Treatment of angiopoietin-like 7 (ANGPTL7)-related diseases

Abstract

Provided herein are oligonucleotide compositions that inhibit ANGPTL7 and reduce intraocular pressure when administered to the eye. The oligonucleotide compositions contain nucleoside modifications.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 852,813, filed May 24, 2019, and U.S. Provisional Application No. 62 / 881,906, filed August 1, 2019, which are hereby incorporated by reference in their entireties.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on May 15, 2020, is named 54462-709_601_SL.txt, and is 3,290 bytes in size. Background Art

[0005] Large-scale human genetic data provides a mechanism for leveraging natural experiments to improve the success rate of drug discovery and development.

[0006] A genome-wide association study (GWAS) is an experimental design used to detect associations between genetic variants and traits in a population sample. The goal is to better understand the biology of a disease and develop treatments based on this understanding. GWAS can utilize genotyping and / or sequencing data and typically involve the 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 with controls. If a variant has a significantly different frequency in cases and controls, the variant is said to be associated with the disease. Commonly reported association statistics for GWAS are the p-value as a measure of statistical significance and the odds ratio (OR), or the beta coefficient (β) as a measure of effect size. Researchers typically assume an additive genetic model and calculate the allelic odds ratio, which is the increased (or decreased) disease risk conferred by each additional copy of the allele (compared to not carrying a copy of the allele). Another important concept in GWAS design and interpretation is linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate the "causal" variant.

[0007] Functional annotation of variants and / or wet lab experiments can identify causal genetic variants identified by GWAS, and in many cases, this leads to the identification of disease-causing genes. In particular, understanding the functional impact of a causal genetic variant (e.g., loss or gain of protein function, increase or decrease in gene expression) allows the variant to be used as a surrogate for therapeutic regulation of a target gene and provides insight into the potential therapeutic efficacy and safety of therapeutic agents that regulate the target.

[0008] The identification of such gene-disease associations provides fundamental insights into disease biology and is rapidly becoming an important tool for the pharmaceutical industry to identify new therapeutic targets. In order to translate therapeutic insights derived from human genetics, the patient's disease biology must be exogenously "programmed" to replicate the observations from human genetics. Today, there are more potential options than ever before for therapeutic modalities that can translate therapeutic targets identified through human genetics into new drugs. These include well-established therapeutic modalities such as small molecules and monoclonal antibodies, established modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality depends on multiple factors, including the location of the target (e.g., intracellular, extracellular, or secreted), the tissue of interest (e.g., lung, liver), and the relevant indication. Summary of the Invention

[0009] Glaucoma is a heterogeneous group of diseases affecting over 70 million people worldwide, characterized by optic nerve damage leading to progressive loss of retinal ganglion cells and resulting vision loss. The different subtypes of glaucoma are often stratified by the iridocorneal angle, with open-angle glaucoma accounting for approximately 75% of cases. Although the pathophysiology of glaucoma remains poorly understood, the primary causal feature and risk factor is elevated intraocular pressure (IOP). IOP is determined by the balance between aqueous humor secretion from the ciliary body and its drainage through the trabecular meshwork and uveoscleral outflow pathways. Lowering IOP is the only strategy proven to prevent the development or slow the progression of glaucoma; therefore, treatment focuses on lowering IOP to target levels by either increasing aqueous humor outflow or decreasing aqueous humor production. Several classes of IOP-lowering medications are used, including prostaglandin analogs, β-adrenergic blockers, α-adrenergic agonists, carbonic anhydrase inhibitors, and, more recently, rho-kinase inhibitors. Surgical procedures, such as laser trabeculoplasty, are also employed to improve aqueous humor drainage through the trabecular meshwork. Despite the availability of medical and surgical therapies for glaucoma, it is the leading cause of irreversible blindness worldwide, and new treatment strategies are needed to further reduce the risk of significant morbidity and decreased quality of life associated with vision loss.

[0010] In one aspect, a composition is provided comprising an inhibitor or modulator of ANGPTL7 effective for treating glaucoma and ocular hypertension. In some embodiments, the inhibitor or modulator of ANGPTL7 is an RNAi. In some embodiments, the RNAi is an siRNA. In some embodiments, the siRNA comprises one or more sense and antisense strand sequences selected from SEQ ID NOs: 1-4412. In some embodiments, the siRNA comprises a sequence comprising the reverse complement of a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90%, or 95% homology to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90%, or 95% identity to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the RNAi is a miRNA. In some embodiments, the RNAi is an antisense oligonucleotide (ASO). In some embodiments, the ASO is double-stranded or single-stranded. In some embodiments, the inhibitor of ANGPTL7 is a small molecule. In some embodiments, the inhibitor of ANGPTL7 is an aptamer. In some embodiments, the aptamer is an oligonucleotide aptamer. In some embodiments, the aptamer is a peptide aptamer. In some embodiments, the inhibitor of ANGPTL7 is an antibody. In some embodiments, the antibody is a monoclonal antibody.

[0011] In another aspect, provided herein are molecules for inhibiting or modulating angiopoietin-like 7 (ANGPTL7) gene products, including dsRNA (dsRNA) agents, such as small interfering RNA (siRNA), or antisense oligonucleotides for therapeutic use. Also provided are methods for inhibiting expression of a target gene by administering a dsRNA agent or antisense oligonucleotide, for example, for treating various diseases involving ANGPTL7 gene products. Also provided are methods for modulating expression of a target gene in a cell, comprising providing a dsRNA agent or antisense oligonucleotide to the cell. In some embodiments, the target gene is ANGPTL7.

[0012] In another aspect, a method of treating one or more ocular conditions in a subject in need thereof is provided, comprising editing an ANGPTL7 gene in the subject, wherein the one or more ocular conditions include glaucoma or ocular hypertension. In some embodiments, editing the ANGPTL7 gene comprises administering CRISPR / Cas9 to the subject. In some embodiments, CRISPR / Cas9 targets the ANGPTL7 gene. In some embodiments, CRISPR / Cas9 edits the ANGPTL7 gene into a loss-of-function mutation. In some embodiments, the loss-of-function mutation comprises a premature stop mutation. In some embodiments, the premature stop mutation occurs at amino acid position 177, according to the human protein sequence numbering. In some embodiments, CRISPR / Cas9 edits the ANGPTL7 gene into a missense mutation. In some embodiments, the missense mutation comprises a glutamine to histidine mutation. In some embodiments, the glutamine to histidine mutation occurs at amino acid position 175, according to the human protein sequence numbering. In some embodiments, CRISPR / Cas9 is delivered systemically to the subject. In some embodiments, CRISPR / Cas9 is delivered locally to the subject. In some embodiments, CRISPR / cas9 is delivered topically to the eye of a subject. In some embodiments, CRISPR / cas9 is delivered topically to the eye of a subject by intraocular injection. In some embodiments, CRISPR / cas9 is delivered topically to the eye of a subject by a topical solution. In some embodiments, editing of the ANGPTL7 gene is effective in treating one or more eye conditions. In some embodiments, the one or more eye conditions are glaucoma. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, the subject has received first-line treatment that includes a topical ocular prostaglandin analog, a beta-adrenergic blocker, an alpha-adrenergic agonist, and a carbonic anhydrase inhibitor for one or more upper eyelid and eye conditions. In some embodiments, editing of the ANGPTL7 gene results in a reduction or modulation of the production of an ANGPTL7 gene product. In some embodiments, editing of the ANGPTL7 gene results in a reduction in intraocular pressure in the subject.

[0013] In another aspect, a composition comprising CRISPR / cas9 targeting ANGPTL7 is provided, which is effective for treating glaucoma or ocular hypertension. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene into a loss-of-function mutation. In some embodiments, the loss-of-function mutation comprises a premature stop mutation. In some embodiments, the premature stop mutation occurs at amino acid position 177, according to the human protein sequence numbering. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene into a missense mutation. In some embodiments, the missense mutation comprises a glutamine to histidine mutation. In some embodiments, the glutamine to histidine mutation occurs at amino acid position 175, according to the human protein sequence numbering.

[0014] A non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is RNA interference (RNAi), where double-stranded RNAi (dsRNA) can be used to block gene expression. Short dsRNAs direct gene-specific post-transcriptional silencing in many organisms, including vertebrates, and provide a new tool for studying gene function. RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multicomponent nuclease that destroys messenger RNA homologous to the silencing trigger. RISC is known to contain a short RNA (approximately 21 nucleotides) derived from the double-stranded RNA trigger, but the protein component responsible for this activity remains unknown.

[0015] Another non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is an antisense oligonucleotide. DNA-RNA and RNA-RNA hybridization are important for many aspects of nucleic acid function, including DNA replication, transcription, and translation. Hybridization is also at the heart of various technologies for detecting specific nucleic acids or altering their expression. For example, antisense nucleotides disrupt gene expression by hybridizing with target RNA, thereby interfering with RNA splicing, transcription, translation, and replication. Antisense DNA has the additional feature that the DNA-RNA hybrid serves as a substrate for digestion by ribonuclease H (RNase H), an activity present in most cell types. Antisense molecules can be delivered into cells, as is the case with oligodeoxynucleotides (ODNs), or they can be expressed as RNA molecules from endogenous genes.

[0016] Another non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is a splice-switching antisense oligonucleotide (SSO). These are short, synthetic, antisense, modified nucleic acids that hybridize to pre-mRNA and disrupt the normal splicing repertoire of the transcript by blocking RNA-RNA base pairing or protein-RNA binding interactions between components of the splicing machinery and the pre-mRNA. Proper expression of the vast majority of protein-coding genes requires pre-mRNA splicing, and therefore, targeting this process provides a means of manipulating protein production from a gene. For example, pre-mRNA splicing can also be used to alter the reading frame downstream of the splice site, resulting in a truncated protein with impaired function.

[0017] Splice switching antisense oligonucleotides differ from mRNA cleavage antisense oligonucleotides in that they do not recruit RNaseH to degrade the pre-mRNA-SSO complex and are strictly steric blocking. This is achieved by using completely or almost completely 2' modified antisense oligonucleotides that lack the necessary DNA-RNA hybridization region recognized by RNaseH. Other types of modified oligonucleotides used to modify splicing are phosphoramidite morpholines (PMOs). PMOs replace the furanose ring found in natural nucleic acids with a morpholine ring and replace the negatively charged phosphodiester backbone with a neutral phosphorodiamidate backbone.

[0018] In some embodiments, the present disclosure provides methods for inhibiting or modulating the effects of a natural transcript by using antisense oligonucleotides (multiple) targeted to any region of the natural transcript. It is also contemplated herein that inhibition or modulation of a natural transcript can be achieved by siRNA, ribozymes, and small molecules. In an exemplary embodiment, the natural transcript encodes ANGPTL7.

[0019] One embodiment provides a method for modulating the function and / or expression of an ANGPTL7 polynucleotide in a cell or tissue of a patient in vivo or in vitro, the method comprising contacting the cell or tissue with an antisense oligonucleotide having a length of 5 to 30 nucleotides, wherein the antisense oligonucleotide has at least 50% sequence identity to the reverse complement of a polynucleotide comprising 5 to 30 consecutive nucleotides within nucleotides 1 to 6333 of SEQ ID NO: 11086, and any variants, alleles, homologs, mutants, derivatives, fragments, and complements thereof, thereby modulating the function and / or expression of the ANGPTL7 polynucleotide in the cell or tissue of the patient in vivo or in vitro. In some embodiments, the oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, the oligonucleotide comprises a sequence selected from SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084.

[0020] In some embodiments, the oligonucleotide targets a native sequence of an ANGPTL7 polynucleotide, such as the nucleotide sequence set forth in SEQ ID NO: 11085, and any variants, alleles, homologs, mutants, derivatives, fragments, and complementary sequences thereof. In some embodiments, the oligonucleotide comprises a sequence selected from the group consisting of SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 4413-11084.

[0021] In some embodiments, the oligonucleotide targets a native sequence of an ANGPTL7 polynucleotide, such as the nucleotide sequence set forth in SEQ ID NO: 11086, and any variants, alleles, homologs, mutants, derivatives, fragments, and complementary sequences thereof. In some embodiments, the oligonucleotide comprises a sequence selected from the group consisting of SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 4413-11084.

[0022] In some embodiments, the composition comprises one or more antisense oligonucleotides that bind to a sense ANGPTL7 polynucleotide. In some embodiments, the oligonucleotide comprises a sequence selected from SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises SEQ ID NO: 11087.

[0023] In some embodiments, the oligonucleotide comprises one or more modified or substituted nucleotides. In some embodiments, the oligonucleotide comprises one or more modified bonds. In some embodiments, the modified nucleotide comprises a modified base comprising a phosphorothioate, a methylphosphonate, a peptide nucleic acid, a 2'-O-methyl, a methoxyethyl, a fluoro- or carbon, a methylene, or other locked nucleic acid (LNA) molecule. In some embodiments, the modified nucleotide is a locked nucleic acid molecule, including aL-LNA.

[0024] In some embodiments, the oligonucleotide is administered to the patient by topical administration, inhalation, intranasal, subcutaneous, intramuscular, intravenous, intraocular, or intraperitoneal administration.

[0025] In some embodiments, the oligonucleotide is administered in the form of a pharmaceutical composition. The treatment regimen includes administering the antisense compound to the patient at least once; however, this treatment can be modified to include multiple doses over a period of time. The treatment can be combined with one or more other types of treatment.

[0026] In some embodiments, the oligonucleotide is encapsulated in liposomes or attached to a carrier molecule (eg, cholesterol, TAT peptide).

[0027] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7), wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, each strand having 14 to 30 nucleotides. In some embodiments, the dsRNA has a length of 17-30 nucleotide pairs. In some embodiments, the sense strand and the antisense strand each have 17-30 nucleotides. In some embodiments, the sense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the antisense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to the reverse complement of the sense strand. In some embodiments, the antisense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the sequence of the sense strand comprises SEQ ID NO: 11089, and the sequence of the antisense strand comprises SEQ ID NO: 11090. In some embodiments, the RNAi agent comprises one or more nucleotide modifications selected from the group consisting of LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, and 2'-deoxy. In some embodiments, the nucleotides are modified with 2'-OCH3 or 2'-F. In some embodiments, the RNAi agent further comprises at least one ligand. In some embodiments, the RNAi agent comprises one or more nucleotide modifications selected from the group consisting of 2'-O-methyl nucleotides, 2'-deoxyfluoro nucleotides, 2'-O-N-methylacetamide (2'-O-NMA) nucleotides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleotides, 2'-O-aminopropyl (2'-O-AP) nucleotides, and 2'-ara-F. In some embodiments, the RNAi agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage. In some embodiments, the nucleotide at position 1 of the 5' end of the antisense strand of the dsRNA is selected from the group consisting of A, dA, dU, U, and dT. In some embodiments, the base pair at position 1 of the 5' end of the dsRNA is an AU base pair.

[0028] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of ANGPTL7, wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the sense strand comprises at least two motifs having three identical modifications on three consecutive nucleotides, the first of the sense strand motifs occurring at the cleavage site in the sense strand, and the second of the sense strand motifs occurring at a different region of the sense strand than the first sense strand motif, and wherein the antisense strand comprises at least two motifs having three identical modifications on three consecutive nucleotides, the first of the antisense strand motifs occurring at or near the cleavage site in the antisense strand, and the second of the antisense strand motifs occurring at a different region of the antisense strand than the first antisense strand motif, wherein the modification in the first antisense strand motif is different from the modification in the second antisense strand motif. In some embodiments, at least one of the nucleotides occurring in the first sense strand motif forms a base pair with one of the nucleotides in the first antisense strand motif. In some embodiments, the dsRNA has 17-30 nucleotide base pairs. In some embodiments, the dsRNA has 17-19 nucleotide base pairs. In some embodiments, each chain has 17-23 nucleotides. In some embodiments, the modification on the nucleotides of the sense strand and / or antisense strand is selected from LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, 2'-deoxy and combinations thereof. In some embodiments, the modification on the nucleotides of the sense strand and / or antisense strand is 2'-OCH3 or 2'-F. In some embodiments, the RNAi agent further comprises a ligand attached to the 3' end of the sense strand.

[0029] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of ANGPTL7, wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the sense strand comprises at least one motif comprising three 2'-F modifications on three consecutive nucleotides, one of which occurs at or near the cleavage site in the sense strand; and wherein the antisense strand comprises at least one motif comprising three 2'-O-methyl modifications on three consecutive nucleotides, one of which occurs at or near the cleavage site in the antisense strand. In some embodiments, the sense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the antisense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to the reverse complement of the sense strand. In some embodiments, the antisense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0030] In one aspect, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in patient cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of 5 to 30 nucleotides, wherein the at least one antisense oligonucleotide has at least 50% sequence identity to the reverse complement sequence of a polynucleotide comprising 5 to 30 consecutive nucleotides within nucleotides 1 to 2224 of SEQ ID NO: 11085; thereby regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in patient cells or tissues in vivo or in vitro.

[0031] In one aspect, the present invention provides a method for regulating the function and / or expression of an Angiopoietin-like 7 (ANGPTL7) polynucleotide in a patient's cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of 5 to 30 nucleotides, wherein the antisense oligonucleotide has at least 50% sequence identity with the antisense oligonucleotide of an Angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby regulating the function and / or expression of an Angiopoietin-like 7 (ANGPTL7) polynucleotide in the patient's cells or tissues in vivo or in vitro.

[0032] In one aspect, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in a patient's cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide that targets a region of a natural antisense oligonucleotide of angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in the patient's cells or tissues in vivo or in vitro.

[0033] In one aspect, provided herein is a method for modulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in a patient's cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of 5 to 30 nucleotides; thereby modulating the function and / or expression of the ANGPTL7 polynucleotide in the patient's cells or tissues in vivo or in vitro.

[0034] In some embodiments, at least one antisense oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to SEQ ID NO: 11087. In some embodiments, the function and / or expression of angiopoietin-like 7 (ANGPTL7) is increased in vivo or in vitro relative to a control oligonucleotide that does not target or does not specifically hybridize to ANGPTL7. In some embodiments, the function and / or expression of angiopoietin-like 7 (ANGPTL7) is decreased in vivo or in vitro relative to a control oligonucleotide that does not target or does not specifically hybridize to ANGPTL7. In some embodiments, at least one antisense oligonucleotide targets a natural antisense sequence of an angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, at least one antisense oligonucleotide targets a nucleic acid sequence that comprises the coding and / or non-coding nucleic acid sequence of an angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, at least one antisense oligonucleotide targets overlapping and / or non-overlapping sequences of angiopoietin-like 7 (ANGPTL7) polynucleotides. In some embodiments, at least one antisense oligonucleotide comprises one or more modifications. In some embodiments, the one or more modifications are selected from: at least one modified sugar moiety, at least one modified internucleoside linkage, at least one modified nucleotide, and combinations thereof. In some embodiments, the one or more modifications comprise at least one modified sugar moiety selected from the group consisting of: 2'-O-methoxyethyl modified sugar moiety, 2'-methoxy modified sugar moiety, 2'-O-alkyl modified sugar moiety, bicyclic sugar moiety, and combinations thereof. In some embodiments, the one or more modifications comprise at least one modified internucleoside linkage selected from the group consisting of: phosphorothioate, 2'-Omethoxyethyl (MOE), 2'-fluoro, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetamate, carboxymethyl ester, and combinations thereof. In some embodiments, the one or more modifications include at least one modified nucleotide selected from the group consisting of peptide nucleic acid (PNA), locked nucleic acid (LNA), arabinose nucleic acid (FANA), analogs, derivatives, and combinations thereof.

[0035] In one aspect, provided herein is a method for regulating the function and / or expression of an Angiopoietin-like 7 (ANGPTL7) gene in a mammalian cell or tissue in vivo or in vitro, the method comprising: contacting the cell or tissue with at least one short interfering RNA (siRNA) oligonucleotide having a length of 5 to 30 nucleotides, the at least one siRNA oligonucleotide being specific for an antisense polynucleotide of an Angiopoietin-like 7 (ANGPTL7) polynucleotide, wherein the at least one siRNA oligonucleotide has at least 50% sequence identity with the complement of at least about five consecutive nucleic acids of the antisense and / or sense nucleic acid molecule of the Angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby regulating the function and / or expression of an Angiopoietin-like 7 (ANGPTL7) gene in the mammalian cell or tissue in vivo or in vitro. In some embodiments, the oligonucleotide has at least 80% sequence identity with the complement of at least about five consecutive nucleic acids of the antisense and / or sense nucleic acid molecule of the Angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, the at least one siRNA oligonucleotide comprises a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, at least one siRNA oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0036] In one aspect, provided herein is a method for modulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) in a mammalian cell or tissue in vivo or in vitro, the method comprising contacting the cell or tissue with at least one antisense oligonucleotide having a length of about 5 to 30 nucleotides, the antisense oligonucleotide being specific to the non-coding and / or coding sequence of the sense and / or natural antisense strand of an angiopoietin-like 7 (ANGPTL7) polynucleotide, wherein the at least one antisense oligonucleotide has at least 50% sequence identity to at least one nucleic acid sequence as set forth in SEQ ID NO: 11085, 1 to 2224, or a complementary sequence thereof; thereby modulating the function and / or expression of angiopoietin-like 7 (AGNPTL7) in the mammalian cell or tissue in vivo or in vitro. In some embodiments, the at least one antisense oligonucleotide comprises the sequence of SEQ ID NO: 11087. In some embodiments, the at least one antisense oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0037] In one aspect, provided herein are synthetic modified oligonucleotides comprising at least one modification, wherein the at least one modification is selected from the group consisting of: at least one modified sugar moiety; at least one modified internucleotide linkage; at least one modified nucleotide, and combinations thereof; wherein the oligonucleotide is an antisense compound that hybridizes to angiopoietin-like 7 (ANGPTL7) polynucleotides in vivo or in vitro and modulates their function and / or expression, compared to a control oligonucleotide that does not specifically hybridize to the ANGPTL7 polynucleotide. In some embodiments, the at least one modification comprises an internucleotide linkage selected from the group consisting of: phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetamidate, carboxymethyl ester, and combinations thereof. In some embodiments, the oligonucleotide comprises at least one phosphorothioate internucleotide linkage. In some embodiments, the oligonucleotide comprises a backbone of phosphorothioate internucleotide linkages. In some embodiments, the oligonucleotide comprises at least one modified nucleotide selected from the group consisting of: peptide nucleic acids, locked nucleic acids (LNA), and analogs, derivatives, and combinations thereof. In some embodiments, oligonucleotide includes multiple modifications, wherein the modification includes a modified nucleotide selected from the following: phosphorothioate, alkyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetoamate, carboxymethyl ester and combination thereof. In some embodiments, oligonucleotide includes multiple modifications, wherein the modification includes a modified nucleotide selected from the following: peptide nucleic acid, locked nucleic acid (LNA) and its analogs, derivatives and combinations. In some embodiments, oligonucleotide includes at least one modified sugar moiety selected from the following: 2'-O-methoxyethyl modified sugar moiety, 2'-methoxy modified sugar moiety, 2-O-alkyl modified sugar moiety, bicyclic sugar moiety and combination thereof. In some embodiments, oligonucleotide includes multiple modifications, wherein the modification includes a modified sugar moiety selected from the following: 2'-O-methoxyethyl modified sugar moiety, 2'-methoxy modified sugar moiety, 2'-O-alkyl modified sugar moiety, bicyclic sugar moiety and combination thereof. In some embodiments, the oligonucleotide is at least about 5 to 30 nucleotides in length and hybridizes to the antisense and / or sense strand of an Angiopoietin-like 7 (ANGPTL7) polynucleotide, wherein the oligonucleotide has at least about 20% sequence identity to the complement of at least about five consecutive nucleic acids of the antisense and / or sense coding and / or non-coding nucleic acid sequence of the Angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, the oligonucleotide has at least about 80% sequence identity to the complement of at least about five consecutive nucleic acids of the antisense and / or sense coding and / or non-coding nucleic acid sequence of the Angiopoietin-like 7 (ANGPTL7) polynucleotide.In some embodiments, the oligonucleotide hybridizes to and modulates expression and / or function of at least one angiopoietin-like 7 (ANGPTL7) polynucleotide in vivo or in vitro compared to a control oligonucleotide. In some embodiments, the oligonucleotide comprises a sequence as set forth in SEQ ID NO: 11087. In some embodiments, the at least one antisense oligonucleotide comprises a sequence at least about 80%, 85%, 90%, or 95% identical to SEQ ID NO: 11087.

[0038] In one aspect, provided herein are compositions comprising one or more oligonucleotides specific for one or more angiopoietin-like 7 (ANGPTL7) polynucleotides, the one or more oligonucleotides comprising an antisense sequence, complementary sequence, allele, homolog, isoform, variant, derivative, mutant, or fragment of the ANGPTL7 polynucleotide, or a combination thereof. In some embodiments, the one or more oligonucleotides have at least about 40% sequence identity compared to the nucleotide sequence set forth in SEQ ID NO: 11087. In some embodiments, the oligonucleotides comprise the nucleotide sequence set forth in SEQ ID NO: 11087. In some embodiments, the one or more oligonucleotides comprise a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the one or more oligonucleotides comprise a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the one or more oligonucleotides comprise one or more modifications or substitutions. In some embodiments, the one or more modifications are selected from phosphorothioates, methylphosphonates, peptide nucleic acids, locked nucleic acid (LNA) molecules, and combinations thereof.

[0039] In one aspect, the present invention provides a method for preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one product encoded thereof, the method comprising: administering to a subject in need thereof a therapeutically effective dose of at least one antisense oligonucleotide that binds to the natural antisense sequence of the at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates the expression of the at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one product encoded thereof.

[0040] In one aspect, the present invention provides a method for preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one product encoded thereof, the method comprising: administering to a subject in need thereof a therapeutically effective dose of at least one antisense oligonucleotide that binds to the natural sense sequence of the at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates the expression of the at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one product encoded thereof.

[0041] In some embodiments, the disease associated with at least one angiopoietin-like 7 (ANGPTL7) polynucleotide is selected from the group consisting of: a disease or condition associated with abnormal function and / or expression of ANGPTL7, a disease or condition associated with optic nerve damage, a disease or condition associated with intraocular pressure, a degenerative retinal disease or condition, an inflammatory eye disease or condition, an allergic eye disease or condition, a disease or condition associated with joint degeneration or inflammation, a disease or condition associated with abnormal lipid metabolism, cancer, Alzheimer's disease, dementia, stroke, and cerebral ischemia. In some embodiments, the disease or condition associated with optic nerve damage comprises primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, pigmentary glaucoma, exfoliation glaucoma, juvenile glaucoma, congenital glaucoma, inflammatory glaucoma, lenticular glaucoma, glaucoma secondary to intraocular hemorrhage, traumatic glaucoma, neovascular glaucoma, drug-induced glaucoma, toxic glaucoma, absolute glaucoma, ocular hypertension, or a combination thereof. In some embodiments, the disease or condition associated with joint degeneration or inflammation comprises osteoarthritis, osteoarthritis, or a combination thereof. In some embodiments, the cancer is selected from lung cancer, epidermoid carcinoma, breast cancer, or a combination thereof.

[0042] In one aspect, provided herein is a method for identifying and selecting at least one oligonucleotide for in vivo administration, comprising: identifying at least one oligonucleotide comprising at least five contiguous nucleotides that are complementary to ANGPTL7 or a polynucleotide that is antisense to ANGPTL7; measuring the thermal melting point of a hybrid of the antisense oligonucleotide and ANGPTL7 or a polynucleotide that is antisense to ANGPTL7 under stringent hybridization conditions; and selecting at least one oligonucleotide for in vivo administration based on the information obtained.

[0043] In one aspect, provided herein is a method of treating a disease or condition mediated by ANGPTL7, comprising administering to a subject in need thereof an oligonucleotide comprising a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the oligonucleotide comprises a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the target is ANGPTL7. In some embodiments, the disease or condition comprises glaucoma (including primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, pigmentary glaucoma, exfoliation glaucoma, juvenile glaucoma, congenital glaucoma, inflammatory glaucoma, lenticular glaucoma, glaucoma secondary to intraocular hemorrhage, traumatic glaucoma, neovascular glaucoma, drug-induced glaucoma, toxic glaucoma, and absolute glaucoma), ocular hypertension, optic neuropathy, or a combination thereof. In some embodiments, the oligonucleotide comprises dsRNA. In some embodiments, the oligonucleotide comprises a sequence having at least about 80%, 85%, 90%, 95%, or 100% identity to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the oligonucleotide comprises a sequence having at least about 80%, 85%, 90%, 95%, or 100% identity to SEQ ID NO: 11087.

[0044] In one aspect, provided herein is a method for treating one or more ocular conditions in a subject in need thereof, comprising editing an ANGPTL7 gene in the subject, wherein the one or more ocular conditions include glaucoma or ocular hypertension. In some embodiments, editing the ANGPTL7 gene comprises administering CRISPR / Cas9 to the subject. In some embodiments, CRISPR / Cas9 targets the ANGPTL7 gene. In some embodiments, CRISPR / Cas9 edits the ANGPTL7 gene into a loss-of-function mutation. In some embodiments, the loss-of-function mutation comprises a premature stop mutation. In some embodiments, the premature stop mutation occurs at amino acid position 177, according to the human protein sequence numbering. In some embodiments, CRISPR / Cas9 edits the ANGPTL7 gene into a missense mutation. In some embodiments, the missense mutation comprises a glutamine to histidine mutation. In some embodiments, the glutamine to histidine mutation occurs at amino acid position 175, according to the human protein sequence numbering. In some embodiments, CRISPR / Cas9 is delivered systemically to the subject. In some embodiments, CRISPR / Cas9 is delivered locally to the subject. In some embodiments, CRISPR / cas9 is delivered topically to the eye of a subject. In some embodiments, editing of the ANGPTL7 gene is effective in treating one or more eye conditions. In some embodiments, the one or more eye conditions are glaucoma. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, imaging from the subject with ocular hypertension reveals optic nerve damage. In some embodiments, the subject has received first-line treatment including topical ocular prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors for one or more eye conditions. In some embodiments, editing of the ANGPTL7 gene results in a reduction or modulation of the production of an ANGPTL7 gene product in the subject. In some embodiments, editing of the ANGPTL7 gene results in a reduction in intraocular pressure in the subject.

[0045] In one aspect, the present invention provides a composition comprising CRISPR / cas9 targeting ANGPTL7, which is effective for treating glaucoma or ocular hypertension. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene into a loss-of-function mutation. In some embodiments, the loss-of-function mutation comprises a premature stop mutation. In some embodiments, the premature stop mutation occurs at amino acid position 177, according to the human protein sequence numbering. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene into a missense mutation. In some embodiments, the missense mutation comprises a glutamine to histidine mutation. In some embodiments, the glutamine to histidine mutation occurs at amino acid position 175, according to the human protein sequence numbering.

[0046] In some embodiments, disclosed herein are compositions comprising oligonucleotides that target angiopoietin-like 7 (ANGPTL7), and when administered to a subject in an effective amount, reduce intraocular pressure, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides. In some embodiments, intraocular pressure is reduced by about 10% or more compared to before administration. In some embodiments, disclosed herein are compositions comprising oligonucleotides that target angiopoietin-like 7 (ANGPTL7), and when administered to a cell, reduce ANGPTL7 expression, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having the nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides. In some embodiments, the composition reduces ANGPTL7 expression compared to baseline ANGPTL7 measurements. In some embodiments, a baseline ANGPLT7 measurement is measured prior to administering the composition to the cells. In some embodiments, the composition reduces ANGPLT7 expression by at least 10% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 20% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 30% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 40% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 50% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 25% to 75% relative to the baseline ANGPTL7 measurement. In some embodiments, the baseline measurement is an ANGPLT7 protein measurement. In some embodiments, the baseline measurement is an ANGPLT7 mRNA measurement. In some embodiments, ANGPLT7 expression comprises ANGPTL7 mRNA expression. In some embodiments, ANGPLT7 expression comprises ANGPTL7 protein expression. In some embodiments, the siRNA binds to human ANGPTL7 mRNA with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not contain a SNP with a minor allele frequency (MAF) greater than or equal to 1% (positions 2-18). In some embodiments, the sense and antisense strands each comprise a seed region that is not identical to a seed region of a human miRNA.In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1 434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the sense strand comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943 ,948,1021,1092,1094,1097,1105,1107,1132,1198,1201,1424,1425,1429,1434,143 6, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 9 23, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1 429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192.In some embodiments, the antisense strand comprises a polypeptide corresponding to SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630 , 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 85% identity to any one of SEQ ID NO: NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2 947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3 635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand comprises SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 340 7, the nucleotide sequence of any one of 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398.In some embodiments, the oligonucleotide comprises one or more modified internucleosides connected. In some embodiments, the one or more modified internucleosides are connected to comprise alkylphosphonates, phosphorothioates, methylphosphonates, phosphorodithioates, alkylphosphonothioates, phosphoramidates, carbamates, carbonates, phosphotriesters, acetamidates or carboxymethyl esters or combinations thereof. In some embodiments, the one or more modified internucleosides are connected to comprise phosphorothioate connections. In some embodiments, the oligonucleotide comprises 2-6 modified internucleosides connected. In some embodiments, the oligonucleotide comprises one or more modified nucleosides. In some embodiments, one or more modified nucleosides include locked nucleic acids (LNA), hexitol nucleic acids (HLA), cyclohexene nucleic acids (CeNA), 2',4' constrained ethyl, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro or 2'-deoxy, 2'-O-methyl nucleosides, 2'-deoxyfluoro nucleosides, 2'-ON-methylacetamido (2'-O-NMA) nucleosides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleosides, 2'-O-aminopropyl (2'-O-AP) nucleosides, 2'-ara-F or a combination thereof. In some embodiments, one or more modified nucleosides include 2'fluoro modified nucleosides. In some embodiments, one or more modified nucleosides include 2'O methyl modified nucleosides. In some embodiments, the oligonucleotide includes 15-23 modified nucleosides. In some embodiments, the oligonucleotide includes a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid includes cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl or α-tocopherol, or a combination thereof. In some embodiments, the lipid includes cholesterol. In some embodiments, the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide includes cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid-derived RGD, or a combination thereof. In some embodiments, the oligonucleotide includes an RGD peptide and a lipid attached to the 3' or 5' end of the oligonucleotide.In some embodiments, the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-lipid-3' (SEQ ID NO: 11384), or modification pattern 5S: 5'nsnsnnNfnNfNfNfnnnnnnnsnsnN-lipid-3' (SEQ ID NO: 11385). NO: 11385); wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises the nucleoside. In some embodiments, the antisense strand includes modification pattern 1 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2 AS: 5'nsNfsnnnNfNfnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), or modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn3' (SEQ ID NO: 11389); wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to the sense strand sequence of an siRNA in any one of Tables 5-13. In some embodiments, the sense strand comprises the sense strand sequence of an siRNA in any one of Tables 5-13.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126, 111 27, 11128, 11129, 11130, 11132, 11133, 11134, 11135, 11136, 11139, 11140, 11143, 11144, 11145, 11146, 11147, 11148, 11149, 11150, 11151, 11152, 11153, 11154, 11155, 11156, 11157, 1115 8. 11159, 11160, 11161, 11162, 11163, 11164, 11165, 11166, 11167, 11168, 11169, 11170, 11171, 11172, 11173, 11174, 11175, 11176, 11177, 11178, 11180, 11181, 11182, 11183, 11184, 1118 5, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 111 26、11127、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、111 56、11157、11158、11159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、111 In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to the antisense strand sequence of an siRNA in any one of Tables 5-13. In some embodiments, the antisense strand comprises the antisense strand sequence of an siRNA in any one of Tables 5-13.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247 47, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 11276, 11277, 11278 8. 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 1130 5, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 112 46, 11247, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 112 76, 11277, 11278, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302 02, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332. In some embodiments, the sense strand or the antisense strand comprises a 3' overhang of at least 2 nucleosides. In some embodiments, the composition is in a solid composition. In some embodiments, the composition is sterile. Some embodiments include a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier includes water, a buffer solution, or a saline solution.

[0047] In some embodiments, disclosed herein are methods of treating an eye condition in a subject in need thereof, the methods comprising administering to the subject a composition comprising an oligonucleotide targeting ANGPTL7. In some embodiments, the eye condition comprises glaucoma. In some embodiments, the composition reduces intraocular pressure in the subject's eye relative to a baseline intraocular pressure measurement obtained from the subject prior to administration of the composition to the subject. In some embodiments, the sense strand comprises a sequence identical to SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1 434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the sense strand comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943 ,948,1021,1092,1094,1097,1105,1107,1132,1198,1201,1424,1425,1429,1434,143 6, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the sense strand comprises SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1 429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the antisense strand comprises a nucleotide sequence corresponding to any one of SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 294 6. 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630 , 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 85% identity to any one of SEQ ID NO: NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2 947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3 635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the antisense strand comprises SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3406, 7, the nucleotide sequence of any one of 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398. In some embodiments, the sense strand comprises modification pattern 1S: 5'-NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-lipid-3' (SEQ ID NO: 11384), or modification pattern 5S: 5'nsnsnnNfnNfNfNfnnnnnnnnnsnsnN-lipid-3' (SEQ ID NO: 11385). NO: 11385); wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises the nucleoside.In some embodiments, the antisense strand includes modification pattern 1 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2 AS: 5'-nsNfsnnnNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), or modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn3' (SEQ ID NO: 11389); wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to the sense strand sequence of an siRNA in any one of Tables 5-13. In some embodiments, the sense strand comprises the sense strand sequence of an siRNA in any one of Tables 5-13.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126, 111 27, 11128, 11129, 11130, 11132, 11133, 11134, 11135, 11136, 11139, 11140, 11143, 11144, 11145, 11146, 11147, 11148, 11149, 11150, 11151, 11152, 11153, 11154, 11155, 11156, 11157, 1115 8. 11159, 11160, 11161, 11162, 11163, 11164, 11165, 11166, 11167, 11168, 11169, 11170, 11171, 11172, 11173, 11174, 11175, 11176, 11177, 11178, 11180, 11181, 11182, 11183, 11184, 1118 5, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 111 26、11127、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、111 56、11157、11158、11159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、111 In some embodiments, the antisense strand comprises a nucleotide sequence that is at least 85% identical to the antisense strand sequence of an siRNA in any one of Tables 5-13. In some embodiments, the antisense strand comprises the antisense strand sequence of an siRNA in any one of Tables 5-13.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247 47, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 11276, 11277, 11278 8. 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 1130 5, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 112 46, 11247, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 112 76, 11277, 11278, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302 02, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332. In some embodiments, the oligonucleotide includes a cholesterol moiety attached to the 3' or 5' terminus of the oligonucleotide. In some embodiments, the oligonucleotide includes a lipid attached to the 3' or 5' terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenoyl, docosahexaenoyl, myristyl, palmitylstearyl or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises cholesterol. In some embodiments, the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid derived RGD, or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figures 1A-1DAn empty plasmid construct used according to some embodiments is shown ( Figure 1A ), GFP-tagged plasmid construct ( Figure 1B ), representative ANGPTL7 pre-mRNA encoding constructs ( Figure 1C ) and representative ANGPTL7 CDS encoding constructs ( Figure 1D ).

[0049] Figure 2 Shown are fluorescence microscopy images of HEK293 cells transfected with pcDNA3.1(+)GFP vector.

[0050] Figure 3 Shown are the results of qPCR measuring ANGPTL7 mRNA expression in HEK293 cells transfected with WT and Q175H pre-mRNA expression constructs.

[0051] Figure 4 Shown are the results of qPCR measuring ANGPTL7 mRNA expression in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0052] Figure 5 Included are images of Western blots of ANGPTL7 in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0053] Figure 6 Included are the results of an ELISA assay measuring ANGPTL7 protein expression in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0054] Figure 7 Shown are the ratios of secreted protein compared to intracellular protein (measured by ELISA) in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0055] Figure 8 Included are images of Western blots of ANGPTL7 in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter CDS expression constructs.

[0056] Figure 9 The relative positions of protein-coding and noncoding ANGPTL7 transcripts and the Q175H missense variant are shown.

[0057] Figure 10Shown is an agarose gel with transcript-specific PCR products from HEK293 cells transfected with WT and Q175H pre-mRNA expression constructs.

[0058] Figure 11 Dexamethasone-induced ANGPTL7 and MYOC expression in HTM cells is shown.

[0059] Figure 12 Shown is an agarose gel with transcript-specific PCR products from dexamethasone-induced primary HTM cells. DETAILED DESCRIPTION

[0060] Glaucoma is the leading cause of irreversible blindness worldwide, affecting approximately 1-2% of people over the age of 40 worldwide. There are multiple subtypes of glaucoma, but two main types exist: primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). POAG accounts for approximately 90% of glaucoma cases in the United States, with the majority of these cases occurring in the setting of ocular hypertension (OHT). In certain populations (i.e., Asian populations), the majority of glaucoma cases occur in the setting of normal intraocular pressure (normal-tension glaucoma, NTG).

[0061] Glaucoma is generally characterized by obstruction of aqueous humor outflow through the conventional outflow pathway. The conventional outflow pathway consists of the trabecular meshwork (TM) and Schlemm's canal at the base of the cornea. There is also an unconventional outflow pathway, which involves uveoscleral drainage and accounts for a portion of the aqueous humor outflow from the anterior compartment. Obstruction of the TM / Schlemm's canal (the conventional pathway) restricts aqueous humor outflow, leading to increased anterior chamber pressure, which translates into increased posterior chamber pressure and optic nerve degeneration and damage.

[0062] Treatment of glaucoma aims to lower intraocular pressure (IOP) to a target level (usually a 20-50% reduction in IOP). Despite normal IOP, treatment of NTG also revolves around lowering IOP. Several classes of medications are used to lower IOP, including prostaglandin analogs (usually first-line treatment), beta-adrenergic blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors. These medications are often ineffective, and surgical approaches (trabeculoplasty / trabeculotomy) are used. However, the beneficial effects of trabeculoplasty / trabeculotomy decrease over time, resulting in a failure rate of approximately 10% per year.

[0063] Angiopoietin-like proteins (ANGPTLs) are a family of eight proteins that share structural and functional similarities with angiopoietins, consisting of an N-terminal coiled-coil domain that mediates homo-oligomerization and a C-terminal fibrinogen domain. ANGPTLs are widely expressed in the liver, vasculature, and hematopoietic system, and play important roles in inflammation, lipid metabolism, angiogenesis, and extracellular matrix (ECM) formation.

[0064] ANGPTL7 was originally discovered in a human corneal cDNA library and named cornea-derived transcript 6 (CDT6). Immunohistochemistry shows ANGPTL7 staining in multiple tissues of the eye. ANGPTL7 is overexpressed in the aqueous humor of glaucoma patients and is upregulated by glaucomatous conditions such as TGFβ and dexamethasone exposure. Despite this, the molecular function of ANGPTL7 in ocular health and disease remains unclear.

[0065] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, if the terms "including," "includes," "having," "has," "with," or variations thereof are used in the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0066] The terms "about" or "approximately" mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined (i.e., the limitations of the measurement system). For example, according to the practice in the art, "about" can mean within 1 or more than 1 standard deviation. In some cases, "about" can mean a range of up to 20%, up to 10%, up to 5%, and up to 1% of a given value. In some cases, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of a value, e.g., within 5-fold, or within 2-fold. Where specific values ​​are described in the application and claims, the term "about" should be assumed to mean that the specific value is within an acceptable error range unless otherwise indicated.

[0067] In some embodiments, the term "mRNA" refers to the currently known mRNA transcript(s) of a target gene, as well as any additional transcripts that may be elucidated.

[0068] In some embodiments, "dsRNA," "siRNA," and "siRNA agent" are used interchangeably as agents that can mediate silencing of a target RNA, such as an mRNA, e.g., a transcript of a protein-encoding gene. In some cases, the target RNA is ANGPTL7. This mRNA may also be referred to herein as the mRNA to be silenced. This gene is also referred to as a target gene. In some cases, the RNA to be silenced is an endogenous gene or a pathogen gene. In addition, RNAs other than mRNAs, such as tRNAs and viral RNAs, can also be targeted.

[0069] In some embodiments, the phrase "mediates RNAi" refers to the ability to silence a target RNA in a sequence-specific manner. While not wishing to be bound by theory, it is believed that silencing utilizes RNAi machinery or processes and guides RNA, such as siRNA agents.

[0070] In some embodiments, "specifically hybridizable" and "complementary" are terms used to indicate a sufficient degree of complementarity to allow stable and specific binding to occur between a compound described herein and a target RNA molecule.

[0071] Specific binding may require a sufficient degree of complementarity to avoid non-specific binding of the oligomeric compound to non-target sequences under conditions where specific binding is desired, i.e., under physiological conditions in the case of an assay or therapeutic treatment, or in the case of an in vitro assay, under the conditions in which the assay is performed. The non-target sequences may differ by at least 5 nucleotides.

[0072] In some embodiments, dsRNA reagent and target RNA, for example, target mRNA are "fully complementary", so that the dsRNA reagent silences the production of proteins encoded by the target mRNA. In some embodiments, dsRNA reagent and target RNA are "fully complementary", for example, the target RNA and dsRNA duplex reagent anneal, for example, forming a hybrid consisting entirely of Watson Crick base pairs in a fully complementary region. The target RNA of "fully complementary" can include an internal region (for example, an internal region of at least 10 nucleotides) that is fully complementary to the target RNA. In addition, in some embodiments, dsRNA reagents specifically distinguish between single nucleotide differences. In this case, if full complementarity is found in the region of single nucleotide differences (for example, within 7 nucleotides), the dsRNA reagent only mediates RNAi.

[0073] In some embodiments, the term "oligonucleotide" refers to a nucleic acid molecule (RNA or DNA) of less than 100, 200, 300, or 400 nucleotides in length.

[0074] In some embodiments, "antisense oligonucleotide" or "antisense compound" refers to an RNA or DNA molecule that is bound to another RNA or DNA (target RNA, DNA). For example, if it is an RNA oligonucleotide, it binds to another RNA target through RNA-RNA interactions and changes the activity of the target RNA. Antisense oligonucleotides can raise or lower the expression and / or function of specific polynucleotides. This definition is intended to include any exogenous RNA or DNA molecule useful from a therapeutic, diagnostic or other perspective. Such molecules include, for example, antisense RNA and DNA molecules, interfering RNA (RNAi), microRNA, decoy RNA molecules, siRNA, enzymatic RNA, therapeutic editing RNA, and agonist and antagonist RNA, antisense oligomeric compounds, antisense oligonucleotides, external guide sequence (EGS) oligonucleotides, alternate splicing agents, primers, probes, and other oligomeric compounds that hybridize to at least a portion of a target nucleic acid. Therefore, these compounds can be introduced in the form of single-stranded, double-stranded, partially single-stranded or cyclic oligomeric compounds.

[0075] In some embodiments, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or its mimetics. The term "oligonucleotide" also includes natural and / or modified monomers or linked linear or cyclic oligomers, including deoxyribonucleosides, ribonucleosides, their substitutions and α-anomeric forms, peptide nucleic acids (PNA), locked nucleic acids (LNA), thiophosphates, methylphosphonates, etc. Oligonucleotides are able to specifically bind to target polynucleotides through regular patterns of monomer-to-monomer interactions, such as Watson-Crick type base pairing, Hoogsteen or reverse Hoogsteen type base pairing, etc.

[0076] In some embodiments, oligonucleotide is " chimeric ", i.e., is made up of different regions." chimeric " oligonucleotide comprises two or more chemical regions, for example, DNA region (multiple), RNA region (multiple), PNA region (multiple) etc. Each chemical region is made up of at least one monomeric unit, that is, is nucleotide in the case of oligonucleotide compounds. These oligonucleotides generally comprise at least one region, wherein the oligonucleotide is modified to show one or more desired characteristics. The desired characteristics of oligonucleotide include, but are not limited to, for example, an increase in resistance to nuclease degradation, an increase in cellular uptake and / or an increase in binding affinity to the target nucleic acid. Therefore, the different regions of oligonucleotide may have different characteristics. Chimeric oligonucleotide can be formed as a mixed structure of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and / or oligonucleotide analogs.

[0077] Oligonucleotides can comprise or consist of regions that can be linked in a "register", i.e., when monomers are linked consecutively, as in natural DNA, or when linked by spacers. Spacers are intended to form covalent "bridges" between regions and in some cases have a length of no more than about 100 carbon atoms. Spacers can have different functionalities, for example, have a positive or negative charge, have special nucleic acid binding properties (intercalators, groove binders, toxins, fluorophores, etc.), be lipophilic, induce special secondary structures, such as, for example, alanine containing peptides that induce alpha helices.

[0078] In some embodiments, "ANGPTL7" and "Angiopoietin-like 7" include all family members, mutants, alleles, fragments, species, coding and non-coding sequences, sense and antisense polynucleotide strands, etc. of the ANGPTL7 transcript (NM_021146; SEQ ID NO: 11085). In some embodiments, "ANGPTL7" and "Angiopoietin-like 7" are used interchangeably herein.

[0079] In some embodiments, an "oligonucleotide specific for" or "oligonucleotide targeting" refers to an oligonucleotide having a sequence that (i) forms a stable complex with a portion of a targeted gene, or (ii) forms a stable duplex with a portion of an mRNA transcript of a targeted gene. The stability of the complex and duplex can be determined by theoretical calculations and / or in vitro assays.

[0080] In some embodiments, the term "target nucleic acid" includes DNA, RNA (including, pre-mRNA and mRNA) transcribed from such DNA, and cDNA, coding sequence, non-coding sequence, sense and antisense polynucleotides derived from such RNA. The specific hybridization of the oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This regulation of the target nucleic acid function by the compound with its specific hybridization is generally referred to as "antisense". The function of the DNA being regulated includes, for example, replication and transcription. The function of the RNA being regulated includes all important functions, such as, for example, RNA translocation to protein translation site, protein translation from RNA, RNA splicing to produce one or more mRNA species, and the catalytic activity that can participate in RNA or promoted by RNA. The overall effect of this interference with the target nucleic acid function is the regulation of the expression of the coded product or oligonucleotide.

[0081] RNA interference "RNAi" is mediated by a double-stranded RNA (dsRNA) molecule with sequence-specific homology to its "target" nucleic acid sequence. In certain embodiments, the mediator is a "small interfering" RNA duplex (siRNA) of 5-25 nucleotides. siRNA is derived from the processing of dsRNA by the RNase enzyme called Dicer. The siRNA duplex product is recruited into a multiprotein siRNA complex called RISC (RNA-induced silencing complex). Without wishing to be bound by any particular theory, it is then believed that RISC is directed to the target nucleic acid (suitable mRNA), where the siRNA duplex interacts in a sequence-specific manner to mediate cutting in a catalytic manner. Small interfering RNA can be synthesized and used. The small interfering RNA used in the methods herein suitably comprises about 1 to about 50 nucleotides (nt). In the example of non-limiting embodiments, siRNA can comprise about 5 to about 40nt, about 5 to about 30nt, about 10 to about 30nt, about 15 to about 25nt, or about 20-25 nucleotides.

[0082] In some embodiments, the selection of suitable oligonucleotide is promoted by using a computer program that automatically compares nucleic acid sequences and indicates identity or homology regions. Such programs are used to compare, for example, the nucleic acid sequences obtained by searching databases such as GenBank or by sequencing PCR products. The selection of nucleic acid sequences from a series of species is allowed to show an appropriate degree of identity between species. When the gene is not sequenced, Southern blotting is carried out to allow determination of the degree of identity between the genes in the target species and other species. By carrying out Southern blotting under different stringencies, as well known in the art, an approximate measurement of identity can be obtained. These programs allow selection to show a high degree of complementarity with the target nucleic acid sequence in the experimenter to be controlled and to show a relatively low degree of complementarity with the corresponding nucleic acid sequence in other species. Those skilled in the art will appreciate that there is considerable freedom of choice in selecting suitable gene regions.

[0083] In some embodiments, "enzymatic RNA" refers to an RNA molecule with enzymatic activity. Enzymatic nucleic acids (ribozymes) work by first binding to a target RNA. This binding occurs through the target binding portion of the enzymatic nucleic acid, which is held in close proximity to the enzymatic portion of the molecule, which acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes the target RNA, then binds to the target RNA through base pairing, and once bound to the correct site, acts enzymatically to cleave the target RNA.

[0084] In some embodiments, "bait RNA" refers to an RNA molecule that mimics the natural binding domain of a ligand. Thus, the bait RNA competes with the natural binding target for binding to a specific ligand. For example, overexpression of HIV transactivation response (TAR) RNA can act as a "bait" and effectively bind to the HIV tat protein, thereby preventing it from binding to the TAR sequence encoded in the HIV RNA. This is meant to be a specific example. Those skilled in the art will recognize that this is just one example and that several embodiments can be easily generated using techniques well known in the art.

[0085] In some embodiments, "monomer" generally refers to a monomer that is linked by a phosphodiester linkage or an analog thereof to form an oligonucleotide ranging in size from a few monomeric units, e.g., about 3-4, to about several hundred monomeric units. Analogs of phosphodiester linkages include: phosphorothioates, phosphorodithioates, methylphosphonates, selenophosphates, phosphoramidates, and the like, as described more fully below.

[0086] In some embodiments, "nucleotide" encompasses naturally occurring nucleotides as well as non-naturally occurring nucleotides. It will be clear to those skilled in the art that various nucleotides previously considered "non-naturally occurring" have subsequently been discovered in nature. Thus, "nucleotide" includes not only known molecules containing purine and pyrimidine heterocycles, but also heterocyclic analogs and tautomers thereof. Illustrative examples of other types of nucleotides are those containing adenine, guanine, thymine, cytosine, uracil, purine, xanthine, diaminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanol cytosine, N6,N6-ethanol-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynyl cytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazole pvridin, isocytosine, isoguanine, inosine, and the "non-naturally occurring" nucleotides described in Benner et al., U.S. Patent No. 5,432,272. The term "nucleotide" is intended to encompass each and all of these examples and their analogs and tautomers. Nucleotides of particular interest are those containing adenine, guanine, thymine, cytosine, and uracil, which are considered to be naturally occurring nucleotides relevant for human therapeutic and diagnostic applications. Nucleotides include naturally occurring 2'-deoxy and 2'-hydroxy sugars, as well as their analogs.

[0087] In some embodiments, "analogs" with respect to nucleotides include synthetic nucleotides with modified base moieties and / or modified sugar moieties. Such analogs include synthetic nucleotides designed to enhance binding properties, such as duplex or triplex stability, specificity, etc.

[0088] In some embodiments, "hybridization" refers to the pairing of at least substantially complementary chains of oligomeric compounds. One mechanism of pairing involves hydrogen bonding between the complementary nucleoside or nucleotide bases (nucleotides) of the chains of oligomeric compounds, which can be Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonds. For example, adenine and thymine are complementary nucleotides that pair by forming hydrogen bonds. Hybridization can occur under different circumstances.

[0089] In some embodiments, antisense compounds are "specifically hybridizable" when binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause modulation of function and / or activity, and there is a sufficient degree of complementarity to avoid nonspecific binding of the antisense compound to non-target nucleic acid sequences under conditions where specific binding is desired, i.e., under physiological conditions for in vivo assays or therapeutic treatments, as well as under conditions where the assay is conducted in the context of an in vitro assay.

[0090] In some embodiments, "stringent hybridization conditions" or "stringent conditions" refer to conditions under which a compound will hybridize to its target sequence but hybridize to a minimum number of other sequences. Stringent conditions are sequence-dependent and vary in different situations, and the "stringent conditions" under which an oligomeric compound hybridizes to a target sequence are determined by the properties and composition of the oligomeric compound and the assay in which they are being studied. In some cases, stringent hybridization conditions include low concentrations (<0.15 M) of salts containing inorganic cations such as Na+ or K+ (i.e., low ionic strength), temperatures above about 20°C to 25°C and below the Tm of the oligomeric compound / target sequence complex, and the presence of denaturing agents such as formamide, dimethylformamide, dimethyl sulfoxide, or the detergent sodium dodecyl sulfate (SDS). For example, for every 1% of formamide, the hybridization rate decreases by 1.1%. An example of high stringency hybridization conditions is 0.1 times sodium chloride-sodium citrate buffer (SSC) / 0.1% (w / v) SDS at 60°C for 30 minutes.

[0091] In some embodiments, "complementarity" refers to the ability of accurate pairing between two nucleotides on one or two oligomer chains. For example, if the core base at a certain position of antisense compounds can form hydrogen bonds with the core base at a certain position of target nucleic acid, and the target nucleic acid is DNA, RNA or oligonucleotide molecules, the position of the hydrogen bond between the oligonucleotide and the target nucleic acid can be considered to be complementary positions. When a sufficient number of complementary positions in each molecule are occupied by nucleotides that can hydrogen bond to each other, the oligomeric compound and other DNA, RNA or oligonucleotide molecules complement each other. Therefore, "specific hybridization" and "complementary" are terms that can be used to indicate the accurate pairing or complementarity of a sufficient degree on a sufficient number of nucleotides, thereby stabilizing and specifically binding between oligomeric compounds and target nucleic acid.

[0092] The sequence of oligomeric compounds does not need to be 100% complementary to the sequence of its target nucleic acid in order to specifically hybridize. In addition, oligonucleotides can hybridize on one or more sections so that the inserted or adjacent sections do not participate in hybridization events (e.g., loop structures, mispairings, or hairpin structures). In some embodiments, oligomeric compounds disclosed herein comprise at least about 70% of the target region within the target nucleic acid sequence they are targeted to, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% sequence complementarity. For example, wherein 18 of the 20 nucleotides of the antisense compound are complementary to the target region and therefore the antisense compound of specific hybridization represents 90% complementarity. In this example, the remaining non-complementary nucleotides can be clustered or interspersed with complementary nucleotides and do not need to be adjacent to each other or adjacent to complementary nucleotides. Therefore, an antisense compound with a length of 18 nucleotides and 4 (four) non-complementary nucleotides, both sides of which are two regions that are completely complementary to the target nucleic acid, has an overall complementarity of 77.8% with the target nucleic acid, and therefore will fall within the scope of the present disclosure. The complementarity percentages of antisense compounds and target nucleic acid regions can be routinely determined using BLAST programs (Basic Local Alignment Search Tool) and PowerBLAST programs known in the art. Percent homology, sequence identity, or complementarity can be determined, for example, using the Gap program (Wisconsin Sequence Analysis Package, Unix Version 8, Genetics Computer Group, University Research Park, Madison Wis.) using default settings, which uses the algorithm of Smith and Waterman.

[0093] In some embodiments, the term "thermal melting point (Tm)" refers to the temperature at which 50% of oligonucleotides complementary to a target sequence hybridize to the target sequence at equilibrium under defined ionic strength, pH, and nucleic acid concentration. Typically, stringent conditions are those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short oligonucleotides (e.g., 10 to 50 nucleotides). Stringent conditions can also be achieved by adding destabilizing agents such as formamide.

[0094] In some embodiments, "modulate" refers to an increase (stimulation) or decrease (inhibition) in gene expression.

[0095] In some embodiments, the term "variant," when used in the context of a polynucleotide sequence, can include polynucleotide sequences related to a wild-type gene. This definition can also include, for example, "allelic," "splicing," "species," or "polymorphic" variants. Splice variants may have significant identity to a reference molecule but will typically have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may have additional functional domains or no domains. Species variants are polynucleotide sequences that vary from one species to another. Particularly useful are variants of a wild-type gene product. Variants can result from at least one mutation in the nucleic acid sequence and can result in an altered mRNA or a polypeptide whose structure or function may or may not be altered. Any given natural or recombinant gene may have none, one, or more allelic forms. Common mutational changes that give rise to variants are generally attributed to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes can occur alone or in combination with other changes, one or more times in a given sequence.

[0096] The resulting polypeptides typically have significant amino acid identity relative to each other. Polymorphic variants are variations in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants can also include "single nucleotide polymorphisms" (SNPs) or single base mutations, in which the polynucleotide sequence changes by one base. The presence of a SNP may indicate, for example, a predisposition to a disease state in a population, i.e., susceptibility versus resistance.

[0097] Derivatized polynucleotides include chemically modified nucleic acids, for example, where hydrogens are replaced by alkyl, acyl, or amino groups. Derivatives, such as derivatized oligonucleotides, can include non-naturally occurring moieties, such as altered sugar moieties or intersugar linkages. Examples include phosphorothioates and other sulfur-containing substances known in the art. Derivatized nucleic acids can also include labels, including radionucleotides, enzymes, fluorescent agents, chemiluminescent agents, color developers, substrates, cofactors, inhibitors, magnetic particles, and the like.

[0098] In some embodiments, a "derivatized" polypeptide or peptide is one that has been modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction / alkylation, acylation, chemical coupling, or mild formalin treatment. Derivatives can also be modified to directly or indirectly include a detectable label, including but not limited to radioisotope, fluorescent, and enzyme labels.

[0099] As used herein, the term "animal" or "patient" is intended to include, for example, humans, sheep, elk, deer, mule deer, mink, mammals, monkeys, horses, cows, pigs, goats, dogs, cats, rats, mice, birds, chickens, reptiles, fish, insects, and arachnids.

[0100] "Mammal" encompasses warm-blooded mammals (e.g., humans and domestic animals) that are typically receiving medical care. Examples include felines, canines, equines, bovines, and humans, as well as just humans.

[0101] "Treating" or "treatment" includes treating a disease state in a mammal and includes: (a) preventing the development of a disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed with the disease; (b) inhibiting the disease state, e.g., arresting its development; and / or (c) alleviating the disease state, e.g., causing the disease state to regress, until a desired endpoint is reached. Treatment also includes improvement in symptoms of the disease (e.g., relief of pain or discomfort), where such improvement may or may not directly affect the disease (e.g., cause, spread, expression, etc.). The term "treatment" is intended to also include prevention, treatment, and cure. Patients receiving such treatment are any animal in need, including primates, particularly humans, and other mammals, such as horses, cattle, pigs, and sheep; as well as poultry and pets.

[0102] All genes, gene names and gene products disclosed herein are intended to correspond to homologs of any species to which the compositions and methods disclosed herein are applicable. Therefore, these terms include, but are not limited to, genes and gene products from humans and mice. It should be understood that when disclosing genes or gene products from specific species, this disclosure is intended to be exemplary only and should not be construed as limiting unless the context in which it appears clearly indicates otherwise. Therefore, for example, for genes disclosed herein, they relate to mammalian nucleic acids in some embodiments, and amino acid sequences are intended to include homologs and / or orthologous genes and gene products from other animals, including but not limited to other mammals, fish, amphibians, reptiles and birds. In some embodiments, the gene or nucleic acid sequence is human.

[0103] In some embodiments, the term "halogen" refers to any group of fluorine, chlorine, bromine or iodine. In some embodiments, the term "alkyl" refers to a saturated and unsaturated non-aromatic hydrocarbon chain, which can be straight or branched, containing a specified number of carbon atoms (these include but are not limited to propyl, allyl or propargyl), which can optionally be inserted with N, O or S. For example, C1-C10 means that the group can have 1 to 10 (inclusive) carbon atoms therein. The term "alkoxy" refers to -O-alkyl. In some embodiments, the term "alkylene" refers to a divalent alkyl (i.e., -R-). The term "alkylenedioxo" refers to a divalent substance of the structure -ORO-, wherein R represents an alkylene group. The term "aminoalkyl" refers to an alkyl substituted with an amino group. In some embodiments, the term "sulfhydryl" refers to a -SH group. The term "thioalkoxy" refers to -S-alkyl.

[0104] In some embodiments, the term "aryl" refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, and the like. In some embodiments, the term "arylalkyl" or the term "aralkyl" refers to an alkyl group substituted with an aryl group. In some embodiments, the term "arylalkoxy" refers to an alkoxy group substituted with an aryl group.

[0105] In some embodiments, as used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, such as 3 to 8 carbons, and such as 3 to 6 carbons, wherein the cycloalkyl group may additionally be optionally substituted. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0106] In some embodiments, the term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), 1-9 heteroatoms (if tricyclic), the heteroatoms being selected from O, N, or S (e.g., 1-3, 1-6, or 1-9 heteroatoms of carbon atoms and N, O, or S, respectively, if monocyclic, bicyclic, or tricyclic), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents. Examples of heteroaryl groups include pyridyl, furfuryl, or furyl, imidazolyl, benzimidazolyl, pyrimidinyl, phenylthio, or thienyl, quinolyl, indolyl, thiazolyl, and the like. In some embodiments, the term "heteroarylalkyl" or the term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group. In some embodiments, the term "heteroarylalkoxy" refers to an alkoxy group substituted with a heteroaryl group.

[0107] In some embodiments, the term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 11-6 heteroatoms (if bicyclic), 1-9 heteroatoms (if tricyclic), wherein the heteroatoms are selected from O, N, or S (e.g., 1-3, 1-6, or 1-9 heteroatoms of carbon atoms and N, O, or S, respectively, if monocyclic, bicyclic, or tricyclic, wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclyl include triazolyl, tetrazolyl, piperazinyl, pyrrolidinyl, dioxane, morpholinyl, tetrahydrofuranyl, and the like.

[0108] In some embodiments, the term "oxo" refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.

[0109] In some embodiments, the term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted with substituents.

[0110] In some embodiments, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with a specified substituent group, including but not limited to: halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkyloxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkyloxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic and aliphatic. It should be understood that the substituent can be further substituted.

[0111] Oligonucleotide compounds and compositions

[0112] Some embodiments refer to nucleic acid sequence information. In some embodiments, any uracil (U) can be interchanged with any thymine (T), and vice versa. For example, in the siRNA with a nucleic acid sequence comprising one or more U, in some embodiments, any one of U can be replaced by T. Similarly, in the siRNA with a nucleic acid sequence comprising one or more T, in some embodiments, any one of T can be replaced by U. In some embodiments, oligonucleotides such as siRNA disclosed herein comprise RNA or are composed of RNA. In some embodiments, oligonucleotides may comprise DNA or are composed of DNA.

[0113] Some embodiments refer to specific nucleic acid sequences comprising modified nucleic acids. In some embodiments, the oligonucleotides described herein comprise or consist of a nucleic acid sequence comprising an unmodified version of a nucleic acid sequence comprising a modified nucleic acid. In some embodiments, the oligonucleotides described herein comprise or consist of a nucleic acid sequence comprising a nucleic acid sequence comprising a modified nucleic acid, but having any one or more additional modifications or different modifications.

[0114] In some embodiments, provided herein are oligonucleotide compounds that target nucleic acid sequences of angiopoietin-like 7 (ANGPTL7), including but not limited to sense and / or antisense non-coding and / or coding sequences associated with ANGPTL7. In some embodiments, the target nucleic acid molecule is not limited to a single ANGPTL7 polynucleotide, but extends to any of the isoforms, receptors, homologs, non-coding regions, etc. of ANGPTL7.

[0115] In some embodiments, a composition is provided that includes one or more antisense oligonucleotides or dsRNA agents that target a first nucleic acid and one or more additional antisense compounds that target a second nucleic acid target. For example, the first target can be a specific sequence of angiopoietin-like 7 (ANGPTL7), and the second target can be a region from another nucleotide sequence. In some embodiments, the composition can include two or more antisense oligonucleotides or dsRNA compounds that target different regions of the same ANGPTL7 nucleic acid target. Many examples of antisense oligonucleotides or dsRNA compounds are illustrated herein, and others can be selected from suitable compounds known in the art. Two or more combined compounds can be used together or sequentially.

[0116] In some embodiments, compositions comprising multiple antisense oligonucleotides or dsRNA reagent species are provided. In some embodiments, antisense oligonucleotides or dsRNA reagent species have sequences that are non-overlapping and non-adjacent with respect to naturally occurring target sequences and another type. In some embodiments, multiple antisense oligonucleotides or dsRNA reagent species have specificity to different natural target genes. In some embodiments, dsRNA reagents are allele-specific.

[0117] The present disclosure provides methods, compositions, and kits for administering and delivering the antisense oligonucleotide or dsRNA agents described herein.

[0118] Composition

[0119] In some embodiments, disclosed herein are compositions comprising oligonucleotides. In some embodiments, the compositions comprise oligonucleotides that target ANGPTL7. In some embodiments, the compositions consist of oligonucleotides that target ANGPTL7. In some embodiments, the compositions described herein are used in methods of treating a condition in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in methods of treating a condition as described herein. Some embodiments relate to the use of compositions comprising oligonucleotides in methods of treating a condition as described herein. The compositions (e.g., oligonucleotide compositions) may comprise or consist of a dsRNA agent as described herein. The compositions (e.g., oligonucleotide compositions) may comprise or consist of an siRNA as described herein. The compositions (e.g., oligonucleotide compositions) may comprise or consist of an antisense oligonucleotide as described herein.

[0120] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7 that, when administered to a subject in an effective amount, reduces ANGPTL7 mRNA levels in a cell or tissue. In some embodiments, the cell is an ANGPTL7. In some embodiments, the tissue is an ANGPTL7 tissue. In some embodiments, ANGPTL7 mRNA levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced by about 10% or more, compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced 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, compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced 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 compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced by no more than about 10% compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced 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% compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced 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% compared to before administration. In some embodiments, ANGPTL7 mRNA levels are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by either of the foregoing two percentages.

[0121] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7 and, when administered to a subject in an effective amount, reduces circulating ANGPTL7 protein levels. In some embodiments, ANGPTL7 protein levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by about 10% or more, compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced 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, compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced 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, compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by no more than about 10% compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced 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% compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced 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% compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by either of the preceding two percentages.

[0122] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL7 and, when administered to a subject in an effective amount, reduces symptoms of glaucoma. In some embodiments, the symptoms of glaucoma are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by about 10% or more, compared to before administration. In some embodiments, the symptoms of glaucoma are reduced 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, compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by no more than about 10%, compared to before administration. In some embodiments, the glaucoma symptoms are reduced 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% compared to before administration. In some embodiments, the glaucoma symptoms are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any one of the above two percentages. In some embodiments, the glaucoma symptom is the incidence of glaucoma or a glaucoma subtype. In some embodiments, the glaucoma symptom is the severity of glaucoma or a glaucoma subtype. Examples of glaucoma subtypes include nonspecific glaucoma, primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG).

[0123] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7 and, when administered to a subject in an effective amount, reduces intraocular pressure. In some embodiments, the intraocular pressure is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, compared to before administration. In some embodiments, the intraocular pressure is reduced by about 10% or more, compared to before administration. In some embodiments, the intraocular pressure is reduced 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, compared to before administration. In some embodiments, the intraocular pressure is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, compared to before administration. In some embodiments, the intraocular pressure is reduced by no more than about 10%, compared to before administration. In some embodiments, the intraocular pressure is reduced 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% compared to before administration. In some embodiments, the intraocular pressure is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by either of the above two percentages.

[0124] Modifier Mode

[0125] In embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, 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 an alkylphosphonate, a phosphorothioate, a methylphosphonate, a phosphorodithioate, an alkylphosphonothioate, a phosphoramidate, a carbamate, a carbonate, a phosphotriester, an acetamoate, or a carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. The benefits of the modified internucleoside linkage may include reduced toxicity or improved pharmacokinetics. The composition (e.g., an oligonucleotide composition) may comprise or consist of a dsRNA agent as described herein. The composition (e.g., an oligonucleotide composition) may comprise or consist of an siRNA as described herein. A composition (eg, an oligonucleotide composition) can comprise or consist of an antisense oligonucleotide described herein.

[0126] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, 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 series of modified internucleoside linkages defined by any two of the foregoing 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, a plurality of 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.

[0127] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a modified nucleoside. In embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl group, a 2'-O-alkyl group, a 2'-O-allyl group, a 2'-fluoro group, or a 2'-deoxy group, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2',4' constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises an HLA. In some embodiments, the modified nucleoside comprises a CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-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, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 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, 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.Benefits of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0128] 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 series of nucleosides defined by any two of the above 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.

[0129] In some embodiments, the hydrophobic moiety is attached to an oligonucleotide (e.g., the sense and / or antisense strand of an siRNA, or an ASO). In some embodiments, the hydrophobic moiety is attached to the 3' end of the oligonucleotide. In some embodiments, the hydrophobic moiety is attached to the 5' end of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol.

[0130] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid is attached to the 3' end of the oligonucleotide. In some embodiments, the lipid is attached to the 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenoyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises cholesterol.

[0131] In some embodiments, the composition comprises an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the RGD peptide is attached to the 3' end of the oligonucleotide. In some embodiments, the RGD peptide is attached to the 5' end 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 the 5' end of the sense strand, or attached to the 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 the 5' end of the antisense strand, or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the oligonucleotide includes an RGD peptide and a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises a ring (-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises aminobenzoic acid-derived RGD. In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid-derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises a plurality of such RGD peptides. For example, the RGD peptide may comprise 2, 3, or 4 RGD peptides.

[0132] In some embodiments, the oligonucleotide comprises a dsRNA agent as described herein. In some embodiments, the oligonucleotide comprises an siRNA as described herein. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide as described herein. In some embodiments, one or more nucleotides in the sense strand and / or antisense strand of an antisense oligonucleotide, a dsRNA agent, or an siRNA are modified according to any modification or modification pattern as described herein.

[0133] In some embodiments, a modification or modification pattern disclosed herein includes a cholesterol moiety.

[0134] dsRNA reagents

[0135] In some embodiments, the composition comprises a double-stranded RNAi (dsRNA) agent. In one aspect, provided herein are dsRNA agents capable of inhibiting the expression of ANGPTL7. The dsRNA agent comprises a sense strand and an antisense strand. In some cases, the sense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412. In some cases, the antisense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to the reverse complement of the sense strand. In some cases, the antisense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0136] In some cases, the length of each strand of the dsRNA agent can be in the range of 12-30 nucleotides. For example, each strand can be between 14-30 nucleotides in length, between 17-30 nucleotides in length, between 25-30 nucleotides in length, between 27-30 nucleotides in length, between 17-23 nucleotides in length, between 17-21 nucleotides in length, between 17-19 nucleotides in length, between 19-25 nucleotides in length, between 19-23 nucleotides in length, between 19-21 nucleotides in length, between 21-25 nucleotides in length, or between 21-23 nucleotides in length.

[0137] In some embodiments, the dsRNA comprises a nucleotide sequence of at least one nucleotide sequence, wherein the length of the dsRNA comprises a nucleotide sequence of at least one nucleotide sequence. Sense strand and antisense strand form duplex dsRNA conventionally. The length in the duplex region of a dsRNA reagent can be 12-30 nucleotide pairs. For example, the length in the duplex region can be between 14-30 nucleotide pairs, between 17-30 nucleotide pairs, between 25-30 nucleotide pairs, between 27-30 nucleotide pairs, between 17-23 nucleotide pairs, between 17-21 nucleotide pairs, between 17-19 nucleotide pairs, between 19-25 nucleotide pairs, between 19-23 nucleotide pairs, between 19-21 nucleotide pairs, between 21-25 nucleotide pairs, or between 21-23 nucleotide pairs. In another example, the duplex region has a length of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27.

[0138] In some embodiments, the dsRNA reagent comprises one or more overhang regions and / or capping groups at the 3'-end or 5'-end or both ends of the chain. In some cases, the length of the overhang is about 1-6 nucleotides, for example, 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhang may be the result that one chain is longer than another, or the result that two chains of equal length are staggered. The overhang can form a mismatch with the target mRNA, or it can be complementary to the targeted gene sequence, or it can be other sequences. The first and second chains can also be connected, for example, by extra bases to form a hairpin, or by other non-base joints.

[0139] In some embodiments, described herein are compositions comprising RNA interference (RNAi) agents. In some embodiments, the RNAi agent is capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7). In some embodiments, the RNAi agent comprises an siRNA as described herein. In some embodiments, the RNAi agent comprises a double-stranded RNA (dsRNA). In some embodiments, the dsRNA comprises a sense strand and an antisense strand (e.g., a sense strand and / or antisense strand described herein). In some embodiments, the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11085. In some embodiments, the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11086. In some embodiments, each strand has 14 to 30 nucleotides.

[0140] In some embodiments, described herein are compositions comprising an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7); wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides.

[0141] In some embodiments, described herein are compositions comprising an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7); wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11086, and each strand having 14 to 30 nucleotides.

[0142] In some embodiments, one or more modifications confer nuclease resistance to an oligonucleotide (e.g., an siRNA or antisense oligonucleotide). In some embodiments, a modification pattern confer nuclease resistance to an oligonucleotide (e.g., an siRNA or antisense oligonucleotide). For example, the modification pattern 1S, 2S, 3S, 4S, 5S, 1AS, 2AS, 3AS, 4AS, or ASO1 can confer nuclease resistance.

[0143] dsRNA modification

[0144] The modifications described herein with respect to dsRNA agents may be applicable to the antisense oligonucleotides described elsewhere herein.The modifications described herein with respect to dsRNA agents may be applicable to the siRNA oligonucleotides described elsewhere herein.

[0145] In some embodiments, one or more nucleotides in the sense strand and / or antisense strand of a dsRNA agent are modified. In some cases, each nucleotide in the sense strand and antisense strand of a dsRNA is modified. The modifications to the sense strand and antisense strand can each independently include at least two different modifications. In some cases, not each nucleotide in the sense strand and antisense strand is modified. In some cases, the nucleotides in the sense strand and / or antisense strand are not modified.

[0146] In some cases, the sense strand comprises at least one motif with three identical modifications on three consecutive nucleotides, wherein at least one of the motifs occurs at or near the cleavage site of the antisense strand. In some cases, the antisense strand comprises at least one motif with three identical modifications on three consecutive nucleotides. The modification pattern of the antisense strand can be shifted by one or more nucleotides relative to the modification pattern of the sense strand.

[0147] In some cases, the sense strand comprises at least two motifs with three identical modifications on three consecutive nucleotides when at least one of the motifs occurs at the cleavage site of the strand and at least one of the motifs occurs at another portion of the strand separated by at least one nucleotide from the motif at the cleavage site. In some cases, the antisense strand comprises at least one motif with three identical modifications on three consecutive nucleotides when at least one of the motifs occurs at or near the cleavage site of the strand and at least one of the motifs occurs at another portion of the strand separated by at least one nucleotide from the motif at or near the cleavage site.

[0148] In some cases, the sense strand comprises at least two motifs with three identical modifications on three consecutive nucleotides, where at least one of the motifs occurs at the cleavage site of the strand and at least one of the motifs occurs at another portion of the strand that is at least one nucleotide away from the motif at the cleavage site. In some cases, the antisense strand comprises at least one motif with three identical modifications on three consecutive nucleotides, where at least one of the motifs occurs at or near the cleavage site of the strand and at least one of the motifs occurs at another portion of the strand that is at least one nucleotide away from the motif at or near the cleavage site. In some cases, the modification of the motif that occurs at the cleavage site in the sense strand is different from the modification of the motif that occurs at or near the cleavage site in the antisense strand.

[0149] In some cases, the sense strand comprises at least one motif of three 2'-F modifications on three consecutive nucleotides, wherein at least one of the motifs occurs at the cleavage site of the strand. In some cases, the antisense strand comprises at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides.

[0150] In some cases, the sense strand comprises one or more motifs having three identical modifications on three consecutive nucleotides, wherein one or more additional motifs occur at another portion of the strand that is at least one nucleotide away from the three 2'-F modifications at the cleavage site. The antisense strand may comprise one or more motifs having three identical modifications on three consecutive nucleotides, wherein one or more additional motifs occur at another portion of the strand that is at least one nucleotide away from the three 2'-O-methyl modifications. In some cases, at least one of the nucleotides having the 2'-F modification can form a base pair with one of the nucleotides having the 2'-O-methyl modification.

[0151] In some embodiments, if the dsRNA agent comprises an overhang, the nucleotides in the overhang region of the dsRNA agent can each independently be a modified or unmodified nucleotide. Non-limiting examples of modifications include, but are not limited to, 2'-sugar modifications, such as 2-F 2'-O methyl, thymidine (T), 2'-O-methoxyethyl-5-methyluridine (Teo), 2'-O-methoxyethyladenosine (Aeo), 2'-O-methoxyethyl-5-methylcytidine (m5Ceo) and any combination thereof. For example, TT can be the overhang sequence at either end of either chain. The overhang can form a mismatch with the target mRNA, or it can be complementary to the targeted gene sequence, or it can be other sequences.

[0152] In some embodiments, if the dsRNA agent comprises an overhang, the 5'- and / or 3'-overhang on the sense strand, antisense strand, or both strands of the dsRNA agent may be phosphorylated. In some embodiments, the overhang region comprises two nucleotides with a phosphorothioate between the two nucleotides, wherein the two nucleotides may be the same or different. In some embodiments, the overhang is present at the 3'-end of the sense strand, antisense strand, or both strands. In some embodiments, the 3'-overhang is present in the antisense strand. In some embodiments, the 3'-overhang is present in the sense strand.

[0153] In some embodiments, the modified dsRNA agent comprises one or more modified nucleotides, including but not limited to 2'OMe nucleotides, 2'-deoxy-2'-fluoro (2'F) nucleotides, 2'-deoxy nucleotides, 2'-O-(2-methoxyethyl) (MOE) nucleotides, locked nucleic acid (LNA) nucleotides, or a combination thereof. In some embodiments, the modified dsRNA agent comprises 2'OMe nucleotides (e.g., 2'Ome purine and / or pyrimidine nucleotides), such as, for example, 2'OMe-guanosine nucleotides, 2'OMe-uridine nucleotides, 2'OMe-adenosine nucleotides, 2'OMe-cytosine nucleotides, or a combination thereof. In some cases, the modified dsRNA agent does not comprise 2'OMe-cytosine nucleotides. In some embodiments, the modified dsRNA agent comprises a hairpin loop structure.

[0154] In certain aspects, the IC50 of the modified dsRNA agent is less than or equal to ten times the IC50 of the corresponding unmodified dsRNA agent (e.g., the IC50 of the modified dsRNA agent is less than or equal to ten times the IC50 of the corresponding unmodified dsRNA agent). In some embodiments, the IC50 of the modified dsRNA agent is less than or equal to three times the IC50 of the corresponding unmodified dsRNA agent. In some embodiments, the IC50 of the modified dsRNA agent is less than or equal to two times the IC50 of the corresponding unmodified dsRNA agent. It will be apparent to those skilled in the art that dose response curves can be generated and IC50 values ​​for modified dsRNA agents and corresponding unmodified dsRNA agents can be readily determined using methods known to those skilled in the art.

[0155] The modified dsRNA agent may have 1, 2, 3, 4 or more nucleotide 3' overhangs on one or both sides of the double-stranded region, or may not have overhangs (i.e., with blunt ends). In some cases, the modified dsRNA agent has two nucleotide 3' overhangs on each side of the double-stranded region. In some cases, the 3' overhang on the antisense strand is complementary to the target sequence, and the 3' overhang on the sense strand is complementary to the complementary strand of the target sequence. In some cases, the 3' overhang does not have complementarity with the target sequence or its complementary strand. In some embodiments, the 3' overhang comprises one, two, three, four or more nucleotides, such as 2'-deoxy (2'H) nucleotides. In some cases, the 3' overhang comprises deoxythymidine (dT) nucleotides.

[0156] In some embodiments, the modified dsRNA agent comprises from about 1% to about 100% (e.g., about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of modified nucleotides in the double-stranded region of the dsRNA agent. In some embodiments, less than about 30% (e.g., less than about 30%, 25%, 20%, 15%, 10%, or 5%) or about 1% to about 30% (e.g., about 1%-30%, 5%-30%, 10%-30%, 15%-30%, 20%-30%, or 25%-30%) of the nucleotides in the double-stranded region of the dsRNA agent comprise modified nucleotides.

[0157] In some embodiments, the dsRNA agent does not comprise a phosphate backbone modification, e.g., in the sense strand and / or antisense strand of the double-stranded region. In some embodiments, the modified dsRNA agent does not comprise a 2'-deoxynucleotide, e.g., in the sense strand and / or antisense strand of the double-stranded region. In some cases, the nucleotides at the 3'-end of the double-stranded region in the sense strand and / or antisense strand are not modified nucleotides. In some cases, the nucleotides near the 3'-end of the double-stranded region in the sense strand and / or antisense strand (e.g., within one, two, three, or four nucleotides of the 3'-end) are not modified nucleotides.

[0158] The dsRNA agent may have a 3' overhang of 1, 2, 3, 4 or more nucleotides on one or both sides of the double-stranded region, or may have no overhang (i.e., have a blunt end). In some cases, the dsRNA agent has a 3' overhang of two nucleotides on each side of the double-stranded region. In some embodiments, the 3' overhang comprises one, two, three, four or more nucleotides, such as 2'-deoxy (2'H) nucleotides. In some cases, the 3' overhang comprises deoxythymidine (dT) nucleotides.

[0159] The dsRNA agent may also have a blunt end located at the 5'-end of the antisense strand (or the 3'-end of the sense strand), or vice versa. In some cases, the antisense strand of the dsRNA has a nucleotide overhang at the 3' end and a blunt end at the 5' end. Although not being bound by theory, the asymmetric blunt end at the 5'-end of the antisense strand and the overhang at the 3'-end of the antisense strand may facilitate the loading of the guide strand into the RISC process.

[0160] In some embodiments, the dsRNA agent may also have two blunt ends at both ends of the dsRNA duplex.

[0161] In some embodiments, each nucleotide in the sense and antisense strands of a dsRNA agent, including nucleotides that are part of a motif, can be modified. Each nucleotide can be modified with the same or different modifications, which can include one or more changes in one or both of the non-linked phosphate oxygens and / or one or more of the linked phosphate oxygens; changes in the composition of the ribose sugar, such as changes in the 2' hydroxyl group on the ribose sugar; wholesale replacement of phosphate moieties with "dephospho" linkers; modification or replacement of naturally occurring bases; and replacement or modification of the ribose-phosphate backbone. In some embodiments, fewer than all nucleotides in the sense and antisense strands are modified.

[0162] Because nucleic acid is the polymer of subunit, in some cases, many modifications occur in the position repeated in nucleic acid, such as the modification of base or phosphate moiety, or the non-connection O of phosphate moiety.In some cases, modification occurs in all tested positions in nucleic acid, but not in other cases.For example, modification may only occur in 3' or 5' terminal position, may only occur in terminal region, such as the position on terminal nucleotide or in the last 2,3,4,5 or 10 nucleotide of chain.Modification can occur in double-stranded region, single-stranded region or both.Modification may only occur in the double-stranded region of RNA or may only occur in the single-stranded region of RNA.For example, the non-connection O position phosphorothioate modification may only occur in one or two ends, may only occur in terminal region, such as the position on terminal nucleotide or in the last 2,3,4,5 or 10 nucleotide of chain, or may occur in double-stranded and single-stranded regions, particularly in end.One or more 5' ends can be phosphorylated.

[0163] For example, stability can be improved to include specific bases in the overhang, or in the single-stranded overhang, for example, in 5' or 3' overhang, or include modified nucleotides or nucleotide substitutes in both.For example, purine nucleotides can be included in the overhang.In some embodiments, all or some bases in 3' or 5' overhang can be modified, for example, with modification as described herein.Modification can include, for example, the use of modification known in the art at the 2' position of ribose, for example, deoxyribonucleotides, 2'-deoxy-2'-fluoro (2'-F) or 2'-O-methyl modified rather than the ribose of core base, and the modification in phosphate group, for example, the use of phosphorothioate modification.In some cases, the overhang does not need to be homologous to the target sequence.

[0164] In some embodiments, each residue in the sense and antisense strands is independently modified with LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-methyl, 2'-O-allyl, 2'-C-allyl, 2'-deoxy, or 2'-fluoro. A strand may contain more than one modification. In some embodiments, each residue in the sense and antisense strands is independently modified with 2'-O-methyl or 2'-fluoro.

[0165] In some embodiments, at least two different modifications are present on the sense strand and the antisense strand, and the two modifications can be 2'-O-methyl or 2'-fluoro modifications, etc.

[0166] In some embodiments, the sense strand and the antisense strand each contain two differently modified nucleotides selected from 2'-O-methyl or 2'-fluoro.

[0167] In some embodiments, each residue of the sense and antisense strands is independently modified with 2'-O-methyl nucleotides, 2'-deoxyfluoro nucleotides, 2-ON-methylacetamide (2'-O-NMA) nucleotides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleotides, 2'-O-aminopropyl (2'-O-AP) nucleotides, or 2'-ara-F nucleotides.

[0168] The types of modifications contained in the alternating motif can be the same or different. For example, if A, B, C, and D each represent a type of modification on a nucleotide, the alternating pattern, i.e., the modification on every other nucleotide, can be the same, but each of the sense and antisense strands can select from several modification possibilities in the alternating motif, such as "ABABAB...", "AC ACAC...", "BDBDBD...", or "CDCDCD...", etc.

[0169] In some embodiments, the dsRNA agent comprises a modification pattern of an alternating motif on the sense strand that is converted relative to the modification pattern of the alternating motif on the antisense strand. This conversion can be such that the modification groups of the nucleotides of the sense strand correspond to different modification groups of the nucleotides of the antisense strand, and vice versa. For example, when the sense strand is paired with the antisense strand in a dsRNA duplex, the alternating motif in the sense strand can start with "ABABAB" from the 5'-3' of the strand, and the alternating motif in the antisense strand can start with "BABABA" from the 3'-5' of the strand within the duplex region. As another example, the alternating motif in the sense strand can start with "AABBAABB" from the 5'-3' of the strand, and the alternating motif in the antisense strand can start with "BBAABBAA" from the 3'-5' of the strand within the duplex region, such that there is a complete or partial conversion of the modification pattern between the sense and antisense strands.

[0170] In some embodiments, the dsRNA agent comprises a pattern of alternating motifs of 2'-O-methyl modifications and 2'-F modifications on the initial sense strand, with a shift relative to the pattern of alternating motifs of 2'-O-methyl modifications and 2'-F modifications on the initial antisense strand, i.e., 2'-O-methyl modified nucleotides on the sense strand base pair with 2'-F modified nucleotides on the antisense strand, and vice versa. Position 1 of the sense strand may begin with a 2'-F modification, and position 1 of the antisense strand may begin with a 2'-O-methyl modification. Introducing one or more motifs of three identical modifications on three consecutive nucleotides into the sense strand and / or antisense strand interrupts the initial modification pattern present in the sense strand and / or antisense strand. This interruption of the modification pattern of the sense strand and / or antisense strand by introducing one or more motifs of three identical modifications on three consecutive nucleotides of the sense strand and / or antisense strand can enhance gene silencing activity against the target gene.

[0171] The dsRNA agent may comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or the antisense strand, or both, in any position of the strand. For example, the internucleotide linkage modification may occur on every nucleotide on the sense strand and / or the antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand or the antisense strand; or the sense strand or the antisense strand may comprise two internucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same as or different from that of the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may be switched relative to the alternating pattern of the internucleotide linkage modification on the antisense strand.

[0172] In some embodiments, dsRNA comprises phosphorothioate or methylphosphonate internucleotide connection modification in the overhang region.For example, the overhang region comprises two nucleotides, has phosphorothioate or methylphosphonate internucleotide connection between these two nucleotides.Can also carry out internucleotide connection modification to connect the overhang nucleotide with the terminal pairing nucleotide in the duplex region.For example, at least 2,3,4 or all overhang nucleotides can be connected by phosphorothioate or methylphosphonate internucleotide connection connection, and optionally, can have other phosphorothioate or methylphosphonate internucleotide connection that overhang nucleotide is connected with the pairing nucleotide adjacent to overhang nucleotide.For example, there may be at least two phosphorothioate internucleotide connection between terminal three nucleotides, wherein two of the three nucleotides are overhang nucleotides, and the third is the pairing nucleotide adjacent to the overhang nucleotide.In some cases, these terminal three nucleotides may be positioned at the 3 '-end of antisense strand.

[0173] In some embodiments, the sense strand of the dsRNA agent comprises 1-10 blocks of 2 to 10 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the sense strand is paired with an antisense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0174] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of two phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0175] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of three phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0176] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of four phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0177] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of five phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0178] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of six phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0179] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of seven phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, or 8 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0180] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of eight phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, or 6 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0181] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of nine phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, or 4 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate linkages.

[0182] In some embodiments, the dsRNA agent comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1-10 of the terminal position(s) of the sense and / or antisense strand. For example, at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides can be linked by phosphorothioate or methylphosphonate internucleotide linkages at one or both ends of the sense and / or antisense strand.

[0183] In some embodiments, the dsRNA agent comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1-10 of the internal region of the duplex of each sense strand and / or antisense strand. For example, at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides can be linked by phosphorothioate methylphosphonate internucleotide linkages at positions 8-16 of the duplex region counted from the 5'-end of the sense strand; the dsRNA can optionally further comprise one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1-10 of the terminal position(s).

[0184] In some embodiments, the dsRNA agent comprises 1 to 5 phosphorothioate or methylphosphonate internucleotide linkage modifications within positions 1-5 and 1 to 5 phosphorothioate or methylphosphonate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the sense strand, and 1 to 5 phosphorothioate or methylphosphonate internucleotide linkage modifications at positions 1 and 2 and 1 to 5 at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0185] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification within positions 1-5 and 1 phosphorothioate or methylphosphonate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 2 phosphorothioate or methylphosphonate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0186] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0187] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counted from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counted from the 5'-end) of the antisense strand. In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counted from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counted from the 5'-end) of the antisense strand.

[0188] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification within positions 1-5 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0189] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification within positions 1-5 and 1 at positions 18-23 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0190] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification within positions 1-5 (counting from the 5'-end), as well as 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0191] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 (counting from the 5'-end), as well as 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0192] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 1 at positions 18-23 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0193] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0194] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counting from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counting from the 5'-end) of the antisense strand.

[0195] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 20 and 21 (counting from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the antisense strand.

[0196] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 20 and 21 (counting from the 5'-end) of the antisense strand.

[0197] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 21 and 22 (counting from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the antisense strand.

[0198] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 21 and 22 (counting from the 5'-end) of the antisense strand.

[0199] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 22 and 23 (counting from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 22 (counting from the 5'-end) of the antisense strand.

[0200] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 23 and 23 (counting from the 5'-end) of the antisense strand.

[0201] In some embodiments, the dsRNA reagent comprises one or more mismatches or combinations thereof with the target in the duplex. Mismatches may occur in the overhang region or the duplex region. Base pairs can be ranked according to their tendency to promote dissociation or melting (for example, according to the free energy of binding or dissociation of a particular pairing, the simplest method is to examine these pairs on the basis of a single pair, although the next nearest neighbor or similar analysis can also be used). In some cases, in terms of promoting dissociation: A: U is better than G: C; G: U is better than G: C; and I: C is better than G: C (I = inosine). In some cases, mismatches, such as non-canonical or better than canonical (A: T, A: U, G: C) pairing in addition to canonical pairing (as described elsewhere herein); and pairing comprising universal bases is better than canonical pairing. In some embodiments, the dsRNA agent comprises at least one of the first 1, 2, 3, 4, or 5 base pairs within the duplex region from the 5'-end of the antisense strand, which can be independently selected from the group consisting of: A:U, G:U, I:C, and mismatched base pairs, e.g., pairs that are non-canonical or in addition to canonical pairings or that include universal bases, to promote dissociation of the antisense strand at the 5' end of the duplex.

[0202] In some embodiments, the nucleotide at position 1 from the 5' end of the antisense strand within the duplex region is selected from A, dA, dU, U, and dT. In some embodiments, at least one of the first 1, 2, or 3 base pairs from the 5' end of the antisense strand within the duplex region is an AU base pair. For example, the first base pair from the 5' end of the antisense strand within the duplex region is an AU base pair.

[0203] In some embodiments, dsRNA agent is conjugated with one or more carbohydrate moieties, which can optimize one or more characteristics of dsRNA agent. In some cases, carbohydrate moieties are attached to the modified subunit of dsRNA agent. For example, the ribose of one or more ribonucleotide subunits of dsRNA agent can be replaced by another part, such as non-carbohydrate (e.g., cyclic) carrier attached to carbohydrate ligand. The ribonucleotide subunit wherein the ribose of subunit is so replaced is referred to as ribose replacement modified subunit (RRMS) in this article. Annular carrier can be a carbocyclic ring system, that is, all annular atoms are carbon atoms, or a heterocyclic ring system, that is, one or more annular atoms can be heteroatoms, such as nitrogen, oxygen, sulfur. Annular carrier can be a monocyclic ring system, or can include two or more rings, such as condensed rings. Annular carrier can be a fully saturated ring system, or it can contain one or more double bonds.

[0204] In some embodiments, the ligand is attached to the dsRNA by a carrier. In some cases, the carrier includes (i) at least one "main chain attachment point" or two "main chain attachment points" and (ii) at least one "tether attachment point". In some cases, "main chain attachment point" refers to a functional group, such as a hydroxyl group, or is generally available for and suitable for incorporating the carrier into the main chain of ribonucleic acid, such as a phosphate, or a modified phosphate, such as a key of a sulfur-containing main chain. In some embodiments, a "tether attachment point" (TAP) refers to a constituent ring atom of a cyclic carrier, such as a carbon atom or a heteroatom (different from the atom providing the main chain attachment point), which connects a selected portion. The portion can be, for example, a carbohydrate, such as a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, and a polysaccharide. Optionally, the selected portion is connected by the insertion tether of the cyclic carrier. Therefore, the cyclic carrier can include a functional group, such as an amino group, or generally provides a key suitable for incorporating or tethering another chemical entity, such as a ligand constituting a ring.

[0205] In some embodiments, the dsRNA agent is conjugated to the ligand via a carrier, wherein the carrier can be a cyclic group or an acyclic group; for example, the cyclic group is selected from pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofurfuryl, and decahydronaphthalene; for example, the acyclic group is selected from a serinol backbone or a diethanolamine backbone. The dsRNA agent can optionally be conjugated to one or more ligands. The ligand can be attached to the sense strand, the antisense strand, or both strands at the 3'-end, the 5'-end, or both ends. For example, the ligand can be conjugated to the sense strand, particularly the 3'-end of the sense strand.

[0206] In some embodiments, dsRNA is modified to promote stability. Synthetic siRNA, such as the dsRNA herein, the stabilization for rapid nuclease degradation can be considered as a prerequisite for in vivo and therapeutic applications. This can be achieved using various stable chemicals previously developed for other nucleic acid drugs (such as ribozymes and antisense molecules). These include chemical modifications to natural 2'-OH groups in the ribose backbone, such as 2'-O-methyl (2'OMe) and 2'-fluoro (2'F) replacements, which can be easily introduced into siRNA, such as 2'-modified nucleotides in RNA synthesis processes. In some cases, introducing chemical modifications to natural siRNA duplexes can have a negative impact on RNAi activity, so the design of chemically modified siRNA may require random screening methods to identify duplexes that retain effective gene silencing activity.

[0207] In some cases, endonucleolytic cleavage of the target mRNA is impaired when cleavage of the sense strand is inhibited. In some cases, incorporation of 2'-O-Me ribose into the Ago2 cleavage site in the sense strand inhibits RNAi. In some cases, for phosphorothioate modifications, effective RNAi may require cleavage of the sense strand.

[0208] In some cases, the dsRNA agent comprises a 2'-F modified residue, for example, at the Ago2 cleavage site. The modification may or may not be motif-specific, for example, a modification comprising a 2'-F modification of all pyrimidines on both the sense and antisense strands, as long as a pyrimidine residue is present, without any selectivity.

[0209] In some cases, the dsRNA agent comprises two 2'-F modified residues, for example, at the Ago2 cleavage site, on the sense strand and / or the antisense strand. In some cases, for each particular strand, all pyrimidines or all purines are modified.

[0210] In some cases, the dsRNA agent comprises a 2'-OMe modification or various combinations of 2'-F, 2'-OMe, and phosphorothioate modifications to stabilize the siRNA. In some cases, the residues at the cleavage site of the antisense strand are not modified with 2'-OMe to increase the stability of the siRNA.

[0211] siRNA

[0212] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand. In some embodiments, the siRNA comprises a double-stranded agent described herein.

[0213] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 14-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by either of the foregoing two numbers. In some embodiments, the composition comprises an antisense strand that is 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by either of the foregoing two numbers.

[0214] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11085. In some embodiments, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more consecutive nucleosides of one of SEQ ID NO: 11085.

[0215] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11086. In some embodiments, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more consecutive nucleosides of one of SEQ ID NO: 11086.

[0216] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, 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.

[0217] 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 above 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 above numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0218] 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 above 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 above numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0219] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 19-mer of human ANGPTL7 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer of human ANGPTL7 mRNA.

[0220] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 17-mer in a non-human primate ANGPTL7 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in a non-human primate ANGPTL7 mRNA.

[0221] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 19-mer or a combination thereof in human ANGPTL7 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in human ANGPTL7 mRNA.

[0222] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to human ANGPTL7 mRNA and fewer than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and fewer than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and fewer than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and fewer than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and fewer than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 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 to human ANGPTL7 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 to human ANGPTL7 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 to human ANGPTL7 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 to human ANGPTL7 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[0223] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not contain a SNP and has a minor allele frequency (MAF) greater than or equal to 1% (positions 2-18). In some embodiments, the MAF is greater than 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%.

[0224] In some embodiments, the siRNA binds to human ANGPTL7 mRNA with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not contain a SNP with a minor allele frequency (MAF) greater than or equal to 1% (positions 2-18). In some embodiments, the sense and antisense strands each comprise a seed region that is not identical to a seed region of a human miRNA. In some embodiments, the sense strand comprises a seed region that is different from a seed region of a human miRNA. In some embodiments, the antisense strand comprises a seed region that is different from a seed region of a human miRNA.

[0225] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand. In some embodiments, the oligonucleotide comprises a nucleic acid sequence (e.g., a sense strand sequence or an antisense strand sequence). In some embodiments, the sense strand comprises a sense strand sequence. In some embodiments, the antisense strand comprises an antisense strand sequence. In some embodiments, the nucleic acid sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 1-4412, a sequence that is at least 80% identical to any one of SEQ ID NOs: 1-4412, a sequence that is at least 85% identical to any one of SEQ ID NOs: 1-4412, a sequence that is at least 90% identical to any one of SEQ ID NOs: 1-4412, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 1-4412. In some embodiments, the nucleic acid sequence comprises the sequence of any one of SEQ ID NO:1-4412, or it has 1, 2, 3 or 4 nucleoside substitutions, additions or deletions or consists of it. In some embodiments, the nucleic acid sequence comprises the sequence of any one of SEQ ID NO:1-4412, or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of it. In some embodiments, the nucleic acid sequence comprises the sequence of any one of SEQ ID NO:1-4412 or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of it. In some embodiments, the nucleic acid sequence comprises the sequence of any one of SEQ ID NO:1-4412 or consists of it. In some embodiments, the oligonucleotide comprises an overhang as described herein. In some embodiments, the oligonucleotide comprises one or more modifications or modification patterns as described herein.

[0226] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset A or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset A. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset B or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset B. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset C or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset C. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset D or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset D. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset E, or siRNAs thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset E.

[0227] In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 1-2206, comprises or consists of a sequence that is at least 80% identical to any one of SEQ ID NOs: 1-2206, comprises or consists of a sequence that is at least 85% identical to any one of SEQ ID NOs: 1-2206, comprises or consists of a sequence that is at least 90% identical to any one of SEQ ID NOs: 1-2206, or comprises or consists of a sequence that is at least 95% identical to any one of SEQ ID NOs: 1-2206. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-2206, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-2206, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-2206. In some embodiments, the sense strand comprises an overhang as described herein. In some embodiments, the sense strand comprises one or more modifications or modification patterns as described herein.

[0228] In some embodiments, the sense strand sequence comprises the same sequence as SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the sense strand sequence comprises SEQ ID NO: NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 9 48, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 1436, 14 38, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having 1, 2, 3 or 4 nucleoside substitutions, additions or deletions, or consisting thereof. In some embodiments, the sense strand sequence comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions, or consisting thereof.In some embodiments, the sense strand sequence comprises SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 14 29, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the sense strand comprises an overhang described herein.

[0229] In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset A, or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset A. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset B, or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset B. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset C, or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset C. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset D, or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset D. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset E, or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset E.

[0230] In some embodiments, the sense strand sequence comprises or consists of a sequence in SEQ ID NO: 11089, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence in SEQ ID NO: 11089.

[0231] In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 2207-4412, a sequence that is at least 80% identical to any one of SEQ ID NOs: 2207-4412, a sequence that is at least 85% identical to any one of SEQ ID NOs: 2207-4412, a sequence that is at least 90% identical to any one of SEQ ID NOs: 2207-4412, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 2207-4412. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2207-4412, 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 the sequence of any one of SEQ ID NOs: 2207-4412, or an antisense strand sequence having 1 or 2 nucleoside substitutions, additions, or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the sequence of SEQ ID NOs: 2207-4412, or consists of them. In some embodiments, the antisense strand comprises an overhang as described herein. In some embodiments, the antisense strand comprises one or more modifications or modification patterns as described herein.

[0232] In some embodiments, the antisense strand sequence comprises the same sequence as SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3635, 3640, 364 2, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand sequence comprises SEQ ID NO: NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 294 7. 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1, 2, 3 or 4 nucleoside substitutions, additions or deletions, or consisting thereof.In some embodiments, the antisense strand sequence comprises SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3632, 5, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions, or consisting thereof. In some embodiments, the antisense strand sequence comprises SEQ ID NO: NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2 946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand comprises an overhang as described herein. In some embodiments, the antisense strand comprises one or more modifications or modification patterns as described herein.

[0233] In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset A, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset A, or an antisense strand thereof. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset B, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset B, or an antisense strand thereof. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset C, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset C, or an antisense strand thereof. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset D, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset D. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset E, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset E.

[0234] In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 11090, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 11090.

[0235] siRNA modification patterns

[0236] The oligonucleotides described herein (e.g., siRNA, antisense oligonucleotide, sense strand, antisense strand, siRNA agent, or dsRNA agent) can include any modification pattern disclosed herein, including but not limited to any one or more of the modification patterns 1S-5S, 1AS-4AS, or ASO1.

[0237] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 11383), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 4S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfnNfsnsnN-lipid-3' (SEQ ID NO: 11384), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises a nucleoside. In some embodiments, the sense strand comprises the modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-lipid-3' (SEQ ID NO: 11385), wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, "s" is a phosphorothioate linkage, and N comprises the nucleoside.

[0238] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, 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' (SEQ ID NO: 11386), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5'nsNfsnnnNfnNfnNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 3AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 11389), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0239] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a pattern of 1S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a pattern of 2S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a pattern of 3S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a pattern of 4S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a modified pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the antisense strand comprises a modified pattern of 1S, 2S, 3S, 4S, or 5S. In some embodiments, either the sense strand or the antisense strand comprises a modified pattern of AS01.

[0240] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and / or the antisense strand comprises one or more modifications or modification patterns. In some embodiments, the oligonucleotide comprises a nucleic acid sequence (e.g., a sense strand sequence or an antisense strand sequence) having one or more modifications or modification patterns.

[0241] In some embodiments, the nucleic acid sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11093-11332, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11093-11332, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11093-11332, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11093-11332, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11093-11332. In some embodiments, the nucleic acid sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11093-11332, or a sequence having 1, 2, 3, or 4 nucleotide substitutions, additions, or deletions thereof. In some embodiments, the nucleic acid sequence comprises the sequence of any one of SEQ ID NO:11093-11332, or a sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions or consisting thereof. In some embodiments, the nucleic acid sequence comprises the sequence of any one of SEQ ID NO:11093-11332 or consisting thereof. In some embodiments, the nucleic acid sequence is an unmodified version of a nucleic acid sequence described herein. In some embodiments, the nucleic acid sequence has more or different sequence modifications than a nucleic acid sequence described herein.

[0242] In some embodiments, the nucleic acid sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11333-11376, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11333-11376, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11333-11376, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11333-11376, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11333-11376. In some embodiments, the nucleic acid sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11376, or a sequence having 1, 2, 3, or 4 nucleotide substitutions, additions, or deletions thereof. In some embodiments, the nucleic acid sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11376, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11376. In some embodiments, the nucleic acid sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0243] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any one of Tables 5-13 or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any one of Tables 5-13. In some embodiments, the oligonucleotide comprises a nucleoside sequence that is at least 85% identical to the sense strand sequence of the siRNA in any one of Tables 5-13.

[0244] In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression in the table is less than 1, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression in the table is less than 1. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression in the table is less than that of the negative control in the table, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression in the table is lower than 0.5, or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression in the table is lower than 0.5. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10, wherein the relative ANGPTL expression in the table is lower than 0.25, or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the oligonucleotide comprises or consists of an unmodified version of any of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the oligonucleotide comprises or consists of a siRNA having a nucleic acid sequence of any of the siRNAs disclosed in any one of Tables 5-10, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the nucleic acid sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to a sequence described herein.

[0245] In some embodiments, the sense strand comprises a sense strand sequence having one or more modifications or modification patterns. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11093-11212, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11093-11212, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11093-11212, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11093-11212, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11093-11212. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11093-11212, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11093-11212, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11093-11212. In some embodiments, the sense strand sequence is an unmodified version of the sense strand sequence described herein. In some embodiments, the sense strand sequence has more or different sequence modifications than the sense strand sequences described herein.

[0246] In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11333-11354, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11333-11354. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11354, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11354, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11354. In some embodiments, the sense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0247] In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the sense strand sequences of any one of the siRNAs disclosed in any one of Tables 5-13, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-13. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to the sense strand sequence of any one of the siRNAs in Table 513.

[0248] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table), or consists of an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table), or consists of an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5), or consists of an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10.In some embodiments, the sense strand sequence comprises or consists of an siRNA having a sense strand sequence of any of the siRNAs disclosed in any of Tables 5-10, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0249] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5, wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.67), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5, wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.67), or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5, wherein the relative ANGPTL expression in the table is lower than 0.5, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5, wherein the relative ANGPTL expression in the table is lower than 0.5. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the sense strand sequence comprises or consists of an siRNA having the sense strand sequence of any one of the siRNAs disclosed in Table 5, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0250] In some embodiments, the sense strand sequence is incorporated into an siRNA that downregulates ANGPTL7. In some embodiments, the sense strand sequence comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126, 11127 、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、11156、11157、11158、1 1159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、11182、11183、11184、11185、111 86, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions therein, or consisting thereof.In some embodiments, the sense strand sequence comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126 6. 11127, 11128, 11129, 11130, 11132, 11133, 11134, 11135, 11136, 11139, 11140, 11143, 11144, 11145, 11146, 11147, 11148, 11149, 11150, 11151, 11152, 11153, 11154, 11155, 11156, 11157、11158、11159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、11182、11 183, 11184, 11185, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or consisting thereof.

[0251] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6, wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 1.06), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6, wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 1.06), or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6, wherein the relative ANGPTL expression in the table is lower than 0.5, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6, wherein the relative ANGPTL expression in the table is lower than 0.5. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the sense strand sequence comprises or consists of an siRNA having the sense strand sequence of any one of the siRNAs disclosed in Table 6, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0252] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression of the siRNA in the table at 1 nM is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.66), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression of the siRNA in the table at 1 nM is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.66), or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 1 nM in the table is less than 1, or an siRNA having 0.5 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 1 nM in the table is less than 0.5 (e.g., siRNAs having the sequence ETD00245, ETD00247, or ETD00252). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 10 nM in the table is less than 1, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 10 nM in the table is less than 1. In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 7.In some embodiments, the sense strand sequence comprises or consists of an siRNA having the sense strand sequence of any one of the siRNAs disclosed in Table 7, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to a sequence described herein.

[0253] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 8, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 8. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 9, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 9. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 10, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 10. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0254] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%), or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%), or consists thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 11. In some embodiments, the sense strand sequence comprises or consists of an siRNA having a sense strand sequence of any one of the siRNAs disclosed in Table 11, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0255] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 12, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 12. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 13, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 13. In some embodiments, the sense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0256] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00269 or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00269. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00270 or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00270. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00353 or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00353. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00356 or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00356. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00358 or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00358. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00370 or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00370. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00377 or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00377. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00378 or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00378. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00382 or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00382.In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 11377, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 11377. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 11378, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 11387. In some embodiments, the sense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0257] In some embodiments, the antisense strand comprises an antisense strand sequence having one or more modifications or modification patterns. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11093-11212, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11093-11212, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11093-11212, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11093-11212, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11093-11212. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11093-11212, or a sequence having 1, 2, 3, or 4 nucleotide substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises the sequence of any one of SEQ ID NOs: 11093-11212, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions or consists thereof. In some embodiments, the antisense strand sequence comprises the sequence of any one of SEQ ID NOs: 11093-11212 or consists thereof. In some embodiments, the antisense strand sequence is an unmodified version of the antisense strand sequence described herein. In some embodiments, the antisense strand sequence has more or different sequence modifications than the antisense strand sequences described herein.

[0258] In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11333-11354, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11333-11354. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11354, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11354, or a sequence thereof having 1 or 2 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: 11333-11354. In some embodiments, the antisense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0259] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the antisense strand sequences of any one of the siRNAs disclosed in any one of Tables 5-13, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-13. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to the antisense strand sequence of any one of the siRNAs in Tables 5-13.

[0260] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table), or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5), or consists thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10.In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0261] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.67)), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.67)), or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is lower than 0.5), or consists thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 5, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0262] In some embodiments, the antisense sequence is incorporated into an siRNA that downregulates ANGPTL7. In some embodiments, the antisense sequence comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247 、11248、11249、11250、11252、11253、11254、11255、11256、11259、11260、11263、11264、11265、11266、11267、11268、11269、11270、11271、11272、11273、11274、11275、11276、11277、11278、1 1279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 11305, 113 06, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions therein, or consisting thereof.In some embodiments, the antisense strand sequence comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246 6. 11247, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 11276, 11277, 11278, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303 303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or consist of the antisense strand sequence.

[0263] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 1.06)), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 1.06)), or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is lower than 0.5), or consists thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 6, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0264] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression of the siRNA in the table at 1 nM is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.66), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression of the siRNA in the table at 1 nM is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.66), or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 1 nM in the table is less than 1, or an siRNA having 0.5 or 2 nucleoside substitutions, additions, or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 1 nM in the table is less than 0.5 (e.g., siRNAs having the sequence ETD00245, ETD00247, or ETD00252). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 10 nM in the table is less than 1, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 10 nM in the table is less than 1. In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 7.In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 7, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to a sequence described herein.

[0265] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 8, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 8, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 9, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 9, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 10, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 10, or consists of them. In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0266] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%), or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%) or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%) or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions or consisting of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%) or consisting of them. In some embodiments, the antisense strand sequence comprises an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 11 or consists of it. In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 11, but has one or more additional or different modifications, or has a different modification pattern. In some embodiments, the antisense strand sequence lacks sequence modification, or has different or additional sequence modification, but is otherwise similar to the sequence described herein.

[0267] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 12, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 12, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 13, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 13, or consists of them. In some embodiments, the antisense strand sequence lacks sequence modification, or has different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0268] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00269 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00269 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00270 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00270 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00353 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00353 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00356 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00356 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00358 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00358 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00370 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00370 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00377 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00377 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00378 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00378 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00382 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00382 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consists thereof.In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00752 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00752 or consists of them. In some embodiments, the antisense strand sequence comprises the sequence of SEQ ID NO: 11379 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consists of them. In some embodiments, the antisense strand sequence comprises the sequence of SEQ ID NO: 11379 or consists of them. In some embodiments, the antisense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0269] Antisense compounds

[0270] In one aspect, provided herein are antisense compounds or oligonucleotides for modulating the activity and / or expression of a target nucleic acid, such as ANGPTL7. In some embodiments, the antisense compound inhibits the expression of ANGPTL7. In some cases, the antisense compound comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 4413-11084. In some cases, the antisense compound comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0271] In some embodiments, the antisense compound can specifically hybridize to the target nucleic acid, wherein the binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause, for example, loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target nucleic acid sequences under conditions where specific binding is desired. Such conditions include physiological conditions in the case of in vivo assays or therapeutic treatments, as well as conditions where the assay is performed in the case of in vitro assays.

[0272] In some embodiments, antisense compounds include variants in which different bases are present at one or more nucleotide positions of the compound. For example, if the first nucleotide is adenine, variants containing thymidine, guanosine, cytidine, or other natural or non-natural nucleotides at that position can be generated. This can be done at any position of the antisense compound. These compounds are then tested using the methods described herein to determine their ability to inhibit the expression of the target nucleic acid.

[0273] In some embodiments, the homology, sequence identity or complementarity between the antisense compound and the target is about 50% to about 60%. In some embodiments, the homology, sequence identity or complementarity is about 60% to about 70%. In some embodiments, the homology, sequence identity or complementarity is about 70% to about 80%. In some embodiments, the homology, sequence identity or complementarity is about 80% to about 90%. In some embodiments, the homology, sequence identity or complementarity is about 90%, about 92%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%.

[0274] In some embodiments, antisense compounds, whether DNA, RNA, chimeric, substituted, etc., are specifically hybridizable, e.g., to render them ineffective, when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA, and there is a sufficient degree of complementarity to avoid nonspecific binding of the antisense compound to non-target sequences under conditions where specific binding is desired, i.e., physiological conditions in the case of in vivo assays or therapeutic treatments, and under the conditions under which the assays are conducted in the case of in vitro assays.

[0275] In some embodiments, targeting of ANGPTL7 includes, but is not limited to, antisense sequences such as one or more of the sequences set forth in SEQ ID NOs: 4413-11084 (e.g., oligonucleotides having at least about 80%, 85%, 90%, 95%, or 100% identity to a sequence selected from SEQ ID NOs: 4413-11084) identified and expanded using, for example, PCR, hybridization, etc., to modulate the expression or function of ANGPTL7. In some embodiments, expression or function is downregulated compared to a control oligonucleotide that does not specifically hybridize to ANGPTL7.

[0276] In some embodiments, the antisense oligonucleotide comprises one or more modified nucleotides, shorter or longer fragments, modified bonds, etc. Examples of modified bonds or internucleotide connections include phosphorothioates, phosphorodithioates, etc. In some embodiments, the nucleotide comprises a phosphorus derivative. The phosphorus derivative (or modified phosphate group) to which the sugar or sugar analogue portion can be attached in the modified oligonucleotide can be a monophosphate, a diphosphate, a triphosphate, an alkyl phosphate, an alkane phosphate, a thiophosphate, etc.

[0277] In embodiments, oligomeric antisense compounds, particularly oligonucleotides, bind to target nucleic acid molecules and regulate the expression and / or function of molecules encoded by the target gene. The function of the DNA disturbed includes, for example, replication and transcription. The function of the RNA disturbed includes all important functions, such as, for example, RNA translocation to protein translation sites, protein translation from RNA, RNA splicing to produce one or more mRNA species, and the catalytic activity that can participate in RNA or promoted by RNA. Depending on the desired function, these functions can be raised or suppressed.

[0278] Antisense compounds include antisense oligomeric compounds, antisense oligonucleotides, external guide sequence (EGS) oligonucleotides, alternative splicing agents, primers, probes and other oligomeric compounds that hybridize to at least a portion of the target nucleic acid. Therefore, these compounds can be introduced in the form of single-stranded, double-stranded, partially single-stranded or circular oligomeric compounds.

[0279] Targeting an antisense compound to a specific nucleic acid molecule can be a multi-step process. The process can begin with identifying a target nucleic acid whose function is to be modulated. The target nucleic acid can be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular condition or disease state. In some embodiments, the target nucleic acid encodes angiopoietin-like 7 (ANGPTL7).

[0280] The targeting process can include determining at least one target region, section or site in the target nucleic acid, so that antisense interactions occur, thereby producing a desired effect, such as regulation of expression. In some embodiments, the term "region" is defined as a portion of a target nucleic acid having at least one identifiable structure, function or feature. Within the target nucleic acid region is a section. A "section" can be defined as a smaller portion or sub-portion of a region in the target nucleic acid. A "site" can be defined as a position in the target nucleic acid.

[0281] In some embodiments, the antisense oligonucleotide binds to the natural antisense sequence of angiopoietin-like 7 (ANGPTL7) and modulates the expression and / or function of ANGPTL7 (SEQ ID NO: 11085).

[0282] In some embodiments, the antisense oligonucleotide binds to one or more segments of angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates the expression and / or function of ANGPTL7. In some cases, the segment comprises at least five consecutive nucleotides of an ANGPTL7 sense or antisense polynucleotide.

[0283] Since the translation initiation codon is typically 5'-AUG (in transcribed mRNA molecules; 5-ATG in corresponding DNA molecules), the translation initiation codon may be referred to as an "AUG codon," "start codon," or "AUG start codon." A few genes have translation initiation codons whose RNA sequences are 5'-GUG, 5'-UUG, or 5'-CUG; and 5'-AUA, 5'-ACG, and 5'-CUG have been shown to function in vivo. Thus, in some cases, the terms "translation initiation codon" and "start codon" may encompass many codon sequences, even though the starting amino acid is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes) in each case. Eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially used for translation initiation in a particular cell type or tissue or under particular conditions. In some embodiments, "start codon" and "translation start codon" refer to one or more codons used in vivo to initiate translation of mRNA transcribed from a gene encoding angiopoietin like 7 (ANGPTL7), regardless of the sequence(s) of such codons. In some cases, the translation termination codon (or "stop codon") of a gene may have one of the following three sequences: 5'-UAA, 5'-UAG, and 5'-UGA (the corresponding DNA sequences are 5'-TAA, 5'-TAG, and 5'-TGA, respectively).

[0284] In some embodiments, the terms "start codon region" and "translation start codon region" refer to a portion of an mRNA or gene that comprises about 25 to about 50 consecutive nucleotides in either direction (i.e., 5' or 3') from the translation start codon. In some cases, the terms "stop codon region" and "translation stop codon region" refer to a portion of an mRNA or gene that comprises about 25 to about 50 consecutive nucleotides in either direction (i.e., 5' or 3') from the translation stop codon. Therefore, both the "start codon region" (or "translation start codon region") and the "stop codon region" (or "translation stop codon region") are regions that the antisense compounds described herein can effectively target.

[0285] The open reading frame (ORF) or "coding region" refers to the region between the translation start codon and the translation stop codon, and is also a region that can be effectively targeted. In some embodiments, the targeted region is an intragenic region containing the translation start or stop codon of the open reading frame (ORF) of the gene.

[0286] Another target region includes the 5' untranslated region (5'-UTR), which refers to the portion of the mRNA in the 5' direction starting from the translation start codon, and therefore includes the nucleotides between the 5' cap site and the translation start codon of the mRNA (or the corresponding nucleotide on the gene). Yet another target region includes the 3' untranslated region (3'-UTR), which refers to the portion of the mRNA in the 3' direction starting from the translation stop codon, and therefore includes the nucleotides between the translation stop codon and the 3' end of the mRNA (or the corresponding nucleotide on the gene). The 5' cap site of the mRNA contains an N7 methylated guanosine residue that is linked to the 5'most residue of the mRNA via a 5-5' triphosphate bond. The 5' cap region of the mRNA is considered to include the 5' cap structure itself and the first 50 nucleotides adjacent to the cap site. Another target region is the 5' cap region.

[0287] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions known as "introns" that are excised from the transcript before being transcribed. The remaining (and therefore translated) regions are referred to as "exons," which are spliced ​​together to form a continuous mRNA sequence. In some embodiments, targeted splice sites, i.e., intron-exon junctions or exon-intron junctions, are particularly useful where abnormal splicing is associated with a disease, or where excessive production of a specific spliced ​​product is associated with a disease. Abnormal fusion junctions due to rearrangement or deletion are another embodiment of the target site. The mRNA transcript produced by the process of splicing two (or more) mRNAs from different gene sources is referred to as a "fusion transcript." Introns can be effectively targeted using antisense compounds targeting, for example, DNA or pre-mRNA.

[0288] In some embodiments, antisense oligonucleotides bind to coding and / or noncoding regions of a target polynucleotide and modulate the expression and / or function of the target molecule.

[0289] In some embodiments, antisense oligonucleotides bind to sense polynucleotides and modulate the expression and / or function of a target molecule.

[0290] Alternative RNA transcripts can be generated from the same genomic region of DNA. These alternative transcripts are often referred to as "variants." More specifically, "pre-mRNA variants" are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in their start or end positions and contain intron and exon sequences.

[0291] Pre-mRNA variants produce smaller "mRNA variants" after one or more exons or introns, or portions thereof, are removed during splicing. Therefore, mRNA variants are processed pre-mRNA variants, and each unique pre-mRNA variant must always undergo splicing to produce a unique mRNA variant. These mRNA variants are also called "alternative splice variants." If splicing does not occur with a pre-mRNA variant, the pre-mRNA variant is identical to the mRNA variant.

[0292] Variants can be produced by starting or stopping transcription using alternative signals. Pre-mRNA and mRNA can have more than one start codon or stop codon. Variants derived from pre-mRNA or mRNA using alternative start codons are referred to as "alternative start variants" of the pre-mRNA or mRNA. Transcripts using alternative stop codons are referred to as "alternative termination variants" of the pre-mRNA or mRNA. A specific type of alternative termination variant is a "poly A variant," in which the multiple transcripts produced are produced by the alternative selection of one of the "poly A termination signals" by the transcriptional machinery, thereby producing transcripts that terminate at unique poly A sites. In some embodiments, the variant types described herein are also embodiments of target nucleic acids.

[0293] In some embodiments, the location on the target nucleic acid to which the antisense compound hybridizes is defined as a portion of the target region that is at least 5 nucleotides long that is targeted by the active antisense compound.

[0294] Although specific sequences of certain exemplary target segments are set forth herein, those skilled in the art will recognize that these are for illustration and description of specific embodiments. In view of this disclosure, those of ordinary skill in the art can readily identify additional target segments.

[0295] Target segments of 5-100 nucleotides in length comprising a stretch of at least five (5) contiguous nucleotides selected from the exemplary target segments are also considered suitable for targeting.

[0296] In some embodiments, the target segment may include a DNA or RNA sequence comprising at least 5 consecutive nucleotides from the 5'-end of one of the target segments (the remaining nucleotides are a continuous segment of the same DNA or RNA starting from immediately upstream of the end of the target fragment and continuing until the DNA or RNA contains about 5 to about 100 nucleotides). In some cases, the target segment is represented by a DNA or RNA sequence comprising at least 5 consecutive nucleotides from the 3'-end of one of the target segments (the remaining nucleotides are a continuous segment of the same DNA or RNA starting from immediately downstream of the 3'-end of the target fragment and continuing until the DNA or RNA contains about 5 to about 100 nucleotides).

[0297] Once one or more target regions, segments or sites are identified, antisense compounds are selected that are sufficiently complementary to the target, ie, hybridize well enough and with sufficient specificity, to produce the desired effect.

[0298] Antisense compounds include antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, siRNA compounds, single-stranded or double-stranded RNA interference (RNAi) compounds, such as siRNA compounds, and other oligomeric compounds that hybridize with at least a portion of the target nucleic acid and regulate its function. Therefore, they can be DNA, RNA, DNA sample, RNA sample or a mixture thereof, or can be one or more of these mimetics. These compounds can be single-stranded, double-stranded, cyclic or hairpin oligomeric compounds, and may include structural elements, such as internal or terminal protrusions, mispairings or loops. Antisense compounds are usually prepared linearly, but can be connected or otherwise prepared into cyclic and / or branched chains. Antisense compounds can include constructs, such as two chains that hybridize to form a complete or partial double-stranded compound or have enough self-complementarity to allow hybridization and formation of a complete or partial double-stranded compound. The two chains can be connected internally and leave free 3' or 5' ends, or can be connected to form a continuous hairpin structure or loop. The hairpin structure can include an overhang at the 5' or 3' end to produce an extension of single-stranded characteristics. Double-stranded compounds can optionally include an overhang at the end. Further modification can include a conjugate group attached to one of the ends, selected nucleotide positions, sugar positions or internucleoside connections. In some cases, the two chains can be connected by a non-nucleic acid moiety or a linking group. When formed by only one chain, dsRNA can take the form of a self-complementary hairpin molecule, which folds in half to form a duplex. Therefore, dsRNA can be completely or partially double-stranded. The specific regulation of gene expression can be achieved by stably expressing dsRNA hairpins in transgenic cell lines, but in some embodiments, gene expression or function are upregulated. When formed by two chains, or when a single chain adopts the form of a self-complementary hairpin molecule to fold in half to form a duplex, the two chains (or the duplex formation region of the single chain) are complementary RNA chains with Watson Crick base pairing.

[0299] Once introduced into the system, the compound can trigger the action of one or more enzymes or structural proteins to achieve cleavage or other modification of the target nucleic acid, or can act through an occupancy-based mechanism. In general, nucleic acids (including oligonucleotides) can be described as "DNA-like" (i.e., typically having one or more 2'-deoxy sugars and typically having T instead of U bases) or "RNA-like" (i.e., typically having one or more 2'-hydroxyl or 2'-modified sugars and typically having U bases instead of T bases). Nucleic acid helices can adopt more than one type of structure, the most common being type A and type B. It is generally believed that oligonucleotides with a type B structure are "DNA-like", and oligonucleotides with a type A structure are "RNA-like". In some (chimeric) embodiments, antisense compounds may contain both type A and type B regions.

[0300] In some embodiments, the desired oligonucleotide or antisense compound includes at least one of: antisense RNA, antisense DNA, chimeric antisense oligonucleotides, antisense oligonucleotides comprising a modified bond, interfering RNA (RNAi), short interfering RNA (siRNA); small interfering RNA (miRNA); small sequential RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activation (RNAa); small activating RNA (saRNA), or a combination thereof.

[0301] In some embodiments, the "target segments" identified herein can be used to screen for additional compounds that modulate the expression of angiopoietin-like 7 (ANGPTL7) polynucleotides. "Modulators" are compounds that reduce or increase the expression of a nucleic acid molecule encoding ANGPTL7 and comprise at least a 5-nucleotide portion that is complementary to the target segment. The screening method comprises contacting the target segment of a nucleic acid molecule encoding a sense or natural antisense polynucleotide of ANGPTL7 with one or more candidate modulators, and selecting one or more candidate modulators that reduce or increase the expression of the nucleic acid molecule encoding the ANGPTL7 polynucleotide. Once one or more candidate modulators are shown to be capable of modulating (e.g., reducing or increasing) the expression of a nucleic acid molecule encoding an ANGPTL7 polynucleotide, the modulators can then be used for further investigation of the function of the ANGPTL7 polynucleotide, or as research, diagnostic, or therapeutic agents.

[0302] Target segments can also be combined with their respective complementary antisense compounds to form stable double-stranded (duplex) oligonucleotides.

[0303] This double-stranded oligonucleotide portion regulates target expression and modulates translation and RNA processing through an antisense mechanism. In addition, the double-stranded portion may be chemically modified. For example, this double-stranded portion inhibits the target through classical hybridization of the antisense strand of the duplex with the target, thereby triggering enzymatic degradation of the target.

[0304] In some embodiments, the antisense oligonucleotide targets angiopoietin-like 7 (ANGPTL7) polynucleotide (e.g., Accession No. NM_021146), variants, alleles, isoforms, homologs, mutants, derivatives, fragments, and sequences complementary thereto. In some cases, the oligonucleotide is an antisense molecule.

[0305] In some embodiments, the target nucleic acid molecule is not limited to ANGPTL7 alone, but extends to any of the isoforms, receptors, homologs, etc. of the ANGPTL7 molecule.

[0306] In some embodiments, the oligonucleotide is complementary to or binds to a nucleic acid sequence of an ANGPTL7 transcript and modulates the expression and / or function of the ANGPTL7 molecule.

[0307] In some embodiments, the oligonucleotide comprises a sequence of at least 5 contiguous nucleotides to modulate the expression and / or function of an ANGPTL7 molecule.

[0308] Polynucleotide targets include ANGPTL7, including its family members, variants of ANGPTL7, mutants of ANGPTL7, including SNPs, non-coding sequences of ANGPTL7, ANGPTL7 alleles, species variants, fragments, etc. In some cases, the oligonucleotide is an antisense molecule.

[0309] In some embodiments, oligonucleotides targeting an ANGPTL7 polynucleotide include: antisense RNA, interfering RNA (RNAi), short interfering RNA (siRNA); small interfering RNA (miRNA); small sequential RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activation (RNAa); or small activating RNA (saRNA). In some embodiments, the siRNA comprises one or more sequences selected from SEQ ID NOs: 1-4412. In some embodiments, the siRNA comprises a sequence comprising the reverse complement of a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90%, or 95% homology to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90%, or 95% identity to a sequence selected from SEQ ID NOs: 1-4412.

[0310] In some embodiments, targeting of angiopoietin-like 7 (ANGPTL7) polynucleotide, such as SEQ ID NO: 11085, modulates the expression or function of the target. In some embodiments, expression or function is downregulated compared to a control.

[0311] In some embodiments, targeting of angiopoietin-like 7 (ANGPTL7) polynucleotide, such as SEQ ID NO: 11086, modulates the expression or function of the target. In some embodiments, expression or function is downregulated compared to a control.

[0312] In some embodiments, antisense compounds are provided. These oligonucleotides may comprise one or more modified nucleotides, shorter or longer fragments, modified bonds, etc. In some embodiments, the antisense compounds comprise sequences as shown in SEQ ID NOs: 4413-11084. In some cases, the antisense compounds comprise sequences that are at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0313] In some embodiments, the antisense compound comprises one or more LNA nucleotides.

[0314] In some embodiments, antisense compounds comprise one or more UNA nucleotides.

[0315] In some embodiments, the antisense compound comprises one or more GNA nucleotides.

[0316] Antisense compounds can comprise an antisense portion that is from about 5 to about 80 nucleotides in length (i.e., from about 5 to about 80 linked nucleosides). This refers to the length of the antisense strand or portion of the antisense compound. In other words, a single-stranded antisense compound can comprise from 5 to about 80 nucleotides, and a double-stranded antisense compound (e.g., dsRNA) can comprise a sense strand and an antisense strand or portion that is from 5 to about 80 nucleotides in length. 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 nucleotides in length, or any range therein.

[0317] In some embodiments, the antisense compounds have an antisense portion that is 10 to 50 nucleotides in length. One of ordinary skill in the art will appreciate that this includes oligonucleotides having an antisense portion that is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length, or any range therein. In some embodiments, the oligonucleotide has a length of 15 nucleotides.

[0318] In some embodiments, the antisense or oligonucleotide compounds have an antisense portion that is about 12 or 13 to 30 nucleotides in length. One of ordinary skill in the art will understand that this includes antisense compounds having an antisense portion that is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length, or any range therein.

[0319] In some embodiments, oligomeric compounds also include variants in which different bases are present at one or more nucleotide positions of the compound. For example, if the first nucleotide is adenosine, a variant containing thymidine, guanosine, or cytidine at that position can be generated. This can be done at any position of the antisense or dsRNA compound. These compounds are then tested using the methods described herein to determine their ability to inhibit the expression of the target nucleic acid.

[0320] In some embodiments, the homology, sequence identity or complementarity between the antisense compound and the target is about 40% to about 60%. In some embodiments, the homology, sequence identity or complementarity is about 60% to about 70%. In some embodiments, the homology, sequence identity or complementarity is about 70% to about 80%. In some embodiments, the homology, sequence identity or complementarity is about 80% to about 90%. In some embodiments, the homology, sequence identity or complementarity is about 90%, about 92%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%.

[0321] In some embodiments, the antisense oligonucleotides, such as, for example, the nucleic acid molecules shown in SEQ ID NOs: 4413-11084, comprise one or more substitutions or modifications. In some embodiments, the nucleotides are replaced by locked nucleic acids (LNA). In some cases, the antisense compound comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0322] In some embodiments, the oligonucleotides target one or more regions of coding and / or non-coding sequences associated with ANGPTL7 and sense and / or antisense nucleic acid molecules of the sequence set forth in SEQ ID NO: 11085.

[0323] In some embodiments, oligonucleotide disclosed herein is chimeric oligonucleotide. "Chimeric oligonucleotide" or "chimera" is an oligonucleotide comprising two or more chemically different regions, each region being composed of at least one nucleotide. These oligonucleotides typically comprise at least one modified nucleotide region (this region imparts one or more beneficial properties (such as, for example, increased nuclease resistance, increased cellular uptake, increased binding affinity to the target)) and a region as a substrate for an enzyme capable of cutting RNA:DNA or RNA:RNA hybrids. For example, RNase H is a cellular endonuclease that cuts the RNA chain of RNA:DNA duplexes. Therefore, the activation of RNase H results in the cutting of RNA targets, thereby greatly improving the efficiency of antisense regulation of gene expression. Therefore, compared with phosphorothioate deoxyoligonucleotides that hybridize to the same target region, when using chimeric oligonucleotides, comparable results can usually be obtained with shorter oligonucleotides. The cutting of RNA targets can be carried out by gel electrophoresis and, if necessary, conventional detection of related nucleic acid hybridization techniques known in the art is performed. In some embodiments, the chimeric oligonucleotide comprises at least one region modified to increase target binding affinity, and typically comprises a region that acts as a substrate for RNAse H. The affinity of an oligonucleotide for its target (in this case, a nucleic acid encoding ras) is typically determined by measuring the Tm of the oligonucleotide-target pair, which is the temperature at which the oligonucleotide and target dissociate; dissociation is detected spectrophotometrically. The higher the Tm, the greater the affinity of the oligonucleotide for the target.

[0324] Chimeric antisense compounds can be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and / or oligonucleotide mimetics as described above. Such compounds may also be referred to as hybrids or gapmers.

[0325] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleotides in length. In some embodiments, the ASO is 14-30 nucleotides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by either of the above two numbers. In some embodiments, the ASO is 15-25 nucleotides in length. In some embodiments, the ASO is 20 nucleotides in length.

[0326] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO) of about 12-30 nucleosides in length and comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11085; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0327] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an ASO of about 12-30 nucleosides in length and comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11086; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0328] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an ASO. In some embodiments, the ASO comprises an ASO sequence. In some embodiments, the ASO sequence comprises or consists of the sequence of any one of SEQ ID NOs: 4413-11084, or a nucleic acid sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the ASO sequence comprises or consists of the sequence of any one of SEQ ID NOs: 4413-11084, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the ASO sequence comprises or consists of the sequence of any one of SEQ ID NOs: 4413-11084. In some embodiments, the ASO sequence comprises or consists of the sequence of SEQ ID NOs: 11087, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the ASO sequence comprises or consists of the sequence of SEQ ID NOs: 11087. In some embodiments, the ASO comprises one or more modifications or modification patterns described herein.

[0329] Antisense compound modification

[0330] In some embodiments, one or more nucleotides in the antisense compound are modified.The modifications described herein with respect to antisense compounds can be applied to dsRNA agents or siRNA.

[0331] In some embodiments, the modified oligonucleotide region comprises at least one nucleotide modified at the 2' position of the sugar, for example, a 2'-O alkyl, 2,-O-alkyl-O-alkyl, or 2'-fluoro-modified nucleotide. In some embodiments, RNA modifications include 2'-fluoro, 2'-amino, and 2'O-methyl modifications on the pyrimidine ribose, abasic residues, or inverted bases at the 3' end of the RNA. Such oligonucleotides may have a higher Tm (i.e., higher target binding affinity) than 2'-deoxy oligonucleotides for a given target. The effect of this increased affinity is to greatly enhance the inhibition of gene expression by RNAi oligonucleotides. RNAse H is a cellular endonuclease that cuts the RNA chain of the RNA:DNA duplex; therefore, activation of the enzyme results in the cutting of the RNA target, which can greatly improve the efficiency of RNAi inhibition. The cutting of the RNA target can be routinely demonstrated by gel electrophoresis. In some embodiments, chimeric oligonucleotides are also modified to enhance nuclease resistance. Cells contain a variety of exo- and endonucleases that can degrade nucleic acids. Many nucleotide and nucleoside modifications render the oligonucleotides into which they are incorporated more resistant to nuclease digestion than native oligodeoxynucleotides. Nuclease resistance is routinely measured by incubating oligonucleotides with cell extracts or isolated nuclease solutions and measuring the degree of intact oligonucleotides retained over time, usually by gel electrophoresis. Oligonucleotides modified to enhance their nuclease resistance survive intact for longer periods of time compared to unmodified oligonucleotides. A variety of oligonucleotide modifications have been shown to enhance or confer nuclease resistance. In some cases, oligonucleotides contain at least one phosphorothioate modification. In some cases, oligonucleotide modifications that enhance target binding affinity can also independently enhance nuclease resistance.

[0332] The instantiation of some oligonucleotides comprises those oligonucleotides comprising modified main chains, such as key between phosphorothioate, phosphotriester, methylphosphonate, short chain alkyl or cycloalkyl sugar or key between short chain heteroatom or heterocycle sugar.In some cases, oligonucleotide comprises phosphorothioate main chain.In some cases, oligonucleotide comprises heteroatom main chain, particularly CH2-NH-O--CH2, CH ,-N (CH3)-O-CH2[being called methylene (methylimino) or MM main chain], CH2-O-N (CH3)-CH2, CH2-N (CH3)-N (CH3)-CH2 and O-N (CH3)-CH2--CH2 main chain, wherein natural phosphodiester main chain is expressed as OPO-CH ').In some cases, oligonucleotide comprises morpholine backbone structure.In some embodiments, such as peptide nucleic acid (PNA) main chain, the phosphodiester main chain of oligonucleotide is replaced by polyamide backbone, and nucleotide is directly or indirectly attached to the aza nitrogen atom of polyamide backbone. The oligonucleotide may also comprise one or more substituted sugar moieties. In some cases, the oligonucleotide comprises one of the following at the 2' position: OH, SH, SCH3, F, OCN, OCH3, OCH3 O(CH2)nCH3, O(CH2)nNH2, or O(CH2)nCH3, wherein n is 1 to about 10; C1 to C10 lower alkyl, alkoxyalkoxy, substituted lower alkyl, alkaryl, or aralkyl; CI; Br; CN; CF3; OCF3; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; SOCH3; SO2CH3; ONO2; NO2; N3; NH2; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; RNA cleavage group; reporter group; intercalator; group for improving the pharmacokinetic properties of the oligonucleotide; or group for improving the pharmacodynamic properties of oligonucleotides and other substituents with similar properties. Non-limiting exemplary modifications include 2'-methoxyethoxy [2-O-CH2 CH2 OCH3, also known as 2'-O-(2-methoxyethyl)]. Other exemplary modifications include 2'-methoxy (2'-O-CH3), 2'-propoxy (2'-OCH2 CH2CH3) and 2'-fluoro (2'-F). Similar modifications can also be made at other positions in the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide and the 5' position of the 5' terminal nucleotide. The oligonucleotide can also have sugar mimics, such as cyclobutyl instead of pentofuranosyl.

[0333] Oligonucleotides can also include modifications or replacements of nucleobases (commonly referred to as "bases"). As used herein, "unmodified" or "natural" nucleotides include adenine (A), guanine (G), mymine (T), cytosine (C), and uracil (U). Modified nucleotides include nucleotides that are only occasionally or transiently found in natural nucleic acids, such as hypoxanthine, 6-methyladenine, 5-methylpyrimidine, particularly 5-methylcytosine (also known as 5-methyl-2'deoxycytosine, commonly referred to as 5-Me-C), 5-hydroxymethylcytosine (HMC), glycosyl HMC and gentiobiosyl HMC, as well as synthetic nucleotides such as 2-aminoadenine, 2-(methylamino)adenine, 2-(imidazolylalkyl)adenine, 2-(aminoalkylamino)adenine or other heterosubstituted alkyladenines, 2-thiouracil, 2-tmothvmine, 5-bromouracil, 5-hydroxymethyluracil, 8-azaguanine, 7-deazaguanine, N6 (6-aminohexyl)adenine and 2,6-diaminopurine. "Universal" bases such as inosine may be included. The 5-Me-C substitution increased nucleic acid duplex stability by 0.6-1.2°C and is a suitable base substitution.

[0334] Another modification of oligonucleotides includes chemical attachment of one or more moieties or conjugates that enhance oligonucleotide activity or cellular uptake to the oligonucleotide. Such moieties include, but are not limited to, lipid moieties, such as cholesterol moieties, cholesterol moieties, fatty chains, such as dodecanediol or undecyl residues...

Claims

1. A composition comprising an oligonucleotide that targets angiopoietin-like 7 (ANGPTL7) and reduces expression of ANGPTL7 when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide sequence of SEQ ID NO: 1424 wherein at least one internucleoside linkage is modified and at least one nucleoside is a modified nucleoside, the antisense strand comprises the oligonucleotide sequence of SEQ ID NO: 3630 wherein at least one internucleoside linkage is modified and at least one nucleoside is a modified nucleoside, wherein the modified nucleoside is selected from a 2'-fluoro nucleoside or a 2'-O-methyl nucleoside or a combination thereof, and wherein the 5' end or the 3' end of the sense strand is conjugated to a lipid moiety.

2. The composition of claim 1, wherein the at least one modified nucleoside comprises a 2'-fluoro nucleoside.

3. The composition of claim 1, wherein the at least one modified nucleoside comprises a 2'-O-methyl nucleoside.

4. The composition of claim 1, wherein the oligonucleotide comprises 15-23 modified nucleosides.

5. The composition of claim 4, wherein the 15-23 modified nucleosides comprise 2'-fluoro nucleosides and 2'-O-methyl nucleosides.

6. The composition of claim 1, wherein the sense strand and antisense strand each comprise two or more modified internucleoside linkages.

7. The composition of claim 6, wherein the sense strand has phosphorothioate linkages between the last three terminal nucleotides in the 5' to 3' direction.

8. The composition of claim 6, wherein the antisense strand has phosphorothioate linkages between the last three terminal nucleotides in the 5' to 3' direction.

9. The composition of claim 1, wherein the at least one modified internucleoside linkage comprises a phosphorothioate linkage.

10. The composition of claim 1, wherein the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), or modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11383); wherein "Nf" is a 2'-fluoro modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.

11. The composition of claim 1, wherein the antisense strand comprises modification pattern 1 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2 AS: 5'nsNfsnnnNfNfnNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388) or modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 11389); wherein "Nf" is a 2'-fluoro modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.

12. The composition of claim 1, wherein the lipid moiety comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenyl, docosahexaenoyl, myristyl, palmitylstearyl, or alpha-tocopherol, or a combination thereof.

13. The composition of claim 12, wherein the lipid portion comprises stearoyl.

14. The composition of claim 1, wherein the sense strand or the antisense strand comprises an overhang.

15. The composition of claim 1, wherein the antisense strand comprises modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386).

16. The composition of claim 1, wherein the antisense strand comprises 5'-usAfsaCfaUfcCfuUfgguAfcAfuAfususu-3' (SEQ ID NO: 11306), wherein "Uf", "Af" and "Cf" are 2'-fluoro modified nucleosides, "a", "c", "g" and "u" are 2'-O-methyl modified nucleosides, and "s" is a phosphorothioate linkage.

17. The composition of claim 1, wherein the antisense strand comprises a 5' alkylphosphonate modification.

18. A pharmaceutical composition comprising the composition according to one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. Use of the composition of claims 1-17 in the preparation of a medicament for treating glaucoma or ocular hypertension in a subject in need thereof.

20. The use according to claim 19, wherein the medicament reduces intraocular pressure in the subject.

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