulmonary disease (COPD) or asthma may lead to increased inflammation and circulating white blood cell counts that may be treated using a composition comprising an oligonucleotide; or lung inflammation concomitant with a lung disorder may include an increase in leukocytes in a lung tissue or lung fluid (e.g., bronchoalveolar fluid or sputum). In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount changes or improves a leukocyte measurement in a cell, fluid or tissue of the subject. In some embodiments, the cell is a lung cell, lung epithelial cell, ciliated airway epithelial cell, type I or II alveolar cell, macrophage, alveolar macrophage, goblet cell, club cell, or fibroblast. In some embodiments, the tissue is lung tissue. In some embodiments, the fluid is a blood, serum, or plasma sample. In some embodiments, the fluid is a lung fluid such as a bronchoalveolar fluid or sputum. The change may be a decrease (for example, when circulating levels of leukocytes, or levels of leukocytes in lungs are increased due to an inflammatory lung disorder). The change may be an increase in some embodiments. In some embodiments, the leukocyte measurement is changed by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the leukocyte measurement is changed by about 10% or more, as compared to prior to administration. In some embodiments, the leukocyte measurement is changed by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more, as compared to prior to administration. In some embodiments, the leukocyte measurement is changed by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the leukocyte measurement is changed by no more than about 10%, as compared to prior to administration. In some embodiments, the leukocyte measurement is changed by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the leukocyte measurement is changed by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,Attorney Docket No. 54462-768.601 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or by a range defined by any of the two aforementioned percentages.

[0029] In some embodiments, the leukocyte measurement includes a circulating leukocyte measurement. In some embodiments, the leukocyte measurement includes a tissue leukocyte measurement. In some embodiments, the leukocyte measurement includes a lung tissue leukocyte measurement. In some embodiments, the leukocyte measurement includes a lung fluid (e.g., bronchoalveolar fluid) or sputum leukocyte measurement. In some embodiments, the leukocyte measurement includes a leukocyte count. In some embodiments, the leukocyte measurement includes a leukocyte concentration. In some embodiments, the leukocyte measurement includes a leukocyte percentage. The percentage may be in relation to other cells. Examples of leukocytes that may be included in the leukocyte measurement include neutrophils, eosinophils, basophils, monocytes, macrophages a neutrophil lymphocyte ratio measurement, or lymphocytes. The leukocytes may include neutrophils. The leukocytes may include eosinophils. The leukocytes may include basophils. The leukocytes may include monocytes. The leukocytes may include macrophages. The leukocytes may include lymphocytes. In some embodiments, the leukocyte measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the leukocyte measurement is normal, relative to a control leukocyte measurement. For example, a subject who has been treated with a composition described herein and who has an inflammatory lung disorder may have had a high leukocyte count that is now low or normal. In some embodiments, the leukocyte measurement is determined in lung tissue or a lung fluid such as bronchoalveolar fluid, and may include a measurement of neutrophils and macrophages.

[0030] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves the level of (e.g., decreases) a viral load measurement. The viral load measurement may include a rhinovirus-C measurement. In some embodiments, the viral load measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the viral load measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the viral load measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the viral load measurement is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the viral load measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the viral load measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the viral load measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more thanAttorney Docket No. 54462-768.601 about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the viral load measurement is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the viral load measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%,700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0031] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves the level of (e.g., decreases) an infection or inflammation measurement. The infection or inflammation measurement may include IFN-β, IFN-λ, CXCL10, CCL5, IL8, IL6, IL4, IL13, IL5, MUC5AC or FeNO measurement. In some embodiments, the infection or inflammation measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the infection or inflammation measurement is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0032] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves (e.g., decreases) chronic obstructiveAttorney Docket No. 54462-768.601 pulmonary disease (COPD) exacerbations or related measurements (e.g., duration of exacerbations, requirement for inpatient admission or medications) in the subject. In some embodiments, the COPD exacerbations or related measurements are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the COPD exacerbations or related measurements are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the COPD exacerbations or related measurements are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the COPD exacerbations or related measurements are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the COPD exacerbations or related measurements are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the COPD exacerbations or related measurements are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the COPD exacerbations or related measurements are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0033] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves (e.g., decreases) asthma exacerbations or related measurements (e.g., duration of exacerbations, requirement for inpatient admission or medications) in the subject. In some embodiments, the asthma exacerbations or related measurements are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the asthma exacerbations or related measurements are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the asthma exacerbations or related measurements are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the asthma exacerbations or related measurements are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the asthma exacerbations or related measurements are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the asthma exacerbations or related measurements are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the asthma exacerbations or related measurements are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.Attorney Docket No. 54462-768.601

[0034] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves (e.g., decreases) respiratory symptoms e.g., cough, sputum, breathlessness / dyspnea, quality of living as (as assessed by questionnaires such as the St. George's Respiratory Questionnaire, COPD Assessment Test and Breathlessness, Cough and Sputum Scale), daily upper and lower respiratory symptom score, In some embodiments, the respiratory symptoms are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the respiratory symptoms are improved by about 10% or more, as compared to prior to administration. In some embodiments, the respiratory symptoms are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the respiratory symptoms are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the respiratory symptoms are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the respiratory symptoms are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the respiratory symptoms are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0035] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount improves (e.g., decreases) blood / sputum / bronchoalveolar fluid levels of COPD- or asthma- or viral infection-related proteins (i.e., IFN-β, IFN-λ, CXCL10, CCL5, IL8, IL6, IL4, IL13, IL5 and MUC5AC, etc.), or fractional exhaled nitric oxide (FeNO) or levels of nasal and bronchial lavage viral load, or sputum viral load in the subject. In some embodiments, the levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the levels are improved by about 10% or more, as compared to prior to administration. In some embodiments, the levels are improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the levels are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the levels are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the levels are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the levels are improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,Attorney Docket No. 54462-768.601 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. A. siRNAs

[0036] In some embodiments, the composition comprises an oligonucleotide that targets CDHR3, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets CDHR3, wherein the oligonucleotide comprises asmall interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strandmay be 14-30 nucleosides in length.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human CDHR3 mRNA sequence such as SEQ ID NO: 12861. In some embodiments, at least one of the sense strands and the antisense strands comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 12861. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 12861. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of one of SEQ ID NO: 12861.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand of the composition 5’-(N)0-7(NB)(N)0-7 -3’ and an antisense strand of composition 5’-(N)0-7(NA)(N)0-7 -3’. Where (N) 0-7 are independently nucleic acid stretches of 0 to 7 nucleotides, (NB) and (NA) contain at least 15 contiguous nucleotides from Table 3 and contain no cyclic ribose nucleotides with 2’ hydroxyl groups. The sense and antisense strand have 1-5 phosphorothioate inter-nucleotide linkages and either the sense or antisense strand has a targeting ligand attached to the 5’ or 3’ end. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strandAttorney Docket No. 54462-768.601 composition. The targeting ligand may be a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Representative examples of the GalNAc moiety include ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, 1gT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety include ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand include epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0040] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0041] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or morenucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0042] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or morenucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0043] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human CDHR3 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human CDHR3 mRNA.

[0044] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand andAttorney Docket No. 54462-768.601 an antisense strand, wherein the siRNA binds with a 17mer in a non-human primate CDHR3 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate CDHR3 mRNA.

[0045] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human CDHR3 mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human CDHR3 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[0046] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human CDHR3 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos.2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0047] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 1-6430 or 13452-13507. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 1-6430 or 13452- 13507, at least 80% identical to any one of SEQ ID NOs: 1-6430, at least 85% identical to of any one of SEQ ID NOs: 1-6430 or 13452-13507, at least 90% identical to any one of SEQ ID NOs: 1-6430 or 13452-13507, or at least 95% identical to any one of SEQ ID NOs: 1-6430 or 13452-13507. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-6430 or 13452-13507, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleosideAttorney Docket No. 54462-768.601 substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-6430 or 13452-13507, or a sense strand sequencethereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sensestrand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 1-6430 or 13452-13507. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 1-6430 or 13452-13507. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v- beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0048] Any of the aforementioned siRNAs may include a sense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to an A, T, C, U, or G. In some embodiments, position 5 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1- 6430 or 13452-13507 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQAttorney Docket No. 54462-768.601 ID NOs 1-6430 or 13452-13507 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to a G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to a G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to a G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to a G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452- 13507 is modified to a C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-6430 or 13452-13507 is modified to a C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to a C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-6430 or 13452-13507 is modified to a C.

[0049] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 6431-12860 or 13508-13563. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 6431-12860 or 13508-13563, at least 80% identical to any one of SEQ ID NOs: 6431-12860 or 13508- 13563, at least 85% identical to of any one of SEQ ID NOs: 6431-12860 or 13508-13563, at least 90% identical to any one of SEQ ID NOs: 6431-12860 or 13508-13563, or at least 95% identical to any one of SEQ ID NOs: 6431-12860 or 13508-13563. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6431-12860 or 13508-13563, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6431-12860 or 13508-13563, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand sequence comprises or consists of a sequenceAttorney Docket No. 54462-768.601 100% identical to SEQ ID NOs: 6431-12860 or 13508-13563. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand attached to antisense strand sequence of one of SEQ ID NO: 6431-12860 or 13508-13563. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v- beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0050] Any of the aforementioned siRNAs may include a strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a strand sequence wherein the 3’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508- 13563 is modified to an A. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508- 13563 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to an G. In some embodiments, position 19 (from the 5’Attorney Docket No. 54462-768.601 end) of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to a G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 6431-12860 or 13508-13563 is modified to a C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 6431- 12860 or 13508-13563 is modified to a C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to a C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs 6431-12860 or 13508-13563 is modified to a C.

[0051] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-6430 or 13452-13507, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1- 6430 or 13452-13507, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-6430 or 13452-13507, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-6430. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.Attorney Docket No. 54462-768.601

[0052] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 6431-12860 or 13508-13563, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 6431-12860 or 13508-13563, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 6431-12860 or 13508-13563, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 6431-12860 or 13508-13563. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v- beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0053] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 1 orAttorney Docket No. 54462-768.601 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A. Any of the aforementioned siRNAs may include a sense strand of subset A, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset A, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0054] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. Any of the aforementioned siRNAs may include a senseAttorney Docket No. 54462-768.601 strand that lacks a 3’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs mayinclude an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of theaforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of the aforementioned siRNAs may include a sense strand of subset B, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset B, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0055] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset C. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C. Any of the aforementioned siRNAs may include a sense strand of subset C, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset C, wherein thenucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0056] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, atAttorney Docket No. 54462-768.601 least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset D. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset D. Any of the aforementioned siRNAs mayinclude an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset D. Any ofthe aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset D. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset D. Any of the aforementioned siRNAs may include a sense strand of subset D, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset D, wherein thenucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0057] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably,Attorney Docket No. 54462-768.601 the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs mayinclude an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of theaforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand of subset E, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset E, wherein thenucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0058] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset F. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset F. Any of the aforementioned siRNAs mayinclude an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset F. Any of theaforementioned siRNAs may include a sense strand of subset F, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset F, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.Attorney Docket No. 54462-768.601

[0059] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset G. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset G, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset G. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset G. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset G. Any of the aforementioned siRNAs may include a sense strand of subset G, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset G, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0060] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Table 3, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Table 3, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Table 3. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32.Attorney Docket No. 54462-768.601 Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. In some embodiments, a sense strand sequence of an siRNA in any one of Table 3 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Table 3 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Table 3 is modified by substitution of the 5’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strandsequence wherein the 5’ nucleoside has been modified to a U.

[0061] The siRNA may comprise the sense strand and / or the antisense strand base sequence (e.g., unmodified sequence, or base sequence with other modifications) of an siRNA in any table included herein; or may include a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions; or may include a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some cases, the sequence does not include an overhang (e.g., UU) that is included in a table.

[0062] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A (Table 3-SubsetA), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sensestrand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereofhaving 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of theAttorney Docket No. 54462-768.601 aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0063] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B (Table 3-SubsetB), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL30 or ETL31. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0064] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C (Table 3-Subset C), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL30 or ETL31. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine-Attorney Docket No. 54462-768.601 aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0065] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D (Table 3-Subset D), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0066] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E (Table 3-Subset E), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moietyAttorney Docket No. 54462-768.601 is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0067] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset F (Table 3-Subset F), or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset F. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) CDHR3 mRNA. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (αvβ6) or integrin alpha-v-beta-3 or arginine-glycine- aspartic acid (RGD) peptide. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. B. ASOs

[0068] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of theAttorney Docket No. 54462-768.601 two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0069] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human CDHR3 mRNA sequence such as SEQ ID NO: 12861; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 12861.

[0070] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human CDHR3 mRNA sequence such as SEQ ID NO: 12861; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage,and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, theASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 12861. C. Modified oligonucleotides

[0071] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0072] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ endAttorney Docket No. 54462-768.601 has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0073] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

[0074] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), 2’,4’ constrained ethyl nucleic acid, hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2’-O- alkyl, 2’-C-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-O-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-C- alkyl group. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O- methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments,Attorney Docket No. 54462-768.601 the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2' O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefitsof the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0075] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:wherein the base can be any pyrimidine or purine.

[0076] An unlocked nucleic acid may comprise the following structure:wherein the base can be any pyrimidine or purine.

[0077] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.Attorney Docket No. 54462-768.601

[0078] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:methylphosphonate 2’-O-methyl Uridine).

[0079] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0080] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide. Examples of moieties include an integrin targeting ligand, a hydrophobic moiety, a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In someembodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0081] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’-fluoro modified nucleoside, a 2’O-methyl modified nucleoside, and 2’O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’-fluoro modified nucleoside, a 2’O-Attorney Docket No. 54462-768.601 methyl modified nucleoside, and 2’O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’O-methyl modified nucleoside, and 2’O-methoxyethyl. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’O-methyl modified nucleoside, and 2’O-methoxyethyl.

[0082] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’O-methyl modified nucleoside.

[0083] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0084] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2’ deoxy nucleoside.

[0085] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.Attorney Docket No. 54462-768.601

[0086] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro.

[0087] Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3’ end and a region of complementarity with an antisense strand; an antisense strand having a 5'end, a 3’end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; an overhang region at the 3 end of the sense strand having at least 3 contiguous phosphorothioated nucleotides; and an overhang region at the 3' end of the antisense strand having at least 3 contiguous phosphorothioated nucleotides.

[0088] Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3’ end and a region of complementarity with an antisense strand; an antisense strand having a 5'end, a 3’end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; and an overhang region at the 3’ end of the sense strand having at least 3 contiguous phosphorothioated nucleotides.

[0089] In some embodiments, the oligonucleotide includes two to eight oligonucleotides attached through a linker. The linker may be hydrophobic. In some embodiments, the oligonucleotides independently have substantial chemical stabilization (e.g., at least 40% of the constituent bases are chemically-modified). In some embodiments, the oligonucleotides have full chemical stabilization (i.e., all of the constituent bases are chemically-modified). In some embodiments, the oligonucleotide includes one or more single-stranded phosphorothioated tails, each independently having two to twenty nucleotides. In some embodiments, each single-stranded tail has eight to ten nucleotides.

[0090] In certain embodiments, a compound (e.g., moiety attached to the oligonucleotide) includes three properties: (1) a branched structure, (2) full metabolic stabilization, and (3) the presence of a single- stranded tail comprising phosphorothioate linkers. In a particular embodiment, a compound has 2 or 3Attorney Docket No. 54462-768.601 branches. The increased overall size of the branched structures promotes increased uptake. Also, without being bound by a particular theory of activity, multiple adjacent branches (e.g., 2 or 3) allow each branch to act cooperatively and thus dramatically enhance rates of internalization, trafficking and release. The compound may include an oligonucleotide described herein, as part of the compound.

[0091] In certain embodiments, a compound includes the following properties: (1) two or more branched oligonucleotides linked via a non-natural linker (2) substantially chemically stabilized, e.g., wherein more than 40%, optimally 100%, of oligonucleotides are chemically modified (e.g., no RNA and optionally no DNA); and (3) phosphorothioated single oligonucleotides containing at least 3, optimally 5- 20 phosphorothioated bonds.

[0092] In some embodiments, the oligonucleotide comprises a phosphate at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate at a 3’ end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 3' end.

[0093] The oligonucleotide may include purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0094] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa.

[0095] In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.

[0096] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines ofAttorney Docket No. 54462-768.601 the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0097] In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’- fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0098] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’- fluoro (2’F) modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’-O-methyl (2’OMe) modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand ofAttorney Docket No. 54462-768.601 the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0099] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0100] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0101] In some embodiments, the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group. In some embodiments, the targeting group includes a cell receptor ligand, such as an integrin targeting ligand. Integrins may include a family of transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. In some embodiments, the moiety includes an epithelial-specific integrin. Integrin alpha-v-beta-6 (αvβ6) may be an example of an epithelial-specific integrin αvβ6 may be a receptor for an ECM protein or TGF-beta latency-associated peptide (LAP). Integrin αvβ6 may be expressed in a cell or tissue. Integrin αvβ6 may be expressed or upregulated in injured pulmonary epithelium.

[0102] In some embodiments, the oligonucleotide is linked to an integrin targeting ligand that has affinity for integrin αvβ6. An integrin targeting ligand may include a compound that has affinity for integrin αvβ6 or integrin alpha-v-beta-3 (αvβ3), may be useful as a ligand to facilitate targeting or delivery of the oligonucleotide to which it is attached to a particular cell type or tissue (e.g., to cells expressing integrin αvβ3 or αvβ6). In some embodiments, multiple integrin targeting ligands are linked to the oligonucleotide. In some embodiments, the oligonucleotide-integrin targeting ligand conjugates areAttorney Docket No. 54462-768.601 selectively internalized by lung epithelial cells, either through receptor-mediated endocytosis or by other means.

[0103] Examples of targeting groups useful for delivering the oligonucleotide that include integrin targeting ligands may be based upon peptides or peptide mimics containing an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide derivative. In some embodiments, the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide, and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. The RGD peptide may be linear. The RGD peptide may be cyclic. An RGD peptide may include a D-amino acid. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises an amino benzoic acid derived RGD. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys), Cyclo(-Arg-Gly-Asp-D-Phe-Lys), Cyclo(-Arg-Gly-Asp-D-Phe-azido), an amino benzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiple of such RGD peptides. For example, the RGD peptide may include 2, 3, or 4 RGD peptides. Some embodiments include an arginine-glycine-glutamic acid peptide.

[0104] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.

[0105] In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotideAttorney Docket No. 54462-768.601 comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.

[0106] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0107] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’- fluoro-modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0108] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’fluoro- modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’-fluoro-modified pyrimidines in a row.Attorney Docket No. 54462-768.601

[0109] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0110] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro- modified nucleotides and unmodified deoxyribonucleotide.

[0111] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5’-end group may be or include a 5’-end phosphorothioate, 5’-end phosphorodithioate, 5’-end vinylphosphonate (5’-VP), 5’-end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans-vinylphosphonateAttorney Docket No. 54462-768.601 or cis-vinylphosphonate. The 5’-end group may include an extra 5’ phosphate. A combination of 5’-end groups may be used.

[0112] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include anextra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used.

[0113] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans-vinylphosphonate . In some embodiments, the vinyl phosphonate comprises a cis-vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.5’ vinylphosphonate 2’-O-Methyl Uridine

[0114] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0115] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. 1. Hydrophobic moieties

[0116] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobicAttorney Docket No. 54462-768.601 moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0117] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof.

[0118] In some embodiments, the oligonucleotide comprises a lipophilic moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis- Othexadecyl glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, a heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine, or a combination thereof. The lipophilic moiety may include a steroid such as cholesterol. The lipophilic moiety may include retinoic acid. The lipophilic moiety may include cholic acid. The lipophilic moiety may include adamantane acetic acid. The lipophilic moiety may include 1-pyrene butyric acid. The lipophilic moiety may include dihydrotestosterone. The lipophilic moiety may include 1,3-bis-O(hexadecyl) glycerol. The lipophilic moiety may include geranyloxyhexyanol. The lipophilic moiety may include hexadecylglycerol. The lipophilic moiety may include bomeol. The lipophilic moiety may include menthol. The lipophilic moiety may include 1,3- propanediol. The lipophilic moiety may include a heptadecyl group. The lipophilic moiety may include palmitic acid. The lipophilic moiety may include myristic acid. The lipophilic moiety may include O3-(oleoyl)lithocholic acid. The lipophilic moiety may include O3-(oleoyl)cholenic acid. The lipophilic moiety may include ibuprofen. The lipophilic moiety may include naproxen. The lipophilic moiety may include dimethoxytrityl. The lipophilic moiety may include phenoxazine.

[0119] In some embodiments, the lipophilic moiety comprises a hydrocarbon chain. The hydrocarbon chain may comprise or consist of a C4-C30 hydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid.

[0120] In some embodiments, the oligonucleotide includes one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand of the oligonucleotide, optionally via a linker or carrier. For instance, some embodiments provide an oligonucleotide comprising: an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand, optionally via aAttorney Docket No. 54462-768.601 linker or carrier. In some embodiments, the lipophilicity of the lipophilic moiety, measured by octanol- water partition coefficient, logP, exceeds 0.

[0121] In some embodiments, the lipophilic moiety is an aliphatic, cyclic such as alicyclic, or polycyclic such as polyalicyclic compound, such as a steroid (e.g., sterol), a linear or branched aliphatic hydrocarbon, or an aromatic. Exemplary lipophilic moieties may include lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-Othexadecyl) glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. Suitable lipophilic moieties may also include those containing a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl), and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. The functional group may be useful to attach the lipophilic moiety to the oligonucleotide. In some embodiments, the lipophilic moiety contains a saturated or unsaturated C6- C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon-carbon double bonds.

[0122] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[0123] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid.

[0124] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, theAttorney Docket No. 54462-768.601 lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[0125] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following. In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In someembodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or arange defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkylgroup contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether. Insome embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkylAttorney Docket No. 54462-768.601 group contains 16 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the oligonucleotide does not comprise a phenyloctyl group. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R is not an octane (Cg). In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the lipid moiety has at least one degree of unsaturation. In some embodiments, the lipid moiety is an omega fatty acid, such as an omega-3, omega-5, omega-6, omega-7, or omega-9 fatty acid.

[0126] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue. Ligands of Table 1 may also be attached via a 3’ terminus of an oligonucleotide.

[0127] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons. Table 1: Hydrophobic moiety examples Hydrophobic Hydrophobic Moiety Moiety Example Conjugation Description Name stearyl ETL3Attorney Docket No. 54462-768.601Attorney Docket No. 54462-768.601 octadecylbenza mide ETL13 hexadecylbenz amide ETL15 octadecylcyclo hexyl ETL16 Myristamido ETL18 methylphenyl Lauramido ETL19 methylphenyl Palmitoamidoet ETL20 hyl-phenylAttorney Docket No. 54462-768.601 phenethyl- ETL21^ myristyl^ ^ phenethyl- ETL22^ lauryl^ ^ phenethyl- ETL28^ stearyl^ ^ C16 CO2H terminal ETL29 Internal palmitoyl ETL31 Internal docosanyl ETL32

[0128] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected toAttorney Docket No. 54462-768.601 the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. Thelipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. Thelipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0129] The lipid moiety may comprise or consist of the following structure:. In some embodiments, the lipid moiety comprises or consists of the following structure:. In some embodiments, the lipid moiety comprises the following structure:some embodiments, the lipid moiety comprises or consist of the following structure:. In some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. In someAttorney Docket No. 54462-768.601 embodiments, R is not octane. In some embodiments, R is a carbon containing 4-7 or 9-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group.

[0130] In some embodiments, the 5’ hydrophobic moiety comprises any one of the followingdotted line indicates a covalent connection to the end of the 5’ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not an octane. In some embodiments, the alkyl group contains 4–7 or 9–18 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the 5’ hydrophobic moiety comprises a hydrophobic moiety in Table 1. In some embodiments, the 5’ hydrophobic moiety comprises phenyl para C12. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is 0–3. In some embodiments, n is 1–3. In some embodiments, n is 1. In some embodiments n is 2. In some embodiments, the hydrophobic moiety comprises an alcohol or an ether. In some embodiments, R is an unsaturated alkyl group. In some embodiments, the unsaturated alkyl group may be monounsaturated. In some embodiments, the unsaturated alkyl group may be unsaturated at the omega-3, position, omega-4 position, omega-5 position, omega-6 position, omega-7 position, omega-8 position, omega-9 position, or a combination thereof. In some embodiments, the 5’ hydrophobic moiety is not a phenyloctyl group.

[0131] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipidAttorney Docket No. 54462-768.601 may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may beattached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.

[0132] In some embodiments, when the lipid moiety comprises the structure:, R is not an octyl group. In some embodiments, R is an unsaturated hydrocarbon. In some embodiments, R is a monounsaturated acyl group. In some embodiments, the monounsaturated acyl group is unsaturated at the omega-3, omega-5, omega-6, omega-7, omega-8, or omega-9 position. In some embodiments, the unsaturated hydrocarbon is a polyunsaturated fatty acyl group. In some embodiments, the polyunsaturated fatty acyl group is unsaturated at least at the omega-3, omega-5, omega-6, omega-7, omega-, omega-9 position, or a combination thereof.

[0133] The lipid moiety may be attached at a 5’ end of the oligonucleotide. The 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’ modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose). A phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.

[0134] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipidmoieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[0135] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may beAttorney Docket No. 54462-768.601 used to produce a hydrophobic conjugate are provided as follows:. some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

[0136] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).Attorney Docket No. 54462-768.601

[0137] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modificationsdescribed herein may be useful for targeting an oligonucleotide composition to a cell or tissue.2. Sugar moieties

[0138] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[0139] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0140] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0141] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):Attorney Docket No. 54462-768.601or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2; Q is selected from: C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and C1-6alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2; R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-,-N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, - OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2is independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7,-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; R3and R4are each independently selected from: -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7,-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7;Attorney Docket No. 54462-768.601 each R5is independently selected from: -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7,- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7is independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; and C3-10carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0142] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, - N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -Attorney Docket No. 54462-768.601 OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2- NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O- )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2is selected from C1-3alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7and -OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, - OC(O)R7, and -S(O)R7. In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from -OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7. In some embodiments, R4is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R4is selected from -OR7- and - OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and - N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, and -NH(C1-6 alkyl). In some embodiments, each R7is independently selected from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O- , and -OP(OR7)O-; R2is C1 alkyl substituted with -OH or -OC(O)CH3;Attorney Docket No. 54462-768.601 R3is -OH or -OC(O)CH3; R4is -OH or -OC(O)CH3; and R5is -NH(O)CH3. In some embodiments, theAttorney Docket No. 54462-768.601Attorney Docket No. 54462-768.601Attorney Docket No. 54462-768.601Attorney Docket No. 54462-768.601

[0143] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, orAttorney Docket No. 54462-768.601 carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0144] Some embodiments include the following, where J is the oligonucleotide:include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0145] Some embodiments include the following, where J is the oligonucleotide:Attorney Docket No. 54462-768.601. J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0146] Some embodiments include the following, where J is the oligonucleotide:. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.Attorney Docket No. 54462-768.601

[0147] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0148] Some embodiments include the following, where J is the oligonucleotide:include one or more additional phosphates, or one or more phosphorothioates linking to theAttorney Docket No. 54462-768.601 oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0149] Some embodiments include the following, where J is the oligonucleotide:. J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0150] Some embodiments include the following, where J is the oligonucleotide:Attorney Docket No. 54462-768.601. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0151] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” andAttorney Docket No. 54462-768.601 is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0152] Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide:

[0153] Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide:

[0154] Some embodiments include the following, where J is the oligonucleotide:Attorney Docket No. 54462-768.601include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0155] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include aAttorney Docket No. 54462-768.601 phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to theoligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0156] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III),Formula IV, orAttorney Docket No. 54462-768.601Formula V, or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20; Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2; R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, - OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-;Attorney Docket No. 54462-768.601 each R7is independently selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0157] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0158] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to theoligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0159] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:Attorney Docket No. 54462-768.601.

[0160] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to theoligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0161] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:.

[0162] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linkingAttorney Docket No. 54462-768.601 to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to theoligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0163] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0164] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances 2-4 GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and KAttorney Docket No. 54462-768.601 in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0165] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:Attorney Docket No. 54462-768.601Attorney Docket No. 54462-768.601Attorney Docket No. 54462-768.601.

[0166] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as H1, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0167] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.Attorney Docket No. 54462-768.601

[0168] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0169] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:.Attorney Docket No. 54462-768.601 The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0170] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0171] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.Attorney Docket No. 54462-768.601

[0172] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:.

[0173] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to theoligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.3. siRNA modification patterns

[0174] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of CDHR3 nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5’- NfsnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 4S: 5’- NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3’. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3’. In some embodiments, the moiety in modification pattern 4S or 5S is a lipophilic moiety. In some embodiments,Attorney Docket No. 54462-768.601 the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 7S: 5’- nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 10S: 5’-NfsnsnnNfnNfnNfnNfnNfnNfnNfnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 11S: 5’- nsnsNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 12S: 5’-NfsnsNfnNfnNfnNfnNfnnnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 13S: 5’-nsnsnnnnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 14S: 5’- snnnnnnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 15S: 5’-snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 16S: 5’-snnnnNfnNfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 17S: 5’-snnnnnNfNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 18S: 5’-snnnnnnNfnNfNfnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 19S: 5’- snnnnNfnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 21S: 5’-snnnnNfNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 22S: 5’-snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 23S: 5’-snnnnnNfnNfNfnnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 24S: 5’- snnnnnnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 25S: 5’-snnnnnNfNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 27S: 5’-snnnnnnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 28S: 5’- snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 29S: 5’-snnnnnnnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 30S: 5’-snnnnNfNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 31S: 5’-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 32S: 5’- snnnnnnNfNfdNNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 33S:5'-snnnnNfnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34S:5'-snnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35S:5'-snnnnnnNfNfNfNfnNfnnnnnnnsnsn-3'. In someAttorney Docket No. 54462-768.601 embodiments, the sense strand comprises modification pattern 36S:5'- snnnnnNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37S:5'-snnnnNfnNfNfdTNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38S:5'-snnnnNfnNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39S:5'-snnnnNfnNfNfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40S:5'-snnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 41S: 5’-snnnnnnnnNfNfnnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 42S:5'- snnnnNfnNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 43S:5'-snnnnnnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 44S:5'-snnnnNfnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 45S:5'-snnnnnNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 46S:5'-snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S:5'-snnnnnNfNfnNfnNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 48S:5'- nnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 49S:5'-NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 50S:5'-nnnnnNfNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 51S:5'- nnnnNfNfNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 52S:5'-snnnnmnNfNfNfNfnnnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 53S:5'-snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 54S:5'-snnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 55S:5'- snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 56S:5'-snnnnnmNfNfNfNfnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 57S:5'-snnnnnmNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 58S:5'- nnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 59S:5’- snsnnnnNfNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 60S:5’-snnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61S:5’-snnnnmNfnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62S:5’-snnnnmnNfNfNfNfnnnnmnnnninsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63S:5’- snnnnmnNfNfNfNfnnnnmnninnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64S:5'-nnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S:5'-nsnsnnmnN(C16)NfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 66S: 5'-nnnnnnnnNfNfnnnnnnnnnsnsn-3'.Attorney Docket No. 54462-768.601 In some embodiments, the sense strand comprises modification pattern 67S: 5'- nnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 68S: 5'-nnnnnnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 69S: 5'-nnnnnNfnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 70S: 5'-nnnnnNfnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 71S: 5'-nnnnnNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 72S: 5'-nnnnnnNfnNfNfnnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 73S: 5'- nnnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 74S: 5'-nnnnNfNfnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 75S: 5'-nnnnNfnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 76S: 5'-nnnnNfNfnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 77S: 5'-nnnnnnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 78S: 5'-nnnnnNfNfnNfnNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 79S: 5'- nnnnnNfNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 80S: 5'-nnnnnNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 81S: 5'-nnnnNfnnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 82S: 5'-nnnnNfnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 83S: 5'-nnnnNfnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 84S: 5'-nnnnNfNfnNfNfnnnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 85S: 5'- nnnnNfNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 86S: 5'-nnnnnnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 87S: 5'-nnnnnnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 88S: 5'-nnnnnnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 89S: 5'-nnnnnNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 90S: 5'- nnnnnNfnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 91S: 5'-nnnnnNfNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 92S: 5'-nnnnNfnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 93S: 5'-nnnnNfnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 94S: 5'-nnnnNfnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 95S: 5'- nnnnNfnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 96S: 5'-nnnnNfNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 97S: 5'-nnnnnnnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 98S: 5'-nnnnNfnNfNfdNnnnnnnnnnnsnsn-3'. In some embodiments, theAttorney Docket No. 54462-768.601 sense strand comprises modification pattern 99S: 5'-nnnnnnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 100S: 5'- nnnnNfnNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 101S: 5'-nnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfnNfNfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 103S: 5'-snnnnnNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 104S: 5'- snnnnNfNfnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 105S: 5'-snnnnNfnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 106S: 5'-snnnnNfnnNfNfnnnnnnnnnnsnsnm-3'. In some embodiments, the sense strand comprises modification pattern 107S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 108S: 5’- snNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 109S: 5’-snnnnnmNfNfNfNfnnnnnmnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 110S: 5'-nnnnnNfNfnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 111S: 5’- NfsnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 112S: 5’-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 113S: 5’-nnnnnnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 114S: 5’- snnnnmnNfNfNfNfnnmnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 115S: 5’-nNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 116S: 5’-snnnnnNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 117S: 5’- snnnnnNfNfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 118S: 5’-snnnnNfnnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 119S: 5’-snnnnNfnnnNfnNfnnnnnnnnsnsn-3’.In some embodiments, the sense strand comprises modification pattern 120S: 5’-snnnnnNfNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 121S: 5’- nsnsnnnnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 122S: 5’-nsnsnnnNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 123S: 5’-nsnsnnnNfNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 124S: 5’-nsnsnnnNfNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 125S: 5’- nsnsnnNfnnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 126S: 5’-nsnsnnNfnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 127S: 5’-nsnsnnNfNfnnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 128S: 5’-nsnsnnnnnnNfNfnnnnnnnnnsnsn-3’. In someAttorney Docket No. 54462-768.601 embodiments, the sense strand comprises modification pattern 129S: 5’- nsnsnnnnnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 130S: 5’-nsnsnnnNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 131S: 5’-nsnsnnNfnnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 132S: 5’-nsnsnnNfNfnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 133S: 5’- nsnsnnnnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 134S: 5’-nsnsnnnNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 135S: 5’-nsnsnnnNfnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 136S: 5’-nsnsnnnNfNfNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 137S: 5’- nsnsnnNfnnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 138S: 5’-nsnsnnNfnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 139S: 5’-nsnsnnNfNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 140S: 5’-nsnsnnNfNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 141S: 5’- nsnsnnnnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 142S: 5’-nsnsnnnNfnnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 143S: 5’-nsnsnnnnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 144S: 5’-nsnsnnnnNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 145S: 5’- nsnsnnnnNfNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 146S: 5’-nsnsnnnNfnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 147S: 5’-nsnsnnnNfNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 148S: 5’-nsnsnnNfnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 149S: 5’- nsnsnnnNfNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 150S: 5’-nsnsnnNfnNfnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 151S: 5’-nsnsnnNfnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 152S:5'-snnnnnNfNfNfNfnnnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 153S:5'- snnnnNfndNnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 154S:5'-snnnnmNfnNfNfNfNfnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 155S:5'-snnnnmNfnNfNfNfNfnnnnmnnnnnsnsn-3'. In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’-deoxy-modified nucleoside or a 2’-deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine,Attorney Docket No. 54462-768.601 “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0175] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of TARGET, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5’- nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 3AS: 5’-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’- nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 5AS: 5’-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’- nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 8AS: 5’-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’- nsNfsnNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 11AS:5'-nsNfsnnnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 12AS:5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 13AS:5'- nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 14AS:5'-nsNfsnnNfnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 15AS:5'-nsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 16AS:5'- nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 17AS:5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 18AS:5'-nsNfsnNfnnNfnnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 19AS:5'- nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 20AS:5'-nsNfsnnnnNfnNfnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 21AS:5'-nsNfsnnnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS:5'- nsNfsnNfnNfnNfnnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 23AS:5'-VPnsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 24AS:5'- VPnsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 25AS:5'- VPnsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprisesAttorney Docket No. 54462-768.601 modification pattern 26AS:5'- VPnsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 27AS:5'- VPnsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 28AS: 5'- nsNfsnnNfnNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 29AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 31AS: 5'- nsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 32AS: 5'-nsNfsnnnNfNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnNfnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35AS: 5'-nsNfsnnnNfNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36AS: 5'-nsNfsnnnnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37AS: 5'- nsNfsnnNfn[NUNA]nnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38AS: 5'-nsNfsnnNf[NUNA]NfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-5VPnsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40AS: 5'- 5VPnsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 41AS: 5'-nnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 42AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 43AS: 5'- nsNfsnnnNfNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 44AS: 5'-nsNfsnnnNfnnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 45AS: 5'-nsNfsnnnNfNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 46AS: 5'- nsNfsnnnnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 47AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 48AS: 5'-nsNfsnnNfnNfNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 49AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 50AS: 5'-nsNfsnnNfnNfnNfnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 51AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 52AS: 5'- nsNfsnNfnNf[UNA]NfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 53AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 54AS: 5'-nsNfsnnnnNfNfnnnNfnNfnNfnnnsnsn-3'. InAttorney Docket No. 54462-768.601 some embodiments, the antisense strand comprises modification pattern 55AS: 5'- nsNfsnnnn[UNA]NfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 56AS: 5’-nsnsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 57AS: 5’‑nsNfsnNfnnNfnnNfnNfnNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 58AS: 5’‑nsNfsnnnNfnNfnNfnNfnNfnnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 59AS: 5’‑nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 60AS:5'-nsNfsnNfnNfnnNfnnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61AS:5'- nsNfsnNfnNfnnNfnNfnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62AS:5'-nsNfsnNfnnNfnNfnNfnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63AS:5'-nsNfsnnNfnNfnNfnNfnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64AS:5'- nsNfsnNfnNfnNfnnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65AS:5'-nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3'.In some embodiments, the sense strand comprises modification pattern 66AS:5'-nsNfsnNfnnNfnNfnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67AS:5'- nsNfsnnnNfnnnNfnNfnNfnNfnNfnsnsn-3'.In some embodiments, the antisense strand comprises modification pattern 68AS: 5'- nsNfsnnNfnNfnNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 69AS: 5'-nsNfsnnn[NUNA]nNfnNfnnnNfnNfnnnsnsn- 3’. In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’- deoxy-modified nucleoside or a 2’-deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine, “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification, VP is a 5'-vinyl phosphonate, “[NUNA]” is an unlocked nucleic acid, “[UNA]” is an unlocked nucleic acid and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0176] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS,Attorney Docket No. 54462-768.601 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS,Attorney Docket No. 54462-768.601 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS,Attorney Docket No. 54462-768.601 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS,10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS,25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS,Attorney Docket No. 54462-768.601 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS,53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS,68AS, or 69AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS,Attorney Docket No. 54462-768.601 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS,15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS,30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, theAttorney Docket No. 54462-768.601 sense strand comprises pattern 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 41S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 42S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 43S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS,Attorney Docket No. 54462-768.601 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 44S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 45S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS,59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, thesense strand comprises pattern 46S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 47S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 48S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 49S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 50S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS,Attorney Docket No. 54462-768.601 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 51S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 52S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS,15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS,30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 53S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 54S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 55S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 56S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 57S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS,Attorney Docket No. 54462-768.601 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 58S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 59S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 61S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 62S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS,5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS,21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 63S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 64S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS,Attorney Docket No. 54462-768.60148AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS,63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 65S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 66S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 67S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 68S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 69S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 70S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 71S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS,Attorney Docket No. 54462-768.601 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 72S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 73S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 74S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 75S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 76S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 77S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 78S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS,Attorney Docket No. 54462-768.601 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 79S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 80S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS,5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS,21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 81S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 82S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS,48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS,63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 83S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 84S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 85S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS,Attorney Docket No. 54462-768.601 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 86S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 87S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 88S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 89S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 90S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 91S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprisesAttorney Docket No. 54462-768.601 pattern 92S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS,10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS,25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 93S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 94S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS,53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS,68AS, or 69AS. In some embodiments, the sense strand comprises pattern 95S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 96S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 97S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 98S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS,Attorney Docket No. 54462-768.601 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 99S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 100S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 101S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 102S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 103S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 104S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 105S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS,Attorney Docket No. 54462-768.601 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 106S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 107S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 108S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 109S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 110S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 111S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 112S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS,Attorney Docket No. 54462-768.601 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 113S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 114S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 115S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 116S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS,...

Claims

Attorney Docket No. 54462-768.601 CLAIMS What is claimed is:

1. A composition comprising an oligonucleotide that targets CDHR3 and when administered to a subject in an effective amount treats a lung disorder.

2. The composition of claim 1, wherein the effective amount of the oligonucleotide improves: (a) a lung function measurement; (b) a leukocyte measurement; (c) a viral load measurement; (d) an infection or inflammation measurement; (e) a chronic obstructive pulmonary disease (COPD) symptom or exacerbation measurement; or (f) an asthma symptom or exacerbation measurement.

3. The composition of claim 2, wherein the lung function measurement comprises a forced expiratory volume in 1 second (FEV1) measurement, a forced expiratory volume in 1 second percent predicted (FEV1pp) measurement, a forced vital capacity (FVC) measurement, a FEV1 / FVC ratio measurement, a forced expiratory volume, or a peak expiratory flow measurement.

4. The composition of claim 2, wherein the lung function measurement is improved by about 10% or more, as compared to prior to administration.

5. The composition of claim 2, wherein the leukocyte measurement comprises a lung leukocyte measurement.

6. The composition of claim 2, wherein the leukocyte measurement comprises a circulating leukocyte measurement.

7. The composition of claim 2, wherein the leukocyte measurement comprises a neutrophil measurement, eosinophil measurement, basophil measurement, monocyte measurement, macrophage measurement, lymphocyte measurement, or neutrophil:lymphocyte ratio measurement, or a combination thereof.

8. The composition of claim 2, wherein the leukocyte measurement is improved by about 10% or more, as compared to prior to administration.

9. The composition of claim 2, wherein the viral load measurement comprises a rhinovirus-C measurement.

10. The composition of claim 2, wherein the viral load measurement is improved by about 10% or more, as compared to prior to administration.

11. The composition of claim 2, wherein the infection or inflammation measurement comprises a IFN- β, IFN-λ, CXCL10, CCL5, IL8, IL6, IL4, IL13, IL5, MUC5AC or FeNO measurement.

12. The composition of claim 2, wherein the infection or inflammation measurement is improved by about 10% or more, as compared to prior to administration.

13. The composition of claim 2, wherein the COPD symptom or exacerbation measurement or asthma exacerbation or symptom measurement is improved by about 10% or more, as compared to prior to administration.Attorney Docket No. 54462-768.601 14. The composition of claim 1, wherein the lung disorder comprises COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis.

15. The composition of any one of claims 1-14, wherein the oligonucleotide comprises a modified internucleoside linkage.

16. The composition of claim 15, wherein the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

17. The composition of claim 15, wherein the modified internucleoside linkage comprises one or more phosphorothioate linkages.

18. The composition of any one of claims 1-17, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.

19. The composition of any one of claims 1-18, wherein the oligonucleotide comprises a modified nucleoside.

20. The composition of claim 19, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’,4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2’-O-alkyl, 2’-C-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

21. The composition of claim 20, wherein the modified nucleoside comprises a LNA.

22. The composition of claim 20, wherein the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid.

23. The composition of claim 19, wherein the modified nucleoside comprises one or more 2’-fluoro modified nucleosides.

24. The composition of claim 19, wherein the modified nucleoside comprises a 2'-O-alkyl modified nucleoside.

25. The composition of any one of claims 1-24, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

26. The composition of any one of claims 1-25, wherein the oligonucleotide comprises a lipidattached at a 3’ or 5’ terminus of the oligonucleotide.

27. The composition of claim 26, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, α-tocopherol, stearyl, alkylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, octadecylcyclohexyl, myristamido methylphenyl, lauramido methylphenyl, palmitoamidoethyl-phenyl or a combination thereof.Attorney Docket No. 54462-768.601 28. .The composition of claim 26, wherein the lipid comprises a lipid moiety depicted in Table 1.

29. The composition of claim 28, wherein the lipid moiety comprises ETL20.

30. The composition of any one of claims 1-29, wherein the oligonucleotide comprises a sugarmoiety attached at a 3’ or 5’ terminus of the oligonucleotide.

31. The composition of claim 30, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N- acetylglucosamine (GlcNAc), or mannose.

32. The composition of any one of claims 1-31, wherein the oligonucleotide comprises an integrintargeting ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

33. The composition of claim 32, wherein the integrin comprises integrin alpha-v-beta-6 or integrin alpha-v-beta-3 (αvβ3) or a combination thereof.

34. The composition of claim 32, wherein the integrin targeting ligand comprises an arginine- glycine-aspartic acid (RGD) peptide.

35. The composition of any one of claims 1-34, wherein the oligonucleotide comprises a smallinterfering RNA (siRNA) comprising a sense strand and an antisense strand.

36. The composition of claim 35, wherein the sense strand is 12-30 nucleosides in length.

37. The composition of claim 35 or 36, wherein the antisense strand is 12-30 nucleosides in length.

38. The composition of any one of claims 1-34, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

39. The composition of claim 38, wherein the ASO is 12-30 nucleosides in length.

40. A method of treating a subject having a lung disorder, comprising administering an effective amount of the composition of any one of claims 1-39 to the subject.

41. A composition comprising an oligonucleotide that inhibits the expression of CDHR3, wherein the oligonucleotide comprises: (a) an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 12861; (b) an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 12861.

42. The composition of claim 41, wherein the sense sequence comprises a modification pattern selected from the group consisting of 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S,Attorney Docket No. 54462-768.601 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S.

43. The composition of claim 41, wherein the antisense sequence comprises a modification pattern selected from the group consisting of 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.

44. The composition of claim 41, wherein any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines.

45. The composition of claim 41, wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines.

46. The composition of claim 41, wherein any one of the following is true with regard to the sense strand:Attorney Docket No. 54462-768.601 (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’ -O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’- O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O- methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside.

47. The composition of any one of claims 1-46, further comprising a pharmaceutically acceptable carrier.

48. A method of treating a subject having a lung disorder, comprising administering an effective amount of the composition of any one of claims 1-47 to the subject.

49. The method of claim 48, wherein the lung disorder comprises COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis.Attorney Docket No. 54462-768.601 50. A method of treating a subject having a lung disorder or who is at risk for developing the lung disorder, the method comprising evaluating a subject’s risk for developing a lung disorder and administering an effective amount of the composition of any one of claims 1-47 to the subject.

51. The method of claim 50, wherein the subject has a genotype at risk for developing an exacerbation of asthma or COPD related to rhinovirus-C (RVC) infection.

52. The method of claim 51, wherein the subject is a heterozygous or homozygous carrier of the CDHR3 rs6967330-A variant.

53. A composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a sequence of Table 3.

54. A composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 12861; and the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, or 155S.

55. A composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 12861; and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.

56. A composition comprising an oligonucleotide that modulates the expression of CDHR3, wherein the oligonucleotide comprises an siRNA comprising an antisense oligonucleotide (ASO) comprising 12-30 nucleosides in length and a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 12861; wherein the ASO comprises modification pattern 1S, 2S, 3S, 4S,Attorney Docket No. 54462-768.601 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, 115S, 116S, 117S, 118S, 119S, 120S, 121S, 122S, 123S, 124S, 125S, 126S, 127S, 128S, 129S, 130S, 131S, 132S, 133S, 134S, 135S, 136S, 137S, 138S, 139S, 140S, 141S, 142S, 143S, 144S, 145S, 146S, 147S, 148S, 149S, 150S, 151S, 152S, 153S, 154S, 155S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS.

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