Treatment of angiopoietin like 7 (angptl7) related diseases

Abstract

SOLUTION: Provided herein are oligonucleotide compositions that inhibit ANGPTL7 and reduce intraocular pressure when administered to an eye. The oligonucleotide compositions contain nucleoside modifications.EFFECT: The oligonucleotide compositions are employed in treating ocular disorders and is beneficial for treatment of glaucoma and ocular hypertension.SELECTED DRAWING: Figure 11

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 852,813, filed May 24, 2019, and U.S. Provisional Patent Application No. 62 / 881,906, filed August 1, 2019, which applications are incorporated herein by reference in their entireties.

[0002] Sequence Listing 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, created on May 15, 2020, has the filename 54462-709_601_SL.txt and is 3,290 kilobytes in size. [Background technology]

[0003] Large-scale human genetic data provides a mechanism to improve the success rate of drug discovery and development by leveraging natural experimentation.

[0004] Genome-wide association studies (GWAS) are experimental designs designed to detect associations between genetic variants and inherited traits in population samples. The goal is to improve our understanding of disease biology and develop treatments based on this understanding. GWAS can utilize genotyping and / or sequencing data and often involve evaluating 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 and controls. If a variant has a significantly different frequency between cases and controls, the variant is said to be associated with disease. Association statistics commonly reported in GWAS are the p-value, an indicator of statistical significance, and the odds ratio (OR) or beta coefficient (β), an indicator of effect size. Researchers often assume an additive genetic model and calculate allele odds ratios, which indicate the increased (or decreased) risk of a given disease for each additional copy of an allele (compared to no copies of that allele). An additional and important concept in the design and interpretation of GWAS is linkage disequilibrium, which is the nonrandom association of alleles. When linkage disequilibrium exists, it can be difficult to determine which variant is the "causative" variant.

[0005] Functional annotation of variants and / or wet-lab experiments can pinpoint causative gene variants identified through GWAS, often resulting in the identification of disease-causing genes. Understanding the functional effect of a causative gene variant (e.g., loss or gain of protein function, increased or decreased gene expression) can enable researchers to use the variant as a surrogate for therapeutic modulation of a target gene, providing insight into the potential therapeutic efficacy and safety of therapeutics that modulate that target.

[0006] Identifying such gene-disease associations provides fundamental insights into disease biology and is rapidly becoming an essential tool for identifying novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights gained from human genetics, disease biology in patients must be exogenously "programmed" to recapitulate observations from human genetics. Today, there are more potential options for therapeutic modalities than ever before that can be used to translate therapeutic targets identified through human genetics into new drugs. These include well-established therapeutic modalities such as small molecules and monoclonal antibodies, mature modalities such as oligonucleotides, and newer 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 relevant tissue (e.g., liver), and the relevant indication. Summary of the Invention

[0007] Glaucoma, a heterogeneous group of diseases affecting more than 70 million people worldwide, is characterized by optic nerve damage resulting in progressive loss of retinal ganglion cells, leading to vision loss. Various subtypes of glaucoma are classified according to the iridocorneal angle, with open-angle glaucoma accounting for approximately 75% of cases. While the pathophysiology of glaucoma remains poorly understood, the primary causative feature and risk factor is elevated intraocular pressure (IOP). IOP is determined by the balance between aqueous humor secretion from the ciliary body and drainage through the trabecular meshwork and uveoscleral pathway. Lowering IOP is the only proven strategy to prevent the onset or slow the progression of glaucoma; consequently, treatment focuses on lowering IOP to a target level by increasing aqueous humor outflow or reducing aqueous humor production. Several classes of IPO-lowering medications are used, including prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, and more recently, Rho-kinase inhibitors. Surgical methods, such as laser trabeculoplasty, which improve aqueous humor outflow through the trabecular meshwork, have also been employed. Despite the availability of medical and surgical treatments for glaucoma, it remains a leading cause of irreversible blindness worldwide, and there remains a need for novel therapeutic strategies that can further reduce the risk of significant morbidity and reduced quality of life associated with vision loss.

[0008] In one aspect, a composition comprising an inhibitor or modulator of ANGPTL7 effective for treating glaucoma and ocular hypertension is provided. 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 an 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 ANGPTL7 inhibitor is a small molecule. In some embodiments, the ANGPTL7 inhibitor 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 ANGPTL7 inhibitor is an antibody. In some embodiments, the antibody is a monoclonal antibody.

[0009] In another aspect, molecules for inhibiting or regulating the angiopoietin-like 7 (ANGPTL7) gene product are provided herein, including dsRNA (dsRNA) agents, such as small interfering RNA (siRNA), or antisense oligonucleotides for therapeutic use. Furthermore, methods are provided for inhibiting the expression of target genes by administering dsRNA agents or antisense oligonucleotides, for example, for the treatment of various diseases involving the ANGPTL7 gene product. Also provided are methods for regulating the expression of target genes in cells, comprising providing the cells with dsRNA agents or antisense oligonucleotides. In some embodiments, the target gene is ANGPTL7.

[0010] In another aspect, a method of treating one or more eye disorders in a subject is provided, the method comprising editing the ANGPTL7 gene in the subject, wherein the one or more eye disorders comprise 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 to 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 of the human protein SEQ ID NO: 1. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to 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 of the human protein SEQ ID NO: 1. In some embodiments, CRISPR / cas9 is delivered systemically to the subject. In some embodiments, CRISPR / cas9 is delivered locally to a subject. In some embodiments, CRISPR / cas9 is delivered locally to the subject's eye. In some embodiments, CRISPR / cas9 is delivered locally to the subject's eye by intraocular injection. In some embodiments, CRISPR / cas9 is delivered locally to the subject's eye by a topical solution. In some embodiments, editing the ANGPTL7 gene is effective in treating one or more ocular disorders. In some embodiments, the one or more ocular disorders are glaucoma. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, the subject has received primary treatment for one or more upper eye and ocular disorders, including a topical ocular prostaglandin analog, a beta-adrenergic blocker, an alpha-adrenergic agonist, and a carbonic anhydrase inhibitor. In some embodiments, editing the ANGPTL7 gene causes a decrease or modulation of production of the ANGPTL7 gene product. In some embodiments, editing the ANGPTL7 gene causes a decrease in intraocular pressure in the subject.

[0011] In another aspect, a composition comprising CRISPR / cas9 targeting ANGPTL7 is provided that is effective for treating glaucoma or ocular hypertension. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to 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 of the human protein SEQ ID NO: 1. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to 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 of the human protein SEQ ID NO: 1.

[0012] A non-limiting example of a therapeutic molecule for inhibiting or regulating ANGPTL7 is RNA interference (RNAi), in which double-stranded RNAi (dsRNA) can be used to inhibit gene expression. Short double-stranded RNAs induce gene-specific posttranscriptional silencing in many organisms, including vertebrates, providing 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 RNAs homologous to the silencing trigger. RISC is known to contain short RNAs (approximately 21 nucleotides) derived from the double-stranded RNA trigger, but the protein structure responsible for this activity remains unknown.

[0013] Another non-limiting example of a therapeutic molecule for inhibiting or regulating ANGPTL7 is 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 the core of various technologies for detecting specific nucleic acids or changing their expression.Antisense nucleotides, for example, disrupt gene expression by hybridizing to target RNA, thereby interfering with RNA splicing, transcription, translation, and replication.Antisense DNA has the additional feature that DNA-RNA hybrids serve as substrates for digestion by ribonuclease H (RNase H), an activity present in most cell types.Antisense molecules can be delivered to cells, as in the case of oligodeoxynucleotides (ODN), or can be expressed from endogenous genes as RNA molecules.

[0014] Another non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is splice-switching antisense oligonucleotides (SSOs). These are short, synthetic, antisense, modified nucleic acids that hybridize with pre-mRNA and disrupt the normal splicing repertoire of transcripts by inhibiting RNA-RNA base pairing or protein-RNA binding interactions between components of the splicing machinery and the pre-mRNA. Pre-mRNA splicing is required for the proper expression of the majority of protein-coding genes; therefore, targeting this process provides a means to manipulate protein production from genes. For example, pre-mRNA splicing can be exploited to alter the reading frame downstream of the splice site, creating a truncated protein with impaired function.

[0015] Splice-switching antisense oligonucleotides differ from mRNA-cleaving antisense oligonucleotides in that they do not recruit RNase H to disassemble the pre-mRNA-SSO complex, but rather strictly sterically block it. This is achieved by using fully or nearly fully 2'-modified antisense oligonucleotides that lack the necessary DNA-RNA hybrid region recognized by RNase H. Another type of modified oligonucleotide for modifying splicing is phosphoramidite morpholinos (PMOs). PMOs have a morpholine ring instead of the furanose ring found in natural nucleic acids and a neutral phosphorodiamidate backbone instead of the negatively charged phosphodiester backbone.

[0016] In some embodiments, the present disclosure provides the method for inhibiting or regulating the action of natural transcript by using antisense oligonucleotide that targets any region of natural transcript.It is also contemplated herein that the inhibition or regulation of natural transcript can be achieved by siRNA, ribozyme and small molecule.In exemplary embodiments, natural transcript encodes ANGPTL7.

[0017] One embodiment provides a method of modulating the function and / or expression of an ANGPTL7 polynucleotide in a patient's cells or tissue in vivo or in vitro, comprising contacting the cell or tissue with an antisense oligonucleotide 5-30 nucleotides in length, wherein the antisense oligonucleotide has at least 50% sequence identity to the reverse complement of a polynucleotide comprising 5-30 contiguous nucleotides within nucleotides 1-6333 of SEQ ID NO: 11086, and any variant, allele, homolog, mutant, derivative, fragment, and complementary sequence thereof, thereby modulating the function and / or expression of an ANGPTL7 polynucleotide in the patient's cells or tissue 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 at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084.

[0018] In one embodiment, the oligonucleotide targets a native sequence of an ANGPTL7 polynucleotide, e.g., the nucleotide 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 SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084.

[0019] In one embodiment, the oligonucleotide targets a native sequence of an ANGPTL7 polynucleotide, e.g., the nucleotide 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 SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084.

[0020] In one embodiment, 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 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.

[0021] In some embodiments, the oligonucleotide comprises one or more modified or substituted nucleotides. In some embodiments, the oligonucleotide comprises one or more modified linkages. In some embodiments, the modified nucleotide comprises a modified base, including phosphorothioate, methylphosphonate, peptide nucleic acid, 2'-O-methyl, methoxyethyl, fluoro-, or carbon, methylene, or other locked nucleic acid (LNA) molecules. In some embodiments, the modified nucleotide is a locked nucleic acid molecule, including α-L-LNA.

[0022] In some embodiments, the oligonucleotide is administered to the patient by topical application, by inhalation, intranasally, subcutaneously, intramuscularly, intravenously, intraocularly, or intraperitoneally.

[0023] In some embodiments, the oligonucleotide is administered in a pharmaceutical composition.The treatment regimen comprises administering antisense compounds to patients at least once, but this treatment can be modified to include multiple administrations over a period of time.The treatment can be combined with one or more other types of treatment.

[0024] In some embodiments, the oligonucleotide is encapsulated in a liposome or conjugated to a carrier molecule (eg, cholesterol, TAT peptide).

[0025] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or modulating expression of angiopoietin-like 7 (ANGPTL7), wherein the RNAi agent comprises double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, each strand having 14-30 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 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 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 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'-0-alkyl, 2'-0-allyl, 2'-C-allyl, 2'-fluoro, and 2'-deoxy. In some embodiments, the nucleotides are modified with either 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'-0-methyl nucleotides, 2'-deoxyfluoro nucleotides, 2'-0-N-methylacetamide (2'-0-NMA) nucleotides, 2'-0-dimethylaminoethoxyethyl (2'-0-DMAEOE) nucleotides, 2'-0-aminopropyl (2'-0-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 the 5'-end 1 position 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 the 5'-end 1 position of the dsRNA is an AU base pair.

[0026] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or modulating expression of ANGPTL7, wherein the RNAi agent comprises double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, each of the strands having 14 to 30 nucleotides, wherein the sense strand comprises at least two motifs of three identical modifications on three consecutive nucleotides, wherein a first one of the sense strand motifs occurs at the cleavage site of the sense strand and a second one of the sense strand motifs occurs in a different region of the sense strand separated by at least one nucleotide from the first sense strand motif, and wherein the antisense strand comprises at least two motifs of three identical modifications on three consecutive nucleotides, wherein the first one of the antisense strand motifs occurs at or near the cleavage site of the antisense strand and the second one of the antisense strand motifs occurs in a different region of the antisense strand separated by at least one nucleotide from the first antisense strand motif, and 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 base pairs 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 strand has 17-23 nucleotides. In some embodiments, the modification on the nucleotides of the sense strand and / or antisense strand is selected from the group consisting of LNA, HNA, CeNA, 2'-methoxyethyl, 2'-0-alkyl, 2'-0-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.

[0027] 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 of three 2'-F modifications on three consecutive nucleotides, one of the motifs occurring at or near the cleavage site of the sense strand; and the antisense strand comprises at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides, one of the motifs occurring at or near the cleavage site of the antisense strand. In some embodiments, the sense strand comprises a sequence 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 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.

[0028] In one aspect, provided herein is a method of modulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in cells or tissues of a patient in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide of 5 to 30 nucleotides in length, wherein the at least one antisense oligonucleotide has at least 50% sequence identity to the reverse complement of a polynucleotide comprising 5-30 contiguous nucleotides within nucleotides 1-2224 of SEQ ID NO: 11085, thereby modulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in cells or tissues of the patient in vivo or in vitro.

[0029] In one aspect, provided herein is a method of modulating the function and / or expression of an angiopoietin-like 7 (ANGPTL7) polynucleotide in a patient's cells or tissue, in vivo or in vitro, comprising contacting the cell or tissue with at least one antisense oligonucleotide of 5 to 30 nucleotides in length, wherein the antisense oligonucleotide has at least 50% sequence identity to an angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby modulating the function and / or expression of an angiopoietin-like 7 (ANGPTL7) polynucleotide in the patient's cells or tissue, in vivo or in vitro.

[0030] In one aspect, provided herein is a method of modulating the function and / or expression of an angiopoietin-like 7 (ANGPTL7) polynucleotide in a patient's cells or tissue in vivo or in vitro, the method comprising contacting the cells or tissue with at least one antisense oligonucleotide that targets a region of a natural antisense oligonucleotide of an angiopoietin-like 7 (ANGPTL7) polynucleotide, thereby modulating the function and / or expression of an angiopoietin-like 7 (ANGPTL7) polynucleotide in the patient's cells or tissue in vivo or in vitro.

[0031] In one aspect, provided herein is a method of modulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotide in a patient's cells or tissue, in vivo or in vitro, comprising contacting the cells or tissue with at least one antisense oligonucleotide of 5 to 30 nucleotides in length, thereby modulating the function and / or expression of the ANGPTL7 polynucleotide in the patient's cells or tissue, in vivo or in vitro.

[0032] 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 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 ANGPTL7 or that 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 ANGPTL7 or that does not specifically hybridize to ANGPTL7. In some embodiments, at least one antisense oligonucleotide targets the natural antisense sequence of an Angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, at least one antisense oligonucleotide targets a nucleic acid sequence comprising a 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 an Angiopoietin-like 7 (ANGPTL7) polynucleotide. 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 a 2'-O-methoxyethyl-modified sugar moiety, a 2'-methoxy-modified sugar moiety, a 2'-O-alkyl-modified sugar moiety, a bicyclic sugar moiety, and combinations thereof.In some embodiments, the one or more modifications comprise at least one modified internucleoside linkage selected from phosphorothioate, 2'-methoxyethyl (MOE), 2'-fluoro, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof. In some embodiments, the one or more modifications comprise at least one modified nucleotide selected from peptide nucleic acid (PNA), locked nucleic acid (LNA), arabino-nucleic acid (FANA), analogs, derivatives, and combinations thereof.

[0033] In one aspect, provided herein is a method of modulating the function and / or expression of the Angiopoietin-like 7 (ANGPTL7) gene in mammalian cells in vivo or in vitro, the method comprising contacting the cell or tissue with at least one short interfering RNA (siRNA) oligonucleotide of 5 to 30 nucleotides in length, wherein the at least one siRNA oligonucleotide is specific to an antisense polynucleotide of an Angiopoietin-like 7 (ANGPTL7) polynucleotide, and the at least one siRNA oligonucleotide has at least 50% sequence identity to a complementary sequence of at least about five contiguous nucleic acids of an antisense and / or sense nucleic acid molecule of an Angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby modulating the function and / or expression of Angiopoietin-like 7 (ANGPTL7) in the mammalian cells in vivo or in vitro. In some embodiments, the oligonucleotides have at least 80% sequence identity to a sequence of at least about 5 contiguous nucleic acids complementary to an antisense and / or sense nucleic acid molecule of an Angiopoietin-like 7 (ANGPTL7) polynucleotide; in some embodiments, 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 at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0034] In one aspect, provided herein are methods of modulating Angiopoietin-like 7 (ANGPTL7) function and / or expression in mammalian cells in vivo or in vitro, the methods comprising contacting the cells or tissue with at least one antisense oligonucleotide 5-30 nucleotides in length, wherein the antisense oligonucleotide is specific to a non-coding sequence and / or coding sequence of the sense strand and / or natural antisense strand of an Angiopoietin-like 7 (ANGPTL7) polynucleotide, and the at least one antisense oligonucleotide has at least 50% sequence identity to at least one nucleic acid sequence set forth as SEQ ID NOs: 110851-2224, or its complement, thereby modulating Angiopoietin-like 7 (ANGPTL7) function and / or expression in mammalian cells or tissue in vivo or in vitro. In some embodiments, the at least one antisense oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises a sequence at least about 80%, 85%, 90%, 95% identical to SEQ ID NO:11087.

[0035] In one aspect, provided herein are synthetic modified oligonucleotides comprising at least one modification, wherein the at least one modification is selected from at least one modified sugar moiety; at least one modified internucleotide linkage; at least one modified nucleotide, and combinations thereof; the oligonucleotides are antisense compounds that hybridize to angiopoietin-like 7 (ANGPTL7) polynucleotides and modulate the function and / or expression of ANGPTL7 in vivo or in vitro, compared to control oligonucleotides that do not specifically hybridize to ANGPTL7 polynucleotides. 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, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof. In some embodiments, the oligonucleotides comprise at least one phosphorothioate internucleotide linkage. In some embodiments, the oligonucleotides comprise a backbone of phosphorothioate internucleotide linkages. In some embodiments, the oligonucleotide comprises at least one modified nucleotide, wherein the modified nucleotide is selected from peptide nucleic acids, locked nucleic acids (LNAs), and analogs, derivatives, and combinations thereof. In some embodiments, the oligonucleotide comprises multiple modifications, wherein the modifications include modified nucleotides selected from phosphorothioates, alkyl phosphonates, phosphorodithioates, alkyl phosphonothioates, phosphoramidates, carbamates, carbonates, phosphotriesters, acetamidates, carboxymethyl esters, and combinations thereof. In some embodiments, the oligonucleotide comprises multiple modifications, wherein the modifications include modified nucleotides selected from peptide nucleic acids, locked nucleic acids (LNAs), and analogs, derivatives, and combinations thereof.In some embodiments, the oligonucleotide comprises at least one modified sugar moiety selected from a 2'-O-methoxyethyl modified sugar moiety, a 2'-methoxy modified sugar moiety, a 2'-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and combinations thereof. In some embodiments, the oligonucleotide comprises multiple modifications, the modifications including a 2'-O-methoxyethyl modified sugar moiety, a 2'-methoxy modified sugar moiety, a 2'-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and combinations thereof. In some embodiments, the oligonucleotide is at least about 5-30 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 complementary sequence of at least about 5 contiguous nucleic acids of the antisense and / or sense coding and / or non-coding nucleic acid sequence of an angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, the oligonucleotide has at least about 80% sequence identity to the complementary sequence of at least about five contiguous nucleic acids of the antisense and / or sense coding and / or non-coding nucleic acid sequence of an Angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, the oligonucleotide hybridizes to at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates the expression and / or function of said ANGPTL7 polynucleotide in vivo or in vitro compared to a control oligonucleotide. In some embodiments, the oligonucleotide comprises the sequence set forth as 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 at least about 80%, 85%, 90%, or 95% identical to SEQ ID NO: 11087.

[0036] In one aspect, provided herein are compositions comprising one or more oligonucleotides specific to one or more Angiopoietin-like 7 (ANGPTL7) polynucleotides, wherein the one or more oligonucleotides comprise an antisense sequence, a complementary sequence, an allele, a homolog, an isoform, a variant, a derivative, a mutant, a fragment, or a combination thereof, of an ANGPTL7 polynucleotide. 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 oligonucleotide comprises 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.

[0037] In one aspect, provided herein is a method for preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one encoded product thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one antisense oligonucleotide that binds to a natural antisense sequence of said at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates expression of said 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 encoded product thereof.

[0038] In one aspect, provided herein is a method for preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one encoded product thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one antisense oligonucleotide that binds to the native sense sequence of said at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates expression of said 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 encoded product thereof.

[0039] In some embodiments, the disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide is selected from diseases or disorders associated with abnormalities in ANGPTL7 function and / or expression, diseases or disorders associated with optic nerve damage, diseases or disorders associated with intraocular pressure, retinal degenerative diseases or disorders, inflammatory eye diseases or disorders, allergic eye diseases or disorders, diseases or disorders associated with joint degeneration or inflammation, diseases or disorders associated with dyslipidemia, cancer, Alzheimer's disease, dementia, stroke, and cerebral ischemia. In some embodiments, the disease or disorder associated with optic nerve damage is associated with primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, pigmentary glaucoma, exfoliation glaucoma, juvenile glaucoma, congenital glaucoma, inflammatory glaucoma, phacogenic 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 disorder 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.

[0040] In one aspect, provided herein is a method for identifying and selecting at least one oligonucleotide for in vivo administration, the method comprising: identifying at least one oligonucleotide comprising at least five consecutive nucleotides that are complementary to ANGPTL7 or a polynucleotide that is antisense to ANGPTL7; measuring the thermal melting point of a hybrid between 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.

[0041] In one aspect, provided herein are methods of treating a disease or condition mediated by ANGPTL7, the method comprising administering to a subject in need thereof an oligonucleotide comprising a sequence 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 (primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, pigmentary glaucoma, exfoliation glaucoma, juvenile glaucoma, congenital glaucoma, inflammatory glaucoma, phacogenic 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 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 at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0042] In one aspect, provided herein are methods of treating one or more eye disorders in a subject, the methods comprising editing the subject's ANGPTL7 gene, wherein the one or more eye disorders comprise 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 to 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 of the human protein SEQ ID NO: 1. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to 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 of the human protein SEQ ID NO: 1. In some embodiments, CRISPR / cas9 is delivered systemically to a subject. In some embodiments, CRISPR / cas9 is delivered locally to a subject. In some embodiments, CRISPR / cas9 is delivered locally to the eye of a subject. In some embodiments, editing the ANGPTL7 gene is effective in treating one or more ocular disorders. In some embodiments, the one or more ocular disorders is glaucoma. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, imaging of the subject's ocular hypertension demonstrates optic nerve damage. In some embodiments, the subject has received primary treatment for one or more ocular disorders, including a topical ocular prostaglandin analog, a beta-adrenergic blocker, an alpha-adrenergic agonist, and a carbonic anhydrase inhibitor. In some embodiments, editing the ANGPTL7 gene causes a decrease or modulation of production of the ANGPTL7 gene product in the subject. In some embodiments, editing the ANGPTL7 gene causes a decrease in intraocular pressure in the subject.

[0043] In one aspect, provided herein is 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 to 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 of the human protein SEQ ID NO: 1. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to 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 of the human protein SEQ ID NO: 1.

[0044] In some embodiments, disclosed herein are compositions comprising an oligonucleotide that targets angiopoietin-like 7 (ANGPTL7) and reduces intraocular pressure when administered to a subject in an effective amount, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11085, and each strand has 14-30 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 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 antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11085, and each strand has 14-30 nucleotides. In some embodiments, the composition reduces expression of ANGPTL7 compared to a baseline ANGPTL7 measurement. In some embodiments, a baseline ANGPLT7 measurement is measured before the composition is administered to the cells. In some embodiments, the composition reduces ANGPLT7 expression by at least 10% relative to the baseline ANGPLT7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 20% relative to the baseline ANGPLT7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 30% relative to the baseline ANGPLT7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 40% relative to the baseline ANGPLT7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 50% relative to the baseline ANGPLT7 measurement. In some embodiments, the composition reduces ANGPLT7 expression by at least 25%-75% relative to the baseline ANGPLT7 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 two mismatches in the antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not harbor a SNP, and the minor allele frequency (MAF) is 1% or greater (positions 2-18). In some embodiments, the sense strand and the antisense strand each comprise a seed region that is not identical to the seed region of a human miRNA. In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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 is selected from the group consisting of SEQ ID NOs: 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 one or two nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 25, 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 nucleoside sequences. In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, and comprising a nucleoside sequence at least 85% identical to 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 antisense strand is selected from the group consisting of SEQ ID NOs: 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, 3636, 3637, 3638, 3640, 3641, 3642, 3643, 3644, 3645, 3646, 3647, 3648, 3649, 3650, 3651, 3652, 3653, 3654, 3655, 3656, 3657, 3658, 3659, 3660, 3661, 3662, 3663, 3664, 3665, 3666, 3667, 3668, 3669, 3670, 3671, 3672, 3673, 3674, 3675, 3676, 3677, 3678, 3679, 3680, 3681, 3682, 3683, 3684, 3685, 368 40, 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 one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, 340 In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, one or more modified internucleoside linkages comprise alkyl phosphonates, phosphorothioates, methyl phosphonates, phosphorodithioates, alkyl phosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, or carboxymethyl esters, or combinations thereof. In some embodiments, one or more modified internucleoside linkages comprise phosphorothioate linkages.In some embodiments, the oligonucleotide comprises two to six modified internucleoside linkages. In some embodiments, the oligonucleotide comprises one or more modified nucleosides. In some embodiments, the one or more modified nucleosides comprise locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (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 combinations thereof. In some embodiments, one or more modified nucleosides comprise a 2'-fluoro-modified nucleoside. In some embodiments, one or more modified nucleosides comprise a 2'-O-methyl-modified nucleoside. In some embodiments, the oligonucleotide comprises 15-23 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholic acid, docosanoyl, 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 at the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys), cyclo(-Arg-Gly-Asp-D-Phe-Lys), cyclo(-Arg-Gly-Asp-D-Phe-azide), aminobenzoic acid-derived RGD, or a combination thereof.In some embodiments, the oligonucleotide comprises an RGD peptide and a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the sense strand has modification pattern 1S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'-NfsnsN fnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-Lipid-3' (SEQ ID NO: 11384), or the modification pattern 5S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsnN-Lipid-3' (SEQ ID NO: 11385), where "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 antisense strand has modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2AS: 5'-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387). The sense strand may comprise modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), or modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11389), where "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 any of the siRNAs in Tables 5-13. In some embodiments, the sense strand comprises the sense strand sequence of any of the siRNAs in Tables 5-13. In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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, 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, 11183, 11184, 11185, 11186, 11187, 11188,1 11207, 11208, 11210, 11211, or 11212, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 1112 4, 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, 1 1156, 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, 1118 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212. In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to the antisense strand sequence of any one of the siRNAs in Tables 5-13. In some embodiments, the antisense strand comprises the antisense strand sequence of any one of the siRNAs in Tables 5-13.In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11300, 11301, 11302, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11310, 11311, 11312, 11313, 11314, 11315, 11316, 11317, 11318, 11319, 11400, 11401, 11402, 11403, 11404, 11405, 11406, 11407, 11408, 11409, 11410, 11411, 246, 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, 11304, 11305, 11306, 11307, 11308, 11 11327, 11328, 11330, 11331, or 11332, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 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, 11300, 11301, 244, 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, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303 In some embodiments, the sense strand or antisense strand comprises any one of the following nucleoside sequences: 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 antisense strand comprises a 3' overhang of at least two nucleosides. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer solution, or saline.

[0045] In some embodiments, disclosed herein are methods for treating an ocular disorder in a subject, the method comprising administering to the subject a composition comprising an oligonucleotide targeting ANGPTL7. In some embodiments, the ocular disorder comprises glaucoma. In some embodiments, the composition reduces intraocular pressure in the subject's eye compared to a baseline intraocular pressure measurement obtained from the subject before administering the composition to the subject. In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, , 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 is selected from the group consisting of SEQ ID NOs: 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 one or two nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 25, 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 nucleoside sequences. In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, and comprising a nucleoside sequence at least 85% identical to 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 antisense strand is selected from the group consisting of SEQ ID NOs: 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, 3636, 3637, 3638, 3640, 3641, 3642, 3643, 3644, 3645, 3646, 3647, 3648, 3649, 3650, 3651, 3652, 3653, 3654, 3655, 3656, 3657, 3658, 3659, 3660, 3661, 3662, 3663, 3664, 3665, 3666, 3667, 3668, 3669, 3670, 3671, 3672, 3673, 3674, 3675, 3676, 3677, 3678, 3679, 3680, 3681, 3682, 3683, 3684, 3685, 368 40, 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 one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, 340 and any one of the following nucleoside sequences: 4, 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 sense strand has modification pattern 1S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'-Nfsns NfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-Lipid-3' (SEQ ID NO: 11384), or modification pattern 5S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsnN-Lipid-3' (SEQ ID NO: 11385), where "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 antisense strand comprises modification pattern 1 AS: 5'-nsNfsnNfnNfnNfnnnNfnNfnnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2 AS: 5'-nsNfsnnNfnNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3 AS: 5'-nsNfsnnNfnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), or modification pattern 4 AS: 5'-nsNfsnNfnNfnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11389), where "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 any siRNA in Tables 5-13. In some embodiments, the sense strand comprises the sense strand sequence of any siRNA in Tables 5-13.In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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, 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, 11183, 11184, 11185, 11186, 11187, 11188,1 11207, 11208, 11210, 11211, or 11212, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 1112 4, 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, 1 1156, 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, 1118 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212. In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to the antisense strand sequence of any one of the siRNAs in Tables 5-13. In some embodiments, the antisense strand comprises the antisense strand sequence of any one of the siRNAs in Tables 5-13.In some embodiments, the antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 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, 44, 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, 1 1276, 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 , 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332, or In some embodiments, the antisense strand comprises a sequence of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 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, 11300, 11301, 11 244, 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, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303 In some embodiments, the oligonucleotide comprises any one of the following nucleoside sequences: 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 comprises a cholesterol moiety attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholic acid, docosanoyl, 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 at the 3' or 5' end of the oligonucleotide, hi some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys), cyclo(-Arg-Gly-Asp-D-Phe-Lys), cyclo(-Arg-Gly-Asp-D-Phe-Azide), aminobenzoic acid-derived RGD, or a combination thereof. [Brief explanation of the drawings]

[0046] [Figure 1A] Shown are an empty plasmid construct (FIG. 1A), a GFP-tagged plasmid construct (FIG. 1B), a representative ANGPTL7 pre-mRNA encoding construct (FIG. 1C), and a representative ANGPTL7 CDS encoding construct (FIG. 1D) used according to some embodiments. [Figure 1B] Shown are an empty plasmid construct (FIG. 1A), a GFP-tagged plasmid construct (FIG. 1B), a representative ANGPTL7 pre-mRNA encoding construct (FIG. 1C), and a representative ANGPTL7 CDS encoding construct (FIG. 1D) used according to some embodiments. [Figure 1C] Shown are an empty plasmid construct (FIG. 1A), a GFP-tagged plasmid construct (FIG. 1B), a representative ANGPTL7 pre-mRNA encoding construct (FIG. 1C), and a representative ANGPTL7 CDS encoding construct (FIG. 1D) used according to some embodiments. [Figure 1D] Shown are an empty plasmid construct (FIG. 1A), a GFP-tagged plasmid construct (FIG. 1B), a representative ANGPTL7 pre-mRNA encoding construct (FIG. 1C), and a representative ANGPTL7 CDS encoding construct (FIG. 1D) used according to some embodiments. [Figure 2] Fluorescence microscope images of HEK293 cells transfected with pcDNA3.1(+)GFP vector are shown. [Figure 3]1 shows the results of qPCR measuring ANGPTL7 mRNA expression in HEK293 cells transfected with WT and Q175H pre-mRNA expression constructs. [Figure 4] 1 shows the results of qPCR measuring the expression of ANGPTL7 mRNA in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter mRNA precursor expression constructs. [Figure 5] Contains images of Western blots of ANGPTL7 in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs. [Figure 6] Contains the results of an ELISA assay measuring ANGPTL7 protein expression in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs. [Figure 7] Shown are the ratios of secreted to intracellular protein (as measured by ELISA) in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs. [Figure 8] Contains images of Western blots of ANGPTL7 in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter CDS expression constructs. [Figure 9] The relative positions of the protein-coding and non-coding ANGPTL7 transcripts and the Q175H missense variant are shown. [Figure 10] Shown is an agarose gel with PCR products specific for transcripts from HEK293 cells transfected with WT and Q175H pre-mRNA expression constructs. [Figure 11] 1 shows the expression of ANGPTL7 and MYOC in dexamethasone-induced HTM cells. [Figure 12] Shown is an agarose gel with PCR products specific for transcripts from dexamethasone-induced primary HTM cells. DETAILED DESCRIPTION OF THE INVENTION

[0047] Glaucoma is the leading cause of irreversible blindness worldwide, with a global prevalence of approximately 1-2% in individuals over the age of 40. There are several subtypes of glaucoma, but two subtypes predominate: primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). POAG accounts for approximately 90% of glaucoma cases in the United States, and the majority of these cases occur in the setting of ocular hypertension (OHT). In some populations (e.g., Asian populations), the majority of glaucoma cases occur in the setting of normal intraocular pressure (normal-tension glaucoma, NTG).

[0048] Glaucoma is generally characterized by the 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 the non-conventional outflow pathway, which includes uveoscleral drainage and is responsible for some of the aqueous humor outflow from the anterior segment of the eye. When the TM / Schlemm's canal (conventional pathway) is obstructed, aqueous humor outflow is restricted, causing increased anterior chamber pressure, which translates into increased posterior chamber pressure and optic nerve degeneration and damage.

[0049] Glaucoma treatment aims to lower intraocular pressure (IOP) to a target level (generally a 20–50% reduction in IOP). Despite normal IOP, NTG treatment also focuses on lowering IOP. Multiple classes of IOP-lowering medications are used, 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 employed. However, the beneficial effects of trabeculoplasty / trabeculotomy diminish over time, with an annual failure rate of approximately 10%.

[0050] Angiopoietin-like proteins (ANGPTLs) are a family of eight proteins that share structural and functional similarity with angiopoietins and consist 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.

[0051] ANGPTL7 was originally discovered in a human corneal cDNA library and named cornea-derived transcript 6 (CDT6). Immunohistochemistry reveals ANGPTL7 staining in multiple ocular tissues. ANGPTL7 is overexpressed in the aqueous humor of glaucoma patients and is upregulated by glaucomatous conditions such as TGFβ and dexamethasone exposure. However, the molecular function of ANGPTL7 in ocular health and disease has not been fully elucidated.

[0052] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. Furthermore, to the extent the terms "including," "includes," "having," "has," "with," or variations thereof, are used in either the detailed description and / or claims, such terms are intended to be included in a manner similar to "comprising."

[0053] The term "about" or "approximately" means within an acceptable error range of 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, "about" can mean 1 or more than 1 standard deviation per practice in the art. In some cases, "about" can mean within 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, e.g., within 5-fold or within 2-fold, of a value. When particular values ​​are described in this application and claims, unless otherwise specified, the term "about" meaning within an acceptable error range of the particular value should be assumed.

[0054] As used herein, the term "mRNA" refers to the currently known mRNA transcripts of a target gene and any additional transcripts that may be elucidated.

[0055] In some embodiments, " dsRNA ", " siRNA " and " siRNA agent " are used interchangeably to refer to the agent that can mediate the silencing of target RNA, for example, mRNA, for example, the transcription product of a gene that encodes a protein. In some cases, the target RNA is ANGPTL7. Such mRNA may also be referred to herein as the mRNA that is silenced. Such gene may also be referred to as target gene. In some cases, the RNA that is silenced is an endogenous gene or a pathogen gene. In addition, RNA other than mRNA, for example, tRNA and viral RNA, may also be targeted.

[0056] In some embodiments, " mediate RNAi " refers to the ability to silence target RNA in a sequence-specific manner.Without wishing to be bound by theory, it is believed that silencing uses RNAi mechanism or process and guide RNA, for example, siRNA agent.

[0057] In some embodiments, "specifically hybridizable" and "complementary" are terms used to indicate a sufficient degree of complementarity such that stable and specific binding occurs between a compound described herein and a target RNA molecule.

[0058] 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., in the case of an assay or therapeutic treatment, or under physiological conditions in the case of an in vitro assay, or under the conditions under which the assay is performed in the case of an in vitro assay. The non-target sequences may differ by at least 5 nucleotides.

[0059] In some embodiments, a dsRNA agent is "sufficiently complementary" to a target RNA, e.g., a target mRNA, such that the dsRNA agent suppresses production of the protein encoded by the target mRNA. In some embodiments, a dsRNA agent is "exactly complementary" to a target RNA, e.g., the target RNA and dsRNA duplex agent anneal to form a hybrid made up of only Watson-Crick base pairs in the region of exact complementarity. A "sufficiently complementary" target RNA can include an internal region (e.g., of at least 10 nucleotides) that is exactly complementary to the target RNA. Furthermore, in some embodiments, the dsRNA agent specifically discriminates between single-nucleotide differences. In this case, the dsRNA agent only mediates RNAi when exact complementarity is found in a region of one-nucleotide difference (e.g., within 7 nucleotides).

[0060] In some embodiments, the term "oligonucleotide" refers to a nucleic acid molecule (RNA or DNA) that is, for example, less than 100, 200, 300, or 400 nucleotides in length.

[0061] In some embodiments, "antisense oligonucleotide" or "antisense compound" refers to an RNA or DNA molecule that binds 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 alters the activity of the target RNA. Antisense oligonucleotides can up- or down-regulate the expression and / or function of a specific polynucleotide. By definition, it is intended to include any heterologous RNA or DNA molecule that is useful therapeutically, diagnostically, or from other perspectives. Such molecules include, for example, antisense RNA or DNA molecules, interfering RNA (RNAi), microRNA, decoy RNA molecules, siRNA, enzymatic RNA, therapeutic editing RNA, and agonist and antagonist RNAs, antisense oligomeric compounds, antisense oligonucleotides, external guide sequence (EGS) oligonucleotides, alternative splicers, primers, probes, and other oligomeric compounds that hybridize to at least a portion of a target nucleic acid. As such, these compounds may be introduced in the form of single-stranded, double-stranded, partially single-stranded, or circular oligomeric compounds.

[0062] In some embodiments, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), or a mimetic thereof. The term "oligonucleotide" further includes linear or circular oligomers of natural and / or modified monomers or chains, including deoxyribonucleosides, ribonucleosides, their substituted and alpha-anomeric forms, peptide nucleic acids (PNAs), locked nucleic acids (LNAs), phosphorothioates, methylphosphonates, etc. Oligonucleotides can specifically bind to target polynucleotides through standard patterns of interactions between monomers, such as Watson-Crick base pairing, Hoogsteen or reverse Hoogsteen base pairing.

[0063] In some embodiments, oligonucleotides are "chimeric" oligonucleotides composed of various regions. "Chimeric" oligonucleotides contain two or more chemical regions, such as DNA regions, RNA regions, PNA regions, etc. Each chemical region is composed of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region, which is modified to exhibit one or more desired properties. Desired properties of oligonucleotides include, but are not limited to, increased resistance to nuclease degradation, increased cellular uptake, and / or increased binding affinity for target nucleic acids. Therefore, different regions of an oligonucleotide can have different properties. Chimeric oligonucleotides can be formed as a mixed structure of two or more oligonucleotides, modified oligonucleotides, oligonucleosides, and / or oligonucleotide analogs.

[0064] Oligonucleotides can contain or consist of regions that can be linked in "register," i.e., when the monomers are linked consecutively as in natural DNA, or linked by spacers. The spacer constitutes a covalent "bridge" between the regions and is intended, in some cases, to have a length not exceeding about 100 carbon atoms. Spacers can, for example, have a positive or negative charge, possess different functionalities, be lipophilic, possess specific nucleic acid binding properties (intercalators, groove binders, toxins, fluorophores, etc.), or induce specific secondary structures, such as alanine-containing peptides that induce alpha-helices.

[0065] In some embodiments, "ANGPTL7" and "angiopoietin-like 7" encompass 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 in this application.

[0066] As used herein, an "oligonucleotide specific for" or "oligonucleotide targeted to" refers to an oligonucleotide having a sequence capable of (i) forming a stable complex with a portion of a target gene or (ii) forming a stable duplex with a portion of an mRNA transcript of the target gene. The stability of the complex and duplex can be determined by theoretical calculations and / or in vitro assays.

[0067] In some embodiments, the term "target nucleic acid" encompasses DNA, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and cDNA, coding sequence, non-coding sequence, sense, or antisense polynucleotides derived from such RNA. Specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of target nucleic acid function by a compound that specifically hybridizes to the target nucleic acid is commonly referred to as "antisense." Modulated DNA functions include, for example, replication and transcription. Modulated RNA functions include all biological functions, such as translocation of RNA to the site of protein translation, translation of protein from RNA, splicing of RNA to produce one or more mRNA species, and catalytic activities that can be associated with or facilitated by RNA. The overall effect of such interference with target nucleic acid function is modulation of expression of the encoded product or oligonucleotide.

[0068] RNA interference, "RNAi," is mediated by double-stranded RNA (dsRNA) molecules that have sequence-specific homology to their "target" nucleic acid sequences. In certain embodiments, the mediators are 5-25 nucleotide "small interfering" RNA duplexes (siRNAs). siRNAs are derived from the processing of dsRNA by an RNase enzyme known as Dicer. The products of the siRNA duplexes are recruited to a multiprotein siRNA complex termed RISC (RNA-induced silencing complex). Without being bound by any particular theory, it is believed that RISC is then guided to the target nucleic acid (suitably mRNA), where the siRNA duplexes interact in a sequence-specific manner to mediate cleavage in a catalytic manner. Small interfering RNAs can be synthesized and used. The small interfering RNAs used in the methods herein suitably contain from about 1 to about 50 nucleotides (nt). In non-limiting example embodiments, the siRNA can comprise about 5 to about 40 nt, about 5 to about 30 nt, about 10 to about 30 nt, about 15 to about 25 nt, or about 20 to 25 nucleotides.

[0069] In some embodiments, the selection of appropriate oligonucleotides is facilitated by the use of computer programs that automatically align nucleic acid sequences and indicate regions of identity or homology. Such programs are used, for example, to compare nucleic acid sequences obtained by searching databases such as GenBank or by sequencing PCR products. Comparison of nucleic acid sequences from various species allows the selection of nucleic acid sequences that exhibit an appropriate degree of identity between species. In the case of unaligned genes, Southern blots are performed to determine the degree of identity between genes in the target species and other species. By performing Southern blots at various degrees of stringency, it is possible to obtain an approximate measure of identity, as is well known in the art. These procedures allow the selection of oligonucleotides that exhibit high complementarity to the target nucleic acid sequence in the control subject and low complementarity to the corresponding nucleic acid sequence in other species. Those skilled in the art will understand that there is considerable latitude in selecting appropriate regions of a gene.

[0070] In some embodiments, "enzymatic RNA" refers to an RNA molecule that has enzymatic activity. Enzymatic nucleic acids (ribozymes) act by first binding to a target RNA. Such binding occurs via the target binding portion of the enzymatic nucleic acid, which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds the target RNA through base pairing, and once bound to the correct site, acts to enzymatically cleave the target RNA.

[0071] In some embodiments, "decoy RNA" refers to an RNA molecule that mimics a natural binding region for a ligand. Thus, the decoy RNA competes with the natural binding target for binding of a specific ligand. For example, overexpression of HIV transactivation response (TAR) RNA can act as a "decoy" to efficiently bind HIV tat protein, thereby preventing it from binding to the TAR sequence encoded in HIV RNA. This is meant to be a specific example. Those skilled in the art will recognize that this is only one example, and multiple embodiments can be easily generated using techniques commonly known in the art.

[0072] In some embodiments, "monomer" refers to monomers linked by phosphodiester bonds or analogs thereof to form oligonucleotides, typically ranging in size from a few monomeric units (e.g., about 3-4) to approximately several hundred monomeric units. Analogs of phosphodiester bonds include phosphorothioates, phosphorodithioates, methylphosphonates, phosphoroselenoates, phosphoramidates, and the like, as described in more detail below.

[0073] In some embodiments, "nucleotide" encompasses naturally occurring nucleotides as well as non-naturally occurring nucleotides. It should be apparent to those skilled in the art that various nucleotides previously considered "non-naturally occurring" have since been discovered in nature. Thus, "nucleotide" includes not only the known purine and pyrimidine heterocycle-containing molecules, but also their heterocyclic analogs and tautomers. Illustrative examples of other types of nucleotides include adenine, guanine, thymine, cytosine, uracil, purine, xanthine, aminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanocytosine, N6,N6-ethano-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-memyl-4-triazolopyridine, isocytosine, isoguanine, inosine, and molecules containing non-naturally occurring nucleotides as described in Benner et al. (U.S. Patent No. 5,432,272). The term "nucleotide" is intended to encompass any and all of these examples, as well as their analogs and tautomers. Nucleotides of particular interest are those containing adenine, guanine, thymine, cytosine, and uracil, which are considered naturally occurring nucleotides relevant to therapeutic and diagnostic applications in humans. Nucleotides contain natural 2'-deoxy and 2'-hydroxyl sugars, as well as their analogs.

[0074] In some embodiments, "analog," with respect to a nucleotide, includes synthetic nucleotides having modified base moieties and / or modified sugar moieties. Such analogs include synthetic nucleotides designed to enhance binding, e.g., duplex or triplex stability, specificity, etc.

[0075] In some embodiments, "hybridization" refers to the pairing of at least substantially complementary strands of oligomeric compounds. One mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases (nucleotides) of the strands of oligomeric compounds. For example, adenine and thymine are complementary nucleotides that pair through the formation of hydrogen bonds. Hybridization can occur under a variety of circumstances.

[0076] In some embodiments, an antisense compound is "specifically hybridizable" when binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid, resulting in modulation of function and / or activity, and when 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., physiological conditions in the case of in vivo assays or therapeutic treatments, and conditions under which the assay is performed in the case of in vitro assays.

[0077] In some embodiments, "stringent hybridization conditions" or "stringent conditions" refer to conditions under which a compound hybridizes to its target sequence and not to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different under different circumstances; the "stringent conditions" under which an oligomeric compound hybridizes to a target sequence are determined by the nature and composition of the oligomeric compound and the assay in which it is being investigated. In some cases, stringent hybridization conditions include low concentrations (<0.15 M) of salt with inorganic cations such as Na or K (i.e., low ionic strength), temperatures greater than about 20°C to 52°C but below the Tm of the oligomeric compound / target sequence complex, and the presence of a denaturing agent such as formamide, dimethylformamide, dimethyl sulfoxide, or the detergent sodium dodecyl sulfate (SDS). For example, the hybridization rate decreases by 1.1% for each 1% formamide. An example of high stringency hybridization conditions is 0.1X sodium chloride-sodium citrate buffer (SSC) / 0.1% (w / v) SDS at 60°C for 30 minutes.

[0078] In some embodiments, "complementary" refers to the capacity for precise pairing between two nucleotides on one or two oligomeric strands. For example, if a nucleobase at a particular position of an antisense compound is capable of hydrogen bonding with a nucleobase at a particular position of a target nucleic acid (the target nucleic acid is a DNA, RNA, or oligonucleotide molecule), the hydrogen bonding positions between the oligonucleotide and the target nucleic acid may be considered complementary positions. An oligomeric compound and an additional DNA, RNA, or oligonucleotide molecule are complementary to each other when a sufficient number of complementary positions in each molecule are occupied by nucleotides that can hydrogen bond with each other. Thus, "specifically hybridizable" and "complementary" are terms that may be used to indicate a sufficient degree of precise pairing or complementarity for a sufficient number of nucleotides such that stable and specific binding occurs between the oligomeric compound and the target nucleic acid.

[0079] The sequence of an oligomeric compound does not need to be 100% complementary to the sequence of its target nucleic acid to be specifically hybridizable. Moreover, an oligonucleotide can hybridize over one or more segments, so that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, a mismatch, or a hairpin structure). In some embodiments, the oligomeric compounds disclosed herein contain at least about 70%, 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 to a target region within the targeted target nucleic acid sequence. For example, an antisense compound in which 18 out of 20 nucleotides are complementary to a target region would therefore exhibit 90 percent complementarity. In this example, the remaining non-complementary nucleotides may be clustered or interspersed with complementary nucleotides and do not need to be adjacent to each other or to complementary nucleotides. Therefore, an antisense compound of 18 nucleotides in length, which has four non-complementary nucleotides flanked by two regions of perfect complementarity with target nucleic acid, will have 77.8% perfect complementarity with target nucleic acid, and therefore will be within the scope of the present disclosure.The percent complementarity of antisense compounds with a region of target nucleic acid can be determined by conventionally using BLAST program (base local sequence search tool) and PowerBLAST program, which are known in the art.Percent homology, sequence identity or complementarity can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.) using the default setting, using the Smith and Waterman algorithm.

[0080] In some embodiments, "thermal melting point" (Tm) refers to the temperature under defined ionic strength, pH, and nucleic acid concentration at which 50% of oligonucleotides complementary to a target sequence hybridize to the target sequence at equilibrium. Typically, stringent conditions are conditions in which the salt concentration is at least about 0.01-1.0 M Na ion (or other salt) at pH 7.0-8.3, and the temperature is at least about 30°C for short oligonucleotides (e.g., 10-50 nucleotides). Stringent conditions can also be achieved by adding destabilizing agents such as formamide.

[0081] In some embodiments, "modulation" refers to either an increase (stimulation) or a decrease (inhibition) in the expression of a gene.

[0082] "Variant," when used in reference to a polynucleotide sequence, can encompass a polynucleotide sequence related to a wild-type gene. This definition can also include, for example, "allelic," "splice," "species," or "polymorphic" variants. Splice variants can have significant identity to a reference molecule but generally have more or fewer polynucleotides due to alternative splicing of exons during mRNA processing. The corresponding polypeptide may or may not have additional functional domains. Species variants are different polynucleotide sequences that vary from species to species. 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 polypeptide, whose structure or function may or may not be altered. Any given natural or recombinant gene can have none, one, or many alleles. Common mutational changes that give rise to variants are generally due to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes can occur alone or in combination with the others, one or more times in a given sequence.

[0083] The resulting polypeptides generally have significant amino acid identity with each other.Polymorphic variants are variations in the polynucleotide sequence of a particular gene between individuals of a given species.Polymorphic variants can include "single nucleotide polymorphisms" (SNPs) or single nucleotide mutations, where the polynucleotide sequence varies by one base.The presence of SNPs can indicate, for example, a particular population that has a tendency to a certain disease state, i.e., susceptibility to resistance.

[0084] Derivative polynucleotides include nucleic acids that have been chemically modified, such as by replacing hydrogen with alkyl, acyl, or amino groups. Derivatives, such as derivative oligonucleotides, can contain non-naturally occurring moieties, such as altered sugar moieties or inter-sugar linkages. Typical of these are phosphorothioates and other sulfur-containing species known in the art. Derivative nucleic acids can also contain labels, including radioactive nucleotides, enzymes, fluorescent agents, chemiluminescent agents, chromogenic agents, substrates, cofactors, inhibitors, magnetic particles, etc.

[0085] In some embodiments, a "derivative" polypeptide or peptide is one that has been modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction / alkylation, acylation, chemical conjugation, or mild formalin treatment. Derivatives may further be modified to contain, directly or indirectly, a detectable label, including but not limited to, radioisotope, fluorescent, and enzymatic labels.

[0086] 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.

[0087] "Mammal" generally encompasses warm-blooded mammals (e.g., humans and domestic animals) under treatment. Examples include felines, canines, equines, bovines, and hominins, in addition to just humans.

[0088] "Treating" or "treatment" includes the treatment of a disease state in a mammal, including (a) preventing the disease state from occurring in the mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as suffering from it; (b) inhibiting the disease state, e.g., arresting its progression; and / or (c) alleviating the disease state, e.g., causing regression of the disease state, until a desired endpoint is achieved. Treatment includes the amelioration of symptoms of the disease (e.g., reducing pain or discomfort), where such amelioration may or may not directly affect the disease (e.g., cause, transmission, manifestation, etc.). The term "treatment" is intended to encompass prophylaxis, therapy, and cure. Patients receiving this treatment include primates, particularly humans, and other mammals, e.g., horses, cattle, pigs, and sheep; and any animal in need thereof, including poultry and pets in general.

[0089] All genes, gene names, and gene products disclosed herein are intended to correspond to homologs from any species to which the compositions and methods disclosed herein are applicable. Thus, these terms include, but are not limited to, genes and gene products from humans and mice. When genes or gene products from a particular species are disclosed, it is understood that this disclosure is intended for illustrative purposes only and is not intended to be limiting unless the context in which it appears clearly indicates otherwise. Thus, for example, in some embodiments, genes disclosed herein related to mammalian nucleic acid and amino acid sequences are intended to encompass homologous 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 genes or nucleic acid sequences are human.

[0090] In some embodiments, the term "halo" refers to any radical of fluorine, chlorine, bromine, or iodine. In some embodiments, the term "alkyl" refers to saturated and unsaturated non-aromatic hydrocarbon chains (including, but not limited to, propyl, allyl, or propargyl) that may be straight or branched, containing the indicated number of carbon atoms, and which may optionally be interrupted by N, O, or S. For example, Ci-Cio indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. The term "alkoxy" refers to an -O-alkyl radical. In some embodiments, the term "alkylene" refers to a divalent alkyl (i.e., -R-). The term "alkylenedioxo" refers to a divalent species of the structure -O-R-O-, where R represents alkylene. The term "aminoalkyl" refers to an alkyl substituted with an amino. In some embodiments, the term "mercapto" refers to an -SH radical. The term "thioalkoxy" refers to an -S-alkyl radical.

[0091] In some embodiments, the term "aryl" refers to a 6-carbon monocyclic or 10-bicyclic aromatic ring system in which 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 "aralkyl" refers to an alkyl substituted with an aryl. In some embodiments, "arylalkoxy" refers to an alkoxy substituted with an aryl.

[0092] In some embodiments, the term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, e.g., 3 to 8 carbons, e.g., 3 to 6 carbons, where the cycloalkyl group may be further optionally substituted. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0093] In some embodiments, the term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic ring, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, or S in the monocyclic, bicyclic, or tricyclic ring, respectively), where 0, 1, 2, 3, or 4 atoms in each ring are optionally substituted. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like. In some embodiments, the term "heteroarylalkyl" or "heteroaralkyl" refers to an alkyl substituted with a heteroaryl. In some embodiments, "heteroarylalkoxy" refers to an alkoxy substituted with a heteroaryl.

[0094] In some embodiments, the term "heterocyclyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic ring, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, or S in the monocyclic, bicyclic, or tricyclic ring, respectively), where 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocyclyl groups include triazolyl, tetrazolyl, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0095] 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, or a sulfoxide or sulfone when attached to sulfur.

[0096] In some embodiments, the term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted.

[0097] In some embodiments, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that a substituent can be further substituted.

[0098] Oligonucleotide Compounds and Compositions Some embodiments refer to nucleic acid sequence information. In some embodiments, any uracil (U) may be replaced with any thymine (T), and vice versa. For example, in an siRNA comprising a nucleic acid sequence containing one or more U, in some embodiments, any U may be replaced with a T. Similarly, in an siRNA comprising a nucleic acid sequence containing one or more T, in some embodiments, any T may be replaced with a U. In some embodiments, an oligonucleotide such as an siRNA disclosed herein comprises or consists of RNA. In some embodiments, an oligonucleotide may comprise or consist of DNA.

[0099] Some embodiments refer to specific nucleic acid sequences that comprise modified nucleic acids. In some embodiments, the oligonucleotides described herein comprise or consist of nucleic acid sequences that comprise unmodified versions of the nucleic acid sequences that comprise modified nucleic acids. In some embodiments, the oligonucleotides described herein comprise or consist of nucleic acid sequences that comprise modified nucleic acids, but have any one or more additional or different modifications.

[0100] In some embodiments, provided herein are oligonucleotide compounds that target angiopoietin-like 7 (ANGPTL7) nucleic acid sequences, including but not limited to, sense and / or antisense non-coding and / or coding sequences related to ANGPTL7. In some embodiments, the target nucleic acid molecule is not limited to ANGPTL7 polynucleotides alone, but extends to any of ANGPTL7 isoforms, receptors, homologs, non-coding regions, etc.

[0101] In some embodiments, compositions are provided that include one or more antisense oligonucleotides or dsRNA agents targeting a first nucleic acid and one or more additional antisense compounds targeting a second nucleic acid target. For example, the first target may be a specific sequence of angiopoietin-like 7 (ANGPTL7), and the second target may be a region from another nucleotide sequence. In some embodiments, the composition may include two or more antisense oligonucleotides or dsRNA compounds targeted to 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.

[0102] In some embodiments, compositions are provided that comprise multiple antisense oligonucleotides or dsRNA agent species.In some embodiments, the antisense oligonucleotides or dsRNA agent species have sequences that are not overlapping and not adjacent to other species with respect to naturally occurring target sequences.In some embodiments, the multiple antisense oligonucleotides or dsRNA agent species are specific to different naturally occurring target genes.In some embodiments, the dsRNA agent is allele-specific.

[0103] The present disclosure provides methods, compositions, and kits for the administration and delivery of the antisense oligonucleotide or dsRNA agents described herein.

[0104] composition In some embodiments, compositions comprising oligonucleotides are disclosed herein. In some embodiments, the compositions comprise an oligonucleotide targeting ANGPTL7. In some embodiments, the compositions consist of an oligonucleotide targeting ANGPTL7. In some embodiments, the compositions described herein are used in methods of treating a disorder in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in methods of treating a disorder described herein. Some embodiments relate to the use of compositions comprising oligonucleotides in methods of treating a disorder as described herein. The composition (e.g., an oligonucleotide composition) may comprise or consist of a dsRNA agent described herein. The composition (e.g., an oligonucleotide composition) may comprise or consist of an siRNA described herein. The composition (e.g., an oligonucleotide composition) may comprise or consist of an antisense oligonucleotide described herein.

[0105] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL7 and, when administered to a subject in an effective amount, reduces ANGPTL7 mRNA levels in cells or tissues. In some embodiments, the cells are ANGPTL7. In some embodiments, the tissue is ANGPTL7 tissue. In some embodiments, the ANGPTL7 mRNA level 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 ANGPTL7 mRNA level is reduced by about 10% or more compared to before administration. In some embodiments, the ANGPTL7 mRNA level 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 ANGPTL7 mRNA level is 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, the ANGPTL7 mRNA level is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the ANGPTL7 mRNA level is reduced by about 10% or less compared to before administration. In some embodiments, the ANGPTL7 mRNA level is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to before administration. In some embodiments, the ANGPTL7 mRNA level is reduced by about 200% or less, about 300% or less, about 400% or less, about 500% or less, about 600% or less, about 700% or less, about 800% or less, about 900% or less, or about 1000% or less compared to before administration. In some embodiments, the ANGPTL7 mRNA level is 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 two aforementioned percentages.

[0106] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL7 and, when administered to a subject in an effective amount, reduces circulating ANGPTL7 protein levels. In some embodiments, the ANGPTL7 protein level 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 ANGPTL7 protein level is reduced by about 10% or more compared to before administration. In some embodiments, the ANGPTL7 protein level 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 ANGPTL7 protein level is 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, the ANGPTL7 protein level is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by about 10% or less compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by about 200% or less, about 300% or less, about 400% or less, about 500% or less, about 600% or less, about 700% or less, about 800% or less, about 900% or less, or about 1000% or less compared to before administration. In some embodiments, the ANGPTL7 protein level is 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.

[0107] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL7 and reduces glaucoma symptoms when administered to a subject in an effective amount. In some embodiments, the glaucoma symptoms 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 glaucoma symptoms are reduced by about 10% or more compared to before administration. In some embodiments, the glaucoma symptoms 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 glaucoma symptoms are reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the glaucoma symptoms are reduced by about 10% or less compared to before administration. In some embodiments, the glaucoma symptoms are reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less 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 by a range defined by any of the foregoing two percentages. In some embodiments, the glaucoma symptoms are the incidence of glaucoma or a glaucoma subtype. In some embodiments, the glaucoma symptoms are 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).

[0108] In some embodiments, the composition comprises an oligonucleotide that targets ANGPTL7 and reduces intraocular pressure when administered to a subject in an effective amount. 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 about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the intraocular pressure is reduced by about 10% or less compared to before administration. In some embodiments, intraocular pressure is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to pre-administration, hi some embodiments, 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 aforementioned two percentages.

[0109] Modification Pattern In some embodiments, the composition comprises an oligonucleotide that inhibits ANGPTL7 expression, wherein the oligonucleotide comprises 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 alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. Benefits of modified internucleoside linkages may include reduced toxicity or improved pharmacokinetics. The composition (e.g., oligonucleotide composition) may comprise or consist of the dsRNA agent described herein.The composition (e.g., oligonucleotide composition) may comprise or consist of the siRNA described herein.The composition (e.g., oligonucleotide composition) may comprise or consist of the antisense oligonucleotide described herein.

[0110] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises a modified internucleoside linkage, and 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 18 or fewer modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 20 or fewer modified internucleoside linkages. In some embodiments, the oligonucleotide has 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, 20 or more modified internucleoside linkages, 21 or more modified internucleoside linkages, 22 or more modified internucleoside linkages, 23 or more modified internucleoside linkages, 24 or more modified internucleoside linkages, 25 or more modified internucleoside linkages, 26 or more modified internucleoside linkages, 27 or more modified internucleoside linkages, 28 or more modified internucleoside linkages, 29 or more modified internucleoside linkages, 30 or more modified internucleoside linkages, 31 or more modified internucleoside linkages, 32 or more modified internucleoside linkages, 33 or more modified internucleoside linkages, 34 or more modified internucleoside linkages, 35 or more modified internucleoside linkages, 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.

[0111] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, 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-methylacetamide (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 a 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. Advantages of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0112] 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 defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises 19 or fewer modified nucleosides. In some embodiments, the oligonucleotide comprises 21 or fewer modified nucleosides. In some embodiments, the oligonucleotide comprises two or more modified nucleosides, three or more modified nucleosides, four or more modified nucleosides, five or more modified nucleosides, six or more modified nucleosides, seven or more modified nucleosides, eight or more modified nucleosides, nine or more modified nucleosides, ten or more modified nucleosides, eleven or more modified nucleosides, twelve or more modified nucleosides, thirteen or more modified nucleosides, fourteen or more modified nucleosides, fifteen or more modified nucleosides, sixteen or more modified nucleosides, seventeen or more modified nucleosides, eighteen or more modified nucleosides, nineteen or more modified nucleosides, twenty or more modified nucleosides, or twenty one or more modified nucleosides.

[0113] In some embodiments, the hydrophobic moiety is attached to the oligonucleotide (e.g., the sense strand and / or antisense strand of an siRNA or ASO). In some embodiments, the hydrophobic moiety is attached at the 3' end of the oligonucleotide. In some embodiments, the hydrophobic moiety is attached at the 5' end of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol.

[0114] In some embodiments, the composition comprises an oligonucleotide that inhibits ANGPTL7 expression, 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, lithochloyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises cholesterol.

[0115] In some embodiments, the composition comprises an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the RGD peptide is attached at the 3' end of the oligonucleotide. In some embodiments, the RGD peptide is attached at 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 at the 3' or 5' end of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide and a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-azide). In some embodiments, the RGD peptide comprises an aminobenzoic acid-derived RGD. In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys), cyclo(-Arg-Gly-Asp-D-Phe-Lys), cyclo(-Arg-Gly-Asp-D-Phe-azide), an aminobenzoic acid-derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiples of such RGD peptides. For example, the RGD peptide may comprise two, three, or four RGD peptides.

[0116] In some embodiments, the oligonucleotide comprises the dsRNA agent described herein.In some embodiments, the oligonucleotide comprises the siRNA described herein.In some embodiments, the oligonucleotide comprises the antisense oligonucleotide described herein.In some embodiments, one or more nucleotides in the sense strand and / or antisense strand of antisense oligonucleotide, dsRNA agent or siRNA are modified according to any of the modifications or modification patterns described herein.

[0117] In some embodiments, the modification or modification pattern disclosed herein comprises a cholesterol moiety.

[0118] dsRNA agents In some embodiments, the composition comprises a double-stranded RNAi (dsRNA) agent. In one aspect, provided herein is a dsRNA agent 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 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 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 at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0119] In some cases, each strand of a dsRNA agent can range from 12 to 30 nucleotides in length. For example, each strand can be 14-30 nucleotides in length, 17-30 nucleotides in length, 25-30 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length.

[0120] Sense strand and antisense strand typically form a duplex dsRNA.The duplex region of dsRNA agent can be 12-30 nucleotide pairs in length.For example, the duplex region can be 14-30 nucleotide pairs in length, 17-30 nucleotide pairs in length, 25-30 nucleotide pairs in length, 27-30 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length.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.

[0121] In some embodiments, a dsRNA agent includes one or more overhang regions and / or capping groups at the 3'-end, 5'-end, or both ends of a strand. In some cases, the overhang is approximately 1-6 nucleotides in length, e.g., 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 of one strand being longer than the other, or may be the result of two strands of the same length being staggered. The overhang may form a mismatch with the target mRNA, or may be complementary to the targeted gene sequence, or may be another sequence. The first and second strands may be linked, for example, by additional bases to form a hairpin, or may be linked by other non-basic linkers.

[0122] In some embodiments, compositions comprising an RNA interference (RNAi) agent are described herein. In some embodiments, the RNAi agent can inhibit or modulate expression of angiopoietin-like 7 (ANGPTL7). In some embodiments, the RNAi agent comprises an siRNA described herein. In some embodiments, the RNAi agent comprises double-stranded RNA (dsRNA). In some embodiments, the dsRNA comprises a sense strand and an antisense strand (such as the 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 14-30 nucleotides.

[0123] In some embodiments, described herein are compositions comprising an RNA interference (RNAi) agent capable of inhibiting or modulating expression of angiopoietin-like 7 (ANGPTL7), wherein the RNAi agent comprises double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11085, and each strand has 14 to 30 nucleotides.

[0124] In some embodiments, described herein are compositions comprising an RNA interference (RNAi) agent capable of inhibiting or modulating expression of angiopoietin-like 7 (ANGPTL7), wherein the RNAi agent comprises double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11086, and each strand has 14 to 30 nucleotides.

[0125] 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, a modification pattern 1S, 2S, 3S, 4S, 5S, 1AS, 2AS, 3AS, 4AS, or ASO1 can confer nuclease resistance.

[0126] dsRNA modification The modifications described herein in relation to dsRNA agents can be applied to the antisense oligonucleotides described elsewhere herein.The modifications described herein in relation to dsRNA agents can be applied to the siRNA oligonucleotides described elsewhere herein.

[0127] In some embodiments, one or more nucleotides of the sense strand and / or antisense strand of dsRNA agent are modified.In some embodiments, all nucleotides of the sense strand and antisense strand of dsRNA are modified.The modifications of the sense strand and antisense strand can each independently comprise at least two different modifications.In some cases, not all nucleotides of the sense strand and antisense strand are modified.In some cases, no nucleotides of the sense strand and / or antisense strand are modified.

[0128] In some cases, the sense strand comprises at least one motif of three identical modifications on three consecutive nucleotides, and 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 of three identical modifications on three consecutive nucleotides.The modification pattern of the antisense strand can be shifted by one or more nucleotides compared with the modification pattern of the sense strand.

[0129] In some cases, the sense strand contains at least two motifs with three identical modifications on three consecutive nucleotides, where at least one of the motifs occurs at the site of strand breakage and at least one of the motifs occurs in another portion of the strand at least one nucleotide away from the motif at the breakage site. In some cases, the antisense strand contains at least one motif of three identical modifications on three consecutive nucleotides, where at least one of the motifs occurs at or near the site of strand breakage and at least one of the motifs occurs in another portion of the strand at least one nucleotide away from the motif at or near the breakage site.

[0130] In some cases, the sense strand contains at least two motifs with three identical modifications on three consecutive nucleotides, at least one of the motifs occurring at the site of strand cleavage and at least one of the motifs occurring in another portion of the strand at least one nucleotide away from the motif at the cleavage site. In some cases, the antisense strand contains at least one motif of three identical modifications on three consecutive nucleotides, at least one of the motifs occurring at or near the site of strand cleavage and at least one of the motifs occurring in another portion of the strand at least one nucleotide away from the motif at or near the cleavage site. In some cases, the modification of the motif occurring at the cleavage site on the sense strand is different from the modification of the motif occurring at or near the cleavage site on the antisense strand.

[0131] In some cases, the sense strand comprises at least one motif of three 2'-F modifications on three consecutive nucleotides, at least one of the motifs occurring at the site of strand cleavage. In some cases, the antisense strand comprises at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides.

[0132] In some cases, the sense strand contains one or more motifs of three identical modifications on three consecutive nucleotides, with one or more additional motifs occurring in another portion of the strand at least one nucleotide away from the three 2'-F modifications at the cleavage site. The antisense strand may contain one or more motifs of three identical modifications on three consecutive nucleotides, with one or more additional motifs occurring in another portion of the strand at least one nucleotide away from the three 2'-0-methyl modifications. In some cases, at least one of the nucleotides with a 2'-F modification may form a base pair with one of the nucleotides with a 2'-0-methyl modification.

[0133] In some embodiments, when a dsRNA agent comprises an overhang, each nucleotide in the overhang region of the dsRNA agent can be independently modified or unmodified.Non-limiting examples of modifications include, but are not limited to, 2'-sugar modifications, such as 2-F 2'-methyl, thymidine (T), 2'-0-methoxyethyl-5-methyluridine (Teo), 2'-0-methoxyethyl adenosine (Aeo), 2'-0-methoxyethyl-5-methylcytidine (m5Ceo), and any combination thereof.For example, TT can be the overhang sequence on either end of either strand.The overhang can form a mismatch with the target mRNA, or can be complementary to the targeted gene sequence, or can be another sequence.

[0134] In some embodiments, when a dsRNA agent includes an overhang, the 5'-overhang 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 includes two nucleotides with a phosphorothioate between them, where 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 on the antisense strand. In some embodiments, the 3'-overhang is present on the sense strand.

[0135] 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 combinations thereof. In some embodiments, the modified dsRNA agent comprises 2'OMe nucleotides (e.g., 2'OMe purine and / or pyrimidine nucleotides), such as 2'OMe-guanosine nucleotides, 2'OMe-uridine nucleotides, 2'OMe-adenosine nucleotides, 2'OMe-cytosine nucleotides, or combinations thereof. In certain embodiments, the modified dsRNA agent does not comprise a 2'OMe-cytosine nucleotide. In some embodiments, the modified dsRNA agent comprises a hairpin loop structure.

[0136] In certain aspects, the modified dsRNA agent has an IC50 that is 10-fold or less than that of the corresponding unmodified dsRNA (e.g., the modified dsRNA agent has an IC50 that is 10-fold or less than that of the corresponding unmodified dsRNA agent). In some embodiments, the modified dsRNA agent has an IC50 that is 3-fold or less than that of the corresponding unmodified dsRNA agent. In some embodiments, the modified dsRNA agent has an IC50 that is 2-fold or less than that of the corresponding unmodified dsRNA agent. It will be readily apparent to those of skill 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 of skill in the art.

[0137] The modified 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 lack an overhang (i.e., have a blunt end). In some aspects, the modified dsRNA agent has a 3' overhang of two nucleotides on each side of the double-stranded region. In some embodiments, 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 to the target sequence or its complementary strand. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, or more nucleotides, such as 2'-deoxy (2'H) nucleotides. In some cases, the 3' overhang comprises deoxythymidine (dT) nucleotides.

[0138] In some embodiments, a modified dsRNA agent comprises 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 the double-stranded region of the dsRNA agent modified nucleotides. 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.

[0139] In some embodiments, the dsRNA agent does not contain a phosphate backbone modification, for example, in the sense strand and / or antisense strand of the double-stranded region. In some embodiments, the modified dsRNA agent does not contain a 2'-deoxynucleotide, for example, in the sense strand and / or antisense strand of the double-stranded region. In some embodiments, the nucleotide at the 3' end of the double-stranded region of the sense strand and / or antisense strand is not a modified nucleotide. In some embodiments, the nucleotide near the 3' end of the double-stranded region of the sense strand and / or antisense strand (e.g., within 1, 2, 3, or 4 nucleotides from the 3' end) is not a modified nucleotide.

[0140] 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 lack an overhang (i.e., have a blunt end). In some cases, the modified dsRNA agent has a 3' overhang of two nucleotides on each side of the double-stranded region. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, or more nucleotides, such as 2'-deoxy (2'H) nucleotides. In some cases, the 3' overhang comprises deoxythymidine (dT) nucleotides.

[0141] dsRNA agent can also have a blunt end located at the 5'-end of antisense strand (or the 3'-end of sense strand), or vice versa.In some cases, the antisense strand of dsRNA has a nucleotide overhang at the 3'-end, and the 5'-end is blunt-ended.Without being bound by theory, the asymmetric blunt end at the 5'-end of antisense strand and the overhang at the 3'-end of antisense strand can be advantageous for the loading of guide strand into RISC process.

[0142] In some embodiments, the dsRNA agent may further have two blunt ends at either end of the dsRNA duplex.

[0143] In some embodiments, all nucleotides of the sense strand and antisense strand of dsRNA agent, including the nucleotide that is part of motif, can be modified.Each nucleotide can be modified with the same or different modifications, and this can include changing one or both of non-linked phosphate oxygen, and / or changing one or more of linked phosphate oxygen; changing the component of ribose sugar, for example, the 2' hydroxyl on ribose sugar; completely replacing phosphate moiety with " dephosphorylation " linker; modifying or replacing naturally occurring base; and replacing or modifying ribose-phosphate backbone.In some embodiments, less than all nucleotides of the sense strand and antisense strand are modified.

[0144] Because nucleic acids are polymers of subunits, in some cases, many modifications, such as modifications of bases, modifications of phosphate moieties, and modifications of non-linked Os at phosphate moieties, occur at positions repeated within the nucleic acid. In some cases, modifications occur at all of the target positions within the nucleic acid, but in other cases, they do not. For example, modifications may occur only at the 3'- or 5'-terminal positions, or only at terminal regions, such as positions on terminal nucleotides, or only at the last 2, 3, 4, 5, or 10 nucleotides of the chain. Modifications may occur in double-stranded regions, single-stranded regions, or both. Modifications may occur only in double-stranded regions of RNA, or only in single-stranded regions of RNA. For example, phosphorothioate modifications at non-linked O positions may occur only at one or both ends, only at terminal regions, such as positions on terminal nucleotides, or only at the last 2, 3, 4, 5, or 10 nucleotides of the chain, or may occur in double-stranded and single-stranded regions, particularly at the ends. The 5' end may be phosphorylated.

[0145] For example, to enhance stability, it may be possible to include specific bases in the overhang, or to include modified nucleotides or nucleotide surrogates in the single-stranded overhang, for example, in the 5' or 3' overhang, or both. For example, purine nucleotides may be included in the overhang. In some embodiments, all or some of the bases in the 3' or 5' overhang may be modified, for example, with the modifications described herein. Modifications may include, for example, the use of modifications at the 2' position of the ribose sugar with modifications known in the art, such as the use of deoxyribonucleotides, 2'-deoxy-2'-fluoro (2'-F), or 2'-0-methyl modified nucleotides in place of the ribosugar of the nucleobase, as well as modifications at the phosphate group, for example, phosphorothioate modifications. In some cases, the overhang need not be homologous to the target sequence.

[0146] In some embodiments, each residue in the sense strand and the antisense strand 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 can contain more than one modification. In some embodiments, each residue in the sense strand and the antisense strand is independently modified with 2'-O-methyl or 2'-fluoro.

[0147] In some embodiments, at least two different modifications are present on the sense and antisense strands, and these two modifications can be 2'-O-methyl or 2'-fluoro modifications, or others.

[0148] In some embodiments, the sense and antisense strands each comprise two differently modified nucleotides selected from 2'-O-methyl or 2'-fluoro.

[0149] In some embodiments, each residue in the sense and antisense strands is independently modified with 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, or 2'-ara-F nucleotides.

[0150] The types of modifications contained in the alternating motifs can be the same or different. For example, if A, B, C, and D each represent one type of modification on a nucleotide, the alternating pattern, i.e., the modifications on every other nucleotide, can be the same, but each of the sense or antisense strands can be selected from multiple modification possibilities within the alternating motif, such as "ABABAB...", "AC AC AC...", "BDBDBD...", or "CDCDCD...".

[0151] In some embodiments, the dsRNA agent comprises a modification pattern of the alternating motif on the sense strand that is shifted relative to the modification pattern of the alternating motif on the antisense strand. The shift can be such that the modified groups of the nucleotides of the sense strand correspond to different modified groups of the nucleotides of the antisense strand, or vice versa. For example, when the sense strand is paired with the antisense strand in a dsRNA duplex, the alternating motif of the sense strand can begin with "ABABAB" from the 5'-3' of the strand, and the alternating motif of the antisense strand can begin with "BABABA" from the 3'-5' of the strand within the duplex region. As another example, the alternating motif of the sense strand can begin with "AABBAABB" from the 5'-3' of the strand, and the alternating motif of the antisense strand can begin with "BBAABBAA" from the 3'-5' of the strand within the duplex region, with a complete or partial shift in the modification pattern between the sense strand and the antisense strand.

[0152] In some embodiments, the dsRNA agent has an initial shift in the pattern of alternating motifs of 2'-O-methyl and 2'-F modifications on the sense strand relative to the pattern of alternating motifs of 2'-O-methyl and 2'-F modifications on the antisense strand, i.e., the 2'-O-methyl modified nucleotides on the sense strand base pair with the 2'-F modified nucleotides on the antisense strand, and vice versa. One position on the sense strand may start with a 2'-F modification, and one position on the antisense strand may start with a 2'-O-methyl modification. By introducing one or more motifs of three identical modifications on three consecutive nucleotides into the sense strand and / or antisense strand, the original modification pattern present in the sense strand and / or antisense strand is interrupted. In this way, interrupting the modification pattern of the sense strand and / or antisense strand by introducing one or more motifs of one or more identical modifications on three consecutive nucleotides into the sense strand and / or antisense strand can enhance gene silencing activity against target genes.

[0153] dsRNA agent may comprise at least one phosphorothioate or methylphosphonate internucleotide bond.Phosphorothioate or methylphosphonate internucleotide bond modification may occur on any nucleotide of sense strand or antisense strand, or at any position of both strands.For example, internucleotide bond modification may occur on every nucleotide of sense strand and / or antisense strand; each internucleotide bond modification may occur alternately on sense strand or antisense strand; or sense strand or antisense strand comprises both internucleotide bond modifications in alternating pattern.The alternating pattern of internucleotide bond modification on sense strand may be the same or different from that of antisense strand, and the alternating pattern of internucleotide bond modification on sense strand may have a shift with respect to the alternating pattern of internucleotide bond modification on antisense strand.

[0154] In some embodiments, dsRNA comprises phosphorothioate or methylphosphonate internucleotide bond modification in overhang region.For example, the overhang region comprises two nucleotides with phosphorothioate or methylphosphonate internucleotide bond between the two nucleotides.Internucleotide bond modification can be performed to link the overhang nucleotide to the terminal pair of nucleotides in the double-stranded region.For example, at least 2, 3, 4, or all of the overhang nucleotides can be linked via phosphorothioate or methylphosphonate internucleotide bond, and optionally, there can be an additional phosphorothioate or methylphosphonate internucleotide bond that connects the overhang nucleotide and the pair of nucleotides next to the overhang nucleotide.For example, there can be at least two phosphorothioate internucleotide bonds between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the third is the pair of nucleotides next to the overhang nucleotide.In some cases, these terminal three nucleotides can be at the 3' end of the antisense strand.

[0155] In some embodiments, the sense strand of a dsRNA agent includes 1 to 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 positioned at any position in the oligonucleotide sequence, and the sense strand is paired with an antisense strand that includes any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand that includes either phosphorothioate or methylphosphonate or phosphonate linkages.

[0156] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either a phosphorothioate or methylphosphonate or phosphonate linkage.

[0157] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0158] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0159] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0160] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0161] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0162] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0163] In some embodiments, the antisense strand of a 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 positioned at any position in the oligonucleotide sequence, and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphonate internucleotide linkages, or an antisense strand comprising either phosphorothioate or methylphosphonate or phosphonate linkages.

[0164] In some embodiments, a dsRNA agent includes one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1 to 10 of the terminal positions of the sense strand and / or antisense strand. For example, at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides may be linked via phosphorothioate or methylphosphonate internucleotide linkages at one or both ends of the sense strand and / or antisense strand.

[0165] In some embodiments, a dsRNA agent comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1 to 10 of the internal region of the duplex of each of the sense and / or antisense strands. For example, at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides may be linked via phosphorothioate methylphosphonate internucleotide linkages at positions 8 to 16 of the duplex region, counting 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 to 10 of the terminal positions.

[0166] In some embodiments, a dsRNA agent includes 1-5 phosphorothioate or methylphosphonate internucleotide linkage modifications within positions 1-5 and 1-5 phosphorothioate or methylphosphonate internucleotide linkage modifications within positions 18-23 of the sense strand (counting from the 5'-end), and 1-5 phosphorothioate or methylphosphonate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5'-end).

[0167] In some embodiments, a dsRNA agent includes one phosphorothioate internucleotide linkage modification within positions 1-5 and one phosphorothioate or methylphosphonate internucleotide linkage modification within positions 18-23 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate or methylphosphonate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5'-end).

[0168] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications within positions 1-5 and one within positions 18-23 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5'-end).

[0169] In some embodiments, a dsRNA agent comprises two phosphorothioate internucleotide linkage modifications within positions 1-5 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 of the antisense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications within positions 18-23. In some embodiments, a dsRNA agent comprises two phosphorothioate internucleotide linkage modifications within positions 1-5 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 of the antisense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification within positions 18-23.

[0170] In some embodiments, a dsRNA agent includes one phosphorothioate internucleotide linkage modification within positions 1-5 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5'-end).

[0171] In some embodiments, a dsRNA agent includes one phosphorothioate internucleotide linkage modification within positions 1-5 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the antisense strand (counting from the 5'-end).

[0172] In some embodiments, the dsRNA agent includes one phosphorothioate internucleotide linkage modification within positions 1-5 (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 of the antisense strand, and one phosphorothioate internucleotide linkage modification within positions 18-23 (counting from the 5'-end).

[0173] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications within positions 1-5 (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 of the antisense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications within positions 18-23.

[0174] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications within positions 1-5 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the antisense strand (counting from the 5'-end).

[0175] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications within positions 1-5 and one phosphorothioate internucleotide linkage modification within positions 18-23 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5'-end).

[0176] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications within positions 1-5 and one within positions 18-23 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5'-end).

[0177] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 20-21 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at position 1 and one phosphorothioate internucleotide linkage modification at position 21 of the antisense strand (counting from the 5'-end).

[0178] In some embodiments, a dsRNA agent includes one phosphorothioate internucleotide linkage modification at position 1 and one phosphorothioate internucleotide linkage modification at position 21 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 20 and 21 of the antisense strand (counting from the 5'-end).

[0179] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 21 and 22 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at position 1 and one phosphorothioate internucleotide linkage modification at position 21 of the antisense strand (counting from the 5'-end).

[0180] In some embodiments, a dsRNA agent includes one phosphorothioate internucleotide linkage modification at position 1 and one phosphorothioate internucleotide linkage modification at position 21 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 21 and 22 of the antisense strand (counting from the 5'-end).

[0181] In some embodiments, a dsRNA agent includes two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 22 and 23 of the sense strand (counting from the 5'-end), and one phosphorothioate internucleotide linkage modification at position 1 and one phosphorothioate internucleotide linkage modification at position 21 of the antisense strand (counting from the 5'-end).

[0182] In some embodiments, a dsRNA agent includes one phosphorothioate internucleotide linkage modification at position 1 and one phosphorothioate internucleotide linkage modification at position 21 of the sense strand (counting from the 5'-end), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications at positions 23 and 23 of the antisense strand (counting from the 5'-end).

[0183] In some embodiments, the dsRNA agent contains mismatches with the target, mismatches within the duplex, or a combination thereof. Mismatches can occur in the overhang region or the duplex region. Base pairs can be ranked based on their tendency to promote dissociation or melting (for example, for the free energy of association or dissociation of a particular pair, the simplest approach is to examine the pair based on individual pairings, but subsequent adjacent or similar analysis can also be used). In some cases, in terms of promoting dissociation: A:U is preferred to G:C; G:U is preferred to G:C; and I:C is preferred to G:C (I=inosine). In some cases, mismatches, such as non-canonical or other than canonical pairings (described elsewhere herein), are preferred to standard (A:T, A:U, G:C) pairings; and pairings involving universal bases are preferred to standard pairings. In some embodiments, the dsRNA agent includes 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 may be selected from the group A:U, G:U, I:C, and a mismatch pair, e.g., a non-canonical or non-canonical pairing, or a pairing containing a universal base, to promote dissociation of the antisense strand at the 5'-end of the duplex.

[0184] In some embodiments, the nucleotide at position 1 in the double-stranded region from the 5'-end of the antisense strand is selected from the group consisting of A, dA, dU, U and dT.In some embodiments, at least one of the first 1, 2 or 3 base pairs in the double-stranded region from the 5'-end of the antisense strand is an AU base pair.For example, the first base pair in the double-stranded region from the 5'-end of the antisense strand is an AU base pair.

[0185] In some embodiments, a dsRNA agent is conjugated to one or more carbohydrate moieties, which can optimize one or more properties of the dsRNA agent. In some cases, the carbohydrate moiety is attached to a modified subunit of the dsRNA agent. For example, the ribose sugar of one or more ribonucleotide subunits of a dsRNA agent can be replaced with another moiety, such as a non-carbohydrate (e.g., cyclic) carrier to which a carbohydrate ligand is attached. A ribonucleotide subunit in which the ribose sugar of the subunit has been replaced in this manner is referred to herein as a ribose-replacement modified subunit (RRMS). The cyclic carrier can be a carbocyclic ring system (i.e., all ring atoms are carbon atoms) or a heterocyclic ring system (i.e., one or more ring atoms can be a heteroatom, such as nitrogen, oxygen, or sulfur). The cyclic carrier can be a monocyclic ring system or can contain two or more rings, such as fused rings. The cyclic carrier can be a fully saturated ring system or can contain one or more double bonds.

[0186] In some embodiments, the ligand is attached to the dsRNA via the carrier. In some cases, the carrier comprises (i) at least one "backbone attachment point" or two "backbone attachment points," and (ii) at least one "tethering attachment point." In some cases, a "backbone attachment point" refers to a functional group, e.g., a hydroxyl group, or generally a bond available and suitable for incorporation of the carrier into a backbone, e.g., a phosphate or modified phosphate, e.g., a sulfur-containing backbone, of a ribonucleic acid. In some embodiments, a "tethering attachment point" (TAP) refers to a ring atom of the cyclic carrier, e.g., a carbon atom or heteroatom (different from the atom providing the backbone attachment point), that connects to the selected moiety. The moiety can be, for example, a carbohydrate, e.g., a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, or polysaccharide. Optionally, the selected moiety is connected to the cyclic carrier by an intervening tether. Thus, the cyclic carrier may contain a functional group, e.g., an amino group, or may generally provide a bond suitable for incorporation or tethering of another chemical entity, e.g., a ligand, to the constituent ring.

[0187] In some embodiments, dsRNA agent is conjugated to ligand via carrier, and carrier can be cyclic or acyclic group; for example, cyclic group is selected from pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuryl and decalin; for example, acyclic group is selected from serinol skeleton or diethanolamine skeleton.Optionally, dsRNA agent can be conjugated to one or more ligands.Ligand can be attached to sense strand, antisense strand, or both strands at 3' end, 5' end, or both ends.For example, ligand can be attached to sense strand, particularly the 3' end of sense strand.

[0188] In some embodiments, dsRNA is modified to promote stability. Stabilization of synthetic siRNA, such as the dsRNA herein, against rapid nuclease degradation can be considered a prerequisite for in vivo and therapeutic use. This can be achieved using a variety of stabilization chemicals previously developed for other nucleic acid drugs, such as ribozymes and antisense molecules. These include chemical modifications to the natural 2'-OH group in the ribose sugar backbone, such as 2'-O-methyl (2'-OMe) and 2'-fluoro (2'-F) substitutions, which can be easily introduced into siRNA as 2'-modified nucleotides during RNA synthesis. In some cases, the introduction of chemical modifications into natural siRNA duplexes can negatively affect RNAi activity; therefore, the design of chemically modified siRNAs may require a stochastic screening approach to identify duplexes that retain strong gene silencing activity.

[0189] In some cases, inhibition of sense strand cleavage impairs endonuclease cleavage of target mRNA. In some cases, incorporation of 2'-0-Me ribose into the Ago2 cleavage site of the sense strand inhibits RNAi. In some cases, phosphorothioate modification may require sense strand cleavage for efficient RNAi.

[0190] In some cases, dsRNA agent comprises 2'-F modified residue, for example, at Ago2 cleavage site.Modification can be motif specific or not, for example, one modification comprises 2'-F modification on all pyrimidines of both sense strand and antisense strand, as long as pyrimidine residue exists, without preference.

[0191] In some cases, the dsRNA agent includes two 2'-F modified residues on the sense strand and / or antisense strand, for example, at the Ago2 cleavage site. In some cases, either all pyrimidines or all purines are modified for each particular strand.

[0192] In some cases, dsRNA agent comprises 2'-OMe modification or various combinations of 2'-F, 2'-OMe and phosphorothioate modification to stabilize siRNA.In some cases, the residue at the cleavage site of antisense strand is not modified with 2'-OMe to increase the stability of siRNA.

[0193] siRNA 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 an siRNA comprising a sense strand and an antisense strand. In some embodiments, the siRNA comprises a double-stranded agent described herein.

[0194] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, the oligonucleotide comprising 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, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or within the range defined by either of the aforementioned 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, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or in the range defined by either of the aforementioned two numbers.

[0195] 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, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous 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 antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 11085.

[0196] 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, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and antisense strand comprises a nucleoside sequence comprising about 14-30 contiguous 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 antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 11086.

[0197] 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, and 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.

[0198] 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 stretch of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 stretch of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides.

[0199] 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 stretch of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 stretch of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides.

[0200] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a 19-mer in human ANGPTL7 mRNA.In some embodiments, the siRNA binds to a 12-mer, a 13-mer, a 14-mer, a 15-mer, a 16-mer, a 17-mer, a 18-mer, a 19-mer, a 20-mer, a 21-mer, a 22-mer, a 23-mer, a 24-mer, or a 25-mer in human ANGPTL7 mRNA.

[0201] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a 17-mer in non-human primate ANGPTL7 mRNA.In some embodiments, the siRNA binds to a 12-mer, a 13-mer, a 14-mer, a 15-mer, a 16-mer, a 17-mer, a 18-mer, a 19-mer, a 20-mer, a 21-mer, a 22-mer, a 23-mer, a 24-mer, or a 25-mer in non-human primate ANGPTL7 mRNA.

[0202] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a 19-mer in human ANGPTL7 mRNA or a combination thereof. In some embodiments, the siRNA binds to a 12-mer, a 13-mer, a 14-mer, a 15-mer, a 16-mer, a 17-mer, and a 18-mer, a 19-mer, a 20-mer, a 21-mer, a 22-mer, a 23-mer, a 24-mer, or a 25-mer in human ANGPTL7 mRNA.

[0203] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to human ANGPTL7 mRNA and 20 or fewer human off-targets with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 10 or fewer human off-targets with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 30 or fewer human off-targets with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 40 or fewer human off-targets with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 50 or fewer human off-targets with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 10 or fewer human off-targets with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 20 or fewer human off-targets with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 30 or fewer human off-targets with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 40 or fewer human off-targets with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and 50 or fewer human off-targets with no more than three mismatches in the antisense strand.

[0204] In some embodiments, the composition comprises an oligonucleotide that inhibits ANGPTL7 expression, 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 harbor a SNP, and the minor allele frequency (MAF) is 1% or greater (positions 2-18). In some embodiments, the MAF is about 2% or greater, about 3% or greater, about 4% or greater, about 5% or greater, about 6% or greater, about 7% or greater, about 8% or greater, about 9% or greater, about 10% or greater, about 11% or greater, about 12% or greater, about 13% or greater, about 14% or greater, about 15% or greater, about 16% or greater, about 17% or greater, about 18% or greater, about 19% or greater, or about 20% or greater.

[0205] 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 carry a SNP, and the minor allele frequency (MAF) is 1% or more (positions 2-18). In some embodiments, the sense strand and the antisense strand each comprise a seed region that is not identical to the seed region of a human miRNA. In some embodiments, the sense strand comprises a seed region that is not identical to the seed region of a human miRNA. In some embodiments, the antisense strand comprises a seed region that is not identical to the seed region of a human miRNA.

[0206] 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. 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 at least 75% identical to any one of SEQ ID NOs: 1-4412, at least 80% identical to any one of SEQ ID NOs: 1-4412, at least 85% identical to any one of SEQ ID NOs: 1-4412, at least 90% identical to any one of SEQ ID NOs: 1-4412, or at least 95% identical to any one of SEQ ID NOs: 1-4412. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 1-4412, or a nucleic acid sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 1-4412, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 1-4412. 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.

[0207] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset A, or an siRNA thereof having a substitution, addition, or deletion of one or two nucleosides. 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 an siRNA thereof having a substitution, addition, or deletion of one or two nucleosides. 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 an siRNA thereof having a substitution, addition, or deletion of one or two nucleosides. 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 an siRNA thereof having a substitution, addition, or deletion of one or two nucleosides. 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 an siRNA thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset E.

[0208] In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to any one of SEQ ID NOs: 1-2206, at least 80% identical to any one of SEQ ID NOs: 1-2206, at least 85% identical to any one of SEQ ID NOs: 1-2206, at least 90% identical to any one of SEQ ID NOs: 1-2206, or at least 95% identical to any one of SEQ ID NOs: 1-2206. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 1-2206, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 1-2206, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 1-2206. In some embodiments, the sense strand comprises an overhang described herein. In some embodiments, the sense strand comprises one or more modifications or modification patterns described herein.

[0209] In some embodiments, the sense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590 639, 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 is selected from the group consisting of SEQ ID NOs: 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, 153 7, 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 one, two, three, or four nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1448, 1449, 1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1540, 1541, 1542, 1543 537, 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 one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480 In some embodiments, the sense strand comprises or consists of the sequence of any one of: 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 sense strand comprises an overhang as described herein.

[0210] In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs in siRNA subset A, or a sense strand thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs in siRNA subset A. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs in siRNA subset B, or a sense strand thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs in siRNA subset B. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs in siRNA subset C, or a sense strand thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs in 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 a substitution, addition, or deletion of one or two nucleosides. 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 a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset E.

[0211] In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 11089, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 11089.

[0212] In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to any one of SEQ ID NOs: 2207-4412, at least 80% identical to any one of SEQ ID NOs: 2207-4412, at least 85% identical to any one of SEQ ID NOs: 2207-4412, at least 90% identical to any one of SEQ ID NOs: 2207-4412, or at least 95% identical to any one of SEQ ID NOs: 2207-4412. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 2207-4412, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 2207-4412, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 2207-4412. 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.

[0213] In some embodiments, the antisense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 3643, 3644, 3645, 3646, 3647, 3648, 3649, 3650, 3651, 3652, 3653, 3654, 3655, 3656, 3657, 3658, 3659, 3660, 3661, 3662, 3663, 3664, 3665, 3666, 3667, 3668, 3669, 3670, 3671, 3672, 3673, 3674, 3675, 3676, 3677, 3678, 3679, 3680, 3681, 3682, 3683, 3684, 3685, 3686, 3687, 3688, 3689, 36 644, 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 is selected from the group consisting of SEQ ID NOs: 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, or consisting of any one of the sequences 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 a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.In some embodiments, the antisense strand sequence is selected from the group consisting of SEQ ID NOs: 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, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 3405, 3416, 3417, 3418, 3419, 3420, 3421, 3422, 3423, 3424, 3425, 3426, 3427, 3428, 3429, 3430, 3431, 3432, 3433, 3434, 3435, 3436, 3437, 3438, 3440, 3441, 3442, 3443, 3444, 3445, 3446, 3447, 3448, 3449, 3451, 3452, 3453, 3454, 3455, 3456, 3457, 3458, 3459, 3460, 3461, 3462, 3463, 3464, 3465, 3466, 3467, 3468, 3469, 34 In some embodiments, the antisense strand comprises or consists of any one of the sequences of SEQ ID NO: 07, 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.

[0214] In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset A, or the antisense strand thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset A. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset B, or the antisense strand thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset B. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset C, or the antisense strand thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset C. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset D, or the antisense strand thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset D. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs in siRNA subset E, or the antisense strand thereof with one or two 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.

[0215] 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 one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 11090.

[0216] siRNA modification pattern The oligonucleotides described herein (e.g., siRNAs, antisense oligonucleotides, sense strands, antisense strands, siRNA agents, or dsRNA agents) 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.

[0217] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises the following modification pattern 1S:5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), where "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 following modification pattern 2S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11382), where "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 following modification pattern: 3S:5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11383), where "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 following modification pattern: 4S:5'-NfsnsNfnNfnNfNfNfNfnNfnNfnNfnNfnNfnNfsnsnN-Lipid-3' (SEQ ID NO: 11384), where "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 following modification pattern 5S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-Lipid-3' (SEQ ID NO: 11385), where "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.

[0218] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises the following modification pattern 1AS:5'-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3' (SEQ ID NO: 11386), where "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 the following modification pattern 2AS:5'-nsNfsnnnNfnNfNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), where "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 the following modification pattern 3AS:5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), where "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 the following modification pattern 4AS:5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11389), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[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 sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, or 4AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, or 5S. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1.

[0220] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and 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.

[0221] In some embodiments, the nucleic acid sequence comprises or consists of a sequence at least 75% identical to any one of SEQ ID NOs: 11903-11332, at least 80% identical to any one of SEQ ID NOs: 11903-11332, at least 85% identical to any one of SEQ ID NOs: 11903-11332, at least 90% identical to any one of SEQ ID NOs: 11903-11332, or at least 95% identical to any one of SEQ ID NOs: 11903-11332. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 11903-11332, or a sequence thereof with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 11903-11332, or a sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 11903-11332. 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 the nucleic acid sequences described herein.

[0222] In some embodiments, the nucleic acid sequence comprises or consists of a sequence at least 75% identical to any one of SEQ ID NOs: 11333-11376, at least 80% identical to any one of SEQ ID NOs: 11333-11376, at least 85% identical to any one of SEQ ID NOs: 11333-11376, at least 90% identical to any one of SEQ ID NOs: 11333-11376, or at least 95% identical to any one of SEQ ID NOs: 11333-11376. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 11333-11376, or a sequence thereof with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists of any one of SEQ ID NOs: 11333-11376, or a sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the nucleic acid sequence comprises or consists 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.

[0223] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-13, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any 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 an siRNA of any of Tables 5-13.

[0224] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, or siRNAs thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, whose relative ANGPTL expression in the table is less than 1, or siRNAs thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, whose relative ANGPTL expression in the table is less than 1. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, whose relative ANGPTL expression in the table is less than that of the negative control in the table, or siRNAs thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, where the relative ANGPTL expression of the siRNA in the table is less than that of the negative control in the table. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, where the relative ANGPTL expression in the table is less than 0.5, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, where the relative ANGPTL expression in the table is less than 0.5.In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, or an siRNA having one or two nucleoside substitutions, additions, or deletions, in which the relative ANGPTL expression in the table is less than 0.25. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any of Tables 5-10, in which 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 one of the siRNAs disclosed in any of Tables 5-10. In some embodiments, the oligonucleotide comprises or consists of an siRNA having the nucleic acid sequence of any one of the siRNAs disclosed in any of Tables 5-10, but with one or more additional or different modifications, or with a different modification pattern. 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.

[0225] 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 at least 75% identical to any one of SEQ ID NOs: 11093-11212, at least 80% identical to any one of SEQ ID NOs: 11093-11212, at least 85% identical to any one of SEQ ID NOs: 11093-11212, at least 90% identical to any one of SEQ ID NOs: 11093-11212, or at least 95% identical to any one of SEQ ID NOs: 11093-11212. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 11093-11212, or a sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 11093-11212, or a sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 11093-11212. In some embodiments, the sense strand sequence is an unmodified version of a sense strand sequence described herein. In some embodiments, the sense strand sequence has more or different sequence modifications than the nucleic acid sequences described herein.

[0226] In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to any one of SEQ ID NOs: 11333-11354, at least 80% identical to any one of SEQ ID NOs: 11333-11354, at least 85% identical to any one of SEQ ID NOs: 11333-11354, at least 90% identical to any one of SEQ ID NOs: 11333-11354, or at least 95% identical to any one of SEQ ID NOs: 11333-11354. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 11333-11354, or a sequence thereof with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 11333-11354, or a sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists 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.

[0227] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any of Tables 5-13, or of an siRNA having one or two 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 any 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 an siRNA in any of Tables 5-13.

[0228] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any of Tables 5-10, or of the sense strand sequence of an siRNA having one or two 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 any 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 of Tables 5-10, or of the siRNA having one or two nucleoside substitutions, additions, or deletions in the tables, for which the relative ANGPTL expression in the tables is less than 1. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any of Tables 5-10, or of the siRNA having one or two nucleoside substitutions, additions, or deletions in the tables, for which the relative ANGPTL expression in the tables is less than 1. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any of Tables 5-10, or of an siRNA having one or two nucleoside substitutions, additions, or deletions, for which the relative ANGPTL expression of the siRNA in the table is less than that of the negative control in the table. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any of Tables 5-10, or of an siRNA having one or two nucleoside substitutions, additions, or deletions, for which the relative ANGPTL expression of the siRNA in the table is less than that of the negative control in the table. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any of Tables 5-10, or of an siRNA having one or two nucleoside substitutions, additions, or deletions, for which the relative ANGPTL expression of the siRNA in the table is less 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 of Tables 5-10 for which the relative ANGPTL expression in the table is less 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 of Tables 5-10 whose relative ANGPTL expression in the table is less than 0.25, or of such an siRNA having one or two 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 any of Tables 5-10 whose 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 of Tables 5-10. 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 any of Tables 5-10 but with one or more additional or different modifications or with a different modification pattern. In some embodiments, the sense strand sequences lack sequence modifications or have different or additional sequence modifications, but are otherwise similar to the sequences described herein.

[0229] 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 of an siRNA having one or two 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, or of an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, for which the relative ANGPTL expression in the table is less than 1. 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 of an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, for which the relative ANGPTL expression in the table is less than 1. 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 of an siRNA having one or two nucleoside substitutions, additions, or deletions, for which the relative ANGPTL expression of the siRNA in the table is less than that of the negative control siRNA in the table (e.g., less than a negative expression level of 0.67). 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 of an siRNA having one or two nucleoside substitutions, additions, or deletions, for which the relative ANGPTL expression of the siRNA in the table is less than that of the negative control siRNA in the table (e.g., less than a negative expression level of 0.67). 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 of an siRNA having one or two nucleoside substitutions, additions, or deletions, for which the relative ANGPTL expression of the siRNA in the table is less 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 that has a relative ANGPTL expression in the table of less 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 whose relative ANGPTL expression in the table is less than 0.25, or of any siRNA having one or two 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 5 whose 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 with one or more additional or different modifications or with a different modification pattern. 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.

[0230] In some embodiments, the sense strand sequence is incorporated into an siRNA that downregulates ANGPTL7. In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 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, 11131, 11132, 11133, 11134, 11135, 11136, 11137, 11138, 11139, 11140, 11141, 11142, 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, 111 1127, 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, 11183, 11184, 11185, 11186, 11187, 11188, 11189, 11191 , 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions.In some embodiments, the sense strand is selected from the group consisting of SEQ ID NOs: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 111 25, 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, 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, 11185, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212.

[0231] 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 of an siRNA thereof having one or two 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 6. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or of an siRNA thereof having one or two nucleoside substitutions, additions, or deletions, in Table 6, for which the relative ANGPTL expression is less than 1. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or of an siRNA thereof having one or two nucleoside substitutions, additions, or deletions, in Table 6, for which the relative ANGPTL expression is less than 1. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression of the siRNA in Table 6 is below that of the negative control siRNA in the table above (e.g., below a relative expression level of 1.06). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression of the siRNA in Table 6 is below that of the negative control siRNA in the table above (e.g., below a relative expression level of 1.06). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression in Table 6 is less 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 above that have a relative ANGPTL expression of less 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 the above table, which has a relative ANGPTL expression of less than 0.25 in Table 6, or an siRNA thereof having one or two 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 the above table, which has a relative ANGPTL expression of less than 0.25 in the table. 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 with one or more additional or different modifications, or with a different modification pattern. 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.

[0232] 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 thereof having one or two 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 7. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions, in Table 7, which has a relative ANGPTL expression at 1 nM of less than 1. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, which has a relative ANGPTL expression at 1 nM of less than 1 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 the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression at 1 nM of the siRNA in Table 7 is below that of the negative control siRNA in the table above (e.g., below a relative expression level of 0.66). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression at 1 nM of the siRNA in Table 7 is below that of the negative control siRNA in the table above (e.g., below a relative expression level of 0.66). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression at 1 nM in Table 7 is less 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 7 above (e.g., siRNAs having the sequence of ETD00245, ETD00247, or ETD00252) that have a relative ANGPTL expression at 1 nM of less 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 the table above that have a relative ANGPTL expression at 10 nM in Table 7 of less than 10, or an siRNA thereof having one or two 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 the table above that have a relative ANGPTL expression at 10 nM in Table 7 of 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 with one or more additional or different modifications or with a different modification pattern. In some embodiments, the sense strand sequence lacks sequence modifications or has different or additional sequence modifications, but is otherwise similar to a sequence described herein.

[0233] 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 thereof having one or two 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 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 thereof having one or two 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 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 thereof having one or two 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 10. In some embodiments, the sense strand sequences lack sequence modifications or have different or additional sequence modifications, but are otherwise similar to the sequences described herein.

[0234] 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 thereof having one or two 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. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions, in which the percent of siRNA remaining in Table 11 at 4 hours is at least 50%. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, in which the percent of siRNA remaining in Table 11 at 4 hours is at least 50%. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, where the percent of siRNA remaining in Table 11 at 4 hours is at least 75%. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, where the percent of siRNA remaining in Table 11 at 4 hours is at least 75%. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, where the percent of siRNA remaining in Table 11 at 24 hours is at least 50%. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, where the percent of siRNA remaining in Table 11 at 24 hours is at least 50%.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 with one or two nucleoside substitutions, additions, or deletions, that have at least 75% of the siRNA remaining at 24 hours 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, that have at least 75% of the siRNA remaining at 24 hours in Table 11. 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 that has the sense strand sequence of any one of the siRNAs disclosed in Table 11, but with one or more additional or different modifications, or with a different modification pattern. In some embodiments, the sense strand sequence lacks sequence modifications or has different or additional sequence modifications, but is otherwise similar to a sequence described herein.

[0235] 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 thereof having one or two 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 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 thereof having one or two 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 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.

[0236] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00269 or an siRNA thereof having one or two 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 one or two 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 one or two 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 one or two 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 one or two 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 one or two 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 thereof having one or two 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 thereof having one or two 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 thereof having one or two 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 SEQ ID NO: 11377, or the sequence of an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of SEQ ID NO: 11377. In some embodiments, the sense strand sequence comprises or consists of SEQ ID NO: 11378, or the sequence of an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists 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.

[0237] 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 at least 75% identical to any one of SEQ ID NOs: 11093-11212, at least 80% identical to any one of SEQ ID NOs: 11093-11212, at least 85% identical to any one of SEQ ID NOs: 11093-11212, at least 90% identical to any one of SEQ ID NOs: 11093-11212, or at least 95% identical to any one of SEQ ID NOs: 11093-11212. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 11093-11212, or a sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 11093-11212, or a sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 11093-11212. In some embodiments, the antisense strand sequence is an unmodified version of an antisense strand sequence described herein. In some embodiments, the antisense strand sequence has more sequence modifications than, or different sequence modifications from, the antisense strand sequences described herein.

[0238] In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to any one of SEQ ID NOs: 11333-11354, at least 80% identical to any one of SEQ ID NOs: 11333-11354, at least 85% identical to any one of SEQ ID NOs: 11333-11354, at least 90% identical to any one of SEQ ID NOs: 11333-11354, or at least 95% identical to any one of SEQ ID NOs: 11333-11354. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 11333-11354, or a sequence thereof with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 11333-11354, or a sequence thereof with one or two 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.

[0239] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of Tables 5-13, or the antisense strand sequence of that siRNA having one or two 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 of Tables 5-13. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 an siRNA in any of Tables 5-13.

[0240] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of Tables 5-10, or the antisense strand sequence of that siRNA having one or two 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 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 of Tables 5-10, or the antisense strand sequence of that siRNA having one or two nucleoside substitutions, additions, or deletions, with a relative ANGPTL expression of less than 1. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Tables 5-10, with a relative ANGPTL expression of less than 1. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of the above tables, or of an siRNA having one or two nucleoside substitutions, additions, or deletions, where the relative ANGPTL expression of the siRNA in Tables 5-10 is below that of the negative control in the table. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of the above tables, or of an siRNA having one or two nucleoside substitutions, additions, or deletions, where the relative ANGPTL expression of the siRNA in Tables 5-10 is below that of the negative control in the table. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of the above tables, or of an siRNA having one or two nucleoside substitutions, additions, or deletions, where the relative ANGPTL expression in Tables 5-10 is less than 0.5. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of the above tables, which has a relative ANGPTL expression in Tables 5-10 of less than 0.5.In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of the above Tables, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions, wherein the relative ANGPTL expression in Tables 5-10 is less than 0.25. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any of the above Tables, wherein the relative ANGPTL expression in Tables 5-10 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 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 of Tables 5-10 but with one or more additional or different modifications or with a different modification pattern. 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.

[0241] 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 thereof having one or two 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. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the tables above, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 5 is less than 1. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the tables above, whose relative ANGPTL expression in Table 5 is less than 1. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, or an siRNA having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 5 is below that of the negative control siRNA in the above table (e.g., below a relative expression level of 0.67). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, or an siRNA having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 5 is below that of the negative control siRNA in the above table (e.g., below a relative expression level of 0.67). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, or an siRNA having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 5 is less than 0.5. 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 above, which have a relative ANGPTL expression in Table 5 of less than 0.5.In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, which has a relative ANGPTL expression in Table 5 of less than 0.25, or an siRNA thereof having one or two 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 the above table, which has a relative ANGPTL expression in Table 5 of 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 with one or more additional or different modifications, or with a different modification pattern. In some embodiments, the antisense strand sequence lacks sequence modifications or has different or additional sequence modifications, but is otherwise similar to a sequence described herein.

[0242] In some embodiments, the antisense strand sequence is incorporated into an siRNA that downregulates ANGPTL7. In some embodiments, the antisense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11300, 11301, 11302, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11310, 11311, 11312, 11313, 11314, 11315, 11316, 11317, 11318, 11319, 11400, 11401, 11402, 11403, 11404, 11405, 11406, 11407, 246, 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, 1 1280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 11305, 11306, 11307, 11308, 11309, The siRNA comprises or consists of the antisense strand sequence of any one of 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions.In some embodiments, the antisense strand sequence is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 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 44, 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, 1127 6, 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, 1130 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332.

[0243] 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 thereof having one or two 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. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the tables above, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 6 is less than 1. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the tables above, whose relative ANGPTL expression in Table 6 is less than 1. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, or an siRNA having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 6 is below that of the negative control siRNA in the above table (e.g., below a relative expression level of 1.06). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, or an siRNA having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 6 is below that of the negative control siRNA in the above table (e.g., below a relative expression level of 1.06). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, or an siRNA having one or two nucleoside substitutions, additions, or deletions, whose relative ANGPTL expression in Table 6 is less than 0.5. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 above, which have a relative ANGPTL expression in Table 6 of less than 0.5.In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the above table, which has a relative ANGPTL expression in Table 6 of less than 0.25, or an siRNA thereof having one or two 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 the above table, which has a relative ANGPTL expression in Table 6 of 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 with one or more additional or different modifications, or with a different modification pattern. 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.

[0244] 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 thereof having one or two 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 7. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above that have a relative ANGPTL expression at 1 nM of less than 1 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 the table above that have a relative ANGPTL expression at 1 nM of less than 1 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 the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression at 1 nM of the siRNA in Table 7 is lower than that of the negative control siRNA in the table above (e.g., below a relative expression level of 0.66). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression at 1 nM of the siRNA in Table 7 is lower than that of the negative control siRNA in the table above (e.g., below a relative expression level of 0.66). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions thereof, where the relative ANGPTL expression at 1 nM in Table 7 is less than 0.5.In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above (e.g., siRNAs having the sequence of ETD00245, ETD00247, or ETD00252) that have a relative ANGPTL expression of less than 0.5 at 1 nM 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 the table above that have a relative ANGPTL expression of less than 10 at 10 nM in Table 7, or an siRNA thereof that has one or two 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 the table above that have a relative ANGPTL expression of less than 1 at 10 nM in Table 7. 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 with one or more additional or different modifications or a different modification pattern. 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.

[0245] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 8, or an siRNA thereof having one or two 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 8. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 9, or an siRNA thereof having one or two 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 9. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 10, or an siRNA thereof having one or two 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 10. 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.

[0246] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 11, or an siRNA thereof having one or two 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 11. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA having one or two nucleoside substitutions, additions, or deletions, in which the percent of siRNA remaining in Table 11 at 4 hours is at least 50%. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, in which the percent of siRNA remaining in Table 11 at 4 hours is at least 50%. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, wherein the percent of siRNA remaining in Table 11 at 4 hours is at least 75%. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, wherein the percent of siRNA remaining in Table 11 at 4 hours is at least 75%. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, wherein the percent of siRNA remaining in Table 11 at 24 hours is at least 50%. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in the table above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, wherein the percent of siRNA remaining in Table 11 at 24 hours is at least 50%.In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 11 above, or an siRNA with one or two nucleoside substitutions, additions, or deletions, that have a percent of siRNA remaining at 24 hours of at least 75%. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 11 above, that have a percent of siRNA remaining at 24 hours of at least 75%. 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 11. In some embodiments, the antisense strand sequence comprises or consists of an siRNA that has the antisense strand sequence of any one of the siRNAs disclosed in Table 11, but with one or more additional or different modifications, or with a different modification pattern. In some embodiments, the antisense strand sequence lacks sequence modifications or has different or additional sequence modifications, but is otherwise similar to a sequence described herein.

[0247] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 12, or an siRNA thereof having one or two 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 12. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 13, or an siRNA thereof having one or two 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 13. 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.

[0248] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00269 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00269. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00270 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00270. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00353 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00353. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00356 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00356. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00358 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00358. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00370 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00370.In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00377 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00377. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00378 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00378. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00382 or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00382. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETD00752, or an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of siRNA ETDETD00752. In some embodiments, the antisense strand sequence comprises or consists of SEQ ID NO: 11379, or the sequence of an siRNA thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 11379. 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.

[0249] Antisense Compounds In one aspect, provided herein are antisense compounds or oligonucleotides for regulating the activity and / or expression of a target nucleic acid, for example, ANGPTL7. In some embodiments, the antisense compounds inhibit the expression of ANGPTL7. In some cases, the antisense compounds comprise a sequence 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 compounds comprise a sequence at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0250] In some embodiments, antisense compounds are capable of specifically hybridizing to a target nucleic acid, where binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid, e.g., causing a loss of 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, including physiological conditions in the case of in vivo assays or therapeutic treatments and conditions under which the assay is performed in the case of in vitro assays.

[0251] In some embodiments, antisense compounds comprise variants, where different bases are present at one or more of the nucleotide positions in the compound.For example, if the first nucleotide is adenine, variants can be generated that contain thymidine, guanosine, cytidine, or other natural or unnatural nucleotides at this position.This can be done at any position of antisense compounds.Then, these compounds are tested using the methods described herein to determine their ability to inhibit the expression of target nucleic acid.

[0252] 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%.

[0253] In some embodiments, an antisense compound, whether DNA, RNA, chimeric, or substituted, is specifically hybridizable if there is a sufficient degree of complementarity to avoid nonspecific binding of the antisense compound to non-target sequences, whether DNA, RNA, chimeric, or substituted, such that binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA, e.g., causing loss of utility, and under conditions where specific binding is desired, i.e., physiological conditions in the case of in vivo assays or therapeutic treatments, and physiological conditions in the case of in vitro assays under the conditions under which the assay is performed.

[0254] In some embodiments, targeting ANGPTL7 includes, without limitation, antisense sequences, such as one or more of the sequences set forth as 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 extended using, for example, but not limited to, PCR, hybridization, etc., to modulate ANGPTL7 expression or function. In some embodiments, expression or function is downregulated compared to a control oligonucleotide that does not specifically hybridize to ANGPTL7.

[0255] In some embodiments, the antisense oligonucleotide comprises one or more modified nucleotides, shorter or longer fragments, modified linkages, etc. Examples of modified linkages or internucleotide linkages include phosphorothioates, phosphorodithioates, etc. In some embodiments, the nucleotide comprises a phosphorus derivative. The phosphorus derivative (or modified phosphate group) that can be attached to the sugar or sugar analog moiety in the modified oligonucleotide can be a monophosphate, diphosphate, triphosphate, alkylphosphate, alkanephosphate, phosphorothioate, etc.

[0256] In some embodiments, oligomeric antisense compounds, particularly oligonucleotides, bind to target nucleic acid molecules and regulate the expression and / or function of the molecules coded by target genes.The function of DNA that is interfered with includes, for example, replication and transcription.The function of RNA that is interfered with includes, for example, RNA translocation to protein translation site, translation of protein from RNA, splicing of RNA to produce one or more mRNA species, and all biological functions that can be involved in or can be promoted by RNA, such as catalytic activity.The above-mentioned function can be upregulated or inhibited according to the function that is desired.

[0257] Antisense compounds include antisense oligomeric compounds, antisense oligonucleotides, external guide sequence (EGS) oligonucleotides, alternative splicers, 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 circular oligomeric compounds.

[0258] Targeting an antisense compound to a specific nucleic acid molecule can be a multistep process. The process begins with identifying the target nucleic acid, the function of which is to be modulated. The target nucleic acid can be, for example, a cellular gene (mRNA transcribed from the gene), the expression of which is associated with a particular disorder or disease state. In some embodiments, the target nucleic acid encodes angiopoietin-like 7 (ANGPTL7).

[0259] The targeting process may include determining at least one target region, segment, or site within the target nucleic acid for antisense interaction to occur, resulting in a desired effect, such as regulating expression. In some embodiments, the term "region" is defined as a portion of the target nucleic acid that has at least one identifiable structure, function, or characteristic. Within the region of the target nucleic acid, there is a segment. A "segment" can be defined as a smaller region or subportion within the target nucleic acid. A "site" can be defined as a position within the target nucleic acid.

[0260] In some embodiments, the antisense oligonucleotides bind to the natural antisense sequence of angiopoietin-like 7 (ANGPTL7) and modulate the expression and / or function of ANGPTL7 (SEQ ID NO: 11085).

[0261] In some embodiments, the antisense oligonucleotides bind to one or more segments of angiopoietin-like 7 (ANGPTL7) polynucleotides and modulate the expression and / or function of ANGPTL7. In some embodiments, the segments comprise at least 5 consecutive nucleotides of an ANGPTL7 sense or antisense polynucleotide.

[0262] Because the translation initiation codon is typically 5'-AUG (5'-ATG in the corresponding DNA molecule in a transcribed mRNA molecule), the translation initiation codon may also be referred to as the "AUG codon," "start codon," or "AUG start codon." A small number of genes have translation initiation codons with the RNA sequences 5'-GUG, 5'-UUG, or 5'-CUG; 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" can encompass many codon sequences, even though the initiation amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). Eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue or under a particular set of conditions. In some embodiments, "start codon" and "translation initiation codon" refer to the codon used in vivo to initiate translation of mRNA transcribed from a gene encoding angiopoietin-like 7 (ANGPTL7), regardless of the sequence of the codon. In some cases, the translation termination codon (or "stop codon") of the gene can have one of three sequences: 5'-UAA, 5'-UAG, and 5'-UGA (the corresponding DNA sequences are 5'-TAA, 5'-TAG, and 5'-TGA, respectively).

[0263] In some embodiments, the terms "start codon region" and "translation initiation codon region" refer to a portion of such an mRNA or gene encompassing about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3') from the translation initiation codon. In some embodiments, the terms "stop codon region" and "translation termination codon region" refer to a portion of such an mRNA or gene encompassing about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3') from the translation termination codon. Consequently, "start codon regions" (or "translation initiation codon regions") and "stop codon regions" (or "translation termination codon regions") are all regions that can be effectively targeted by the antisense compounds described herein.

[0264] The open reading frame (ORF) or "coding region," which refers to the region between the translation start codon and the translation stop codon, is also a region that can be effectively targeted. In some embodiments, the target region is an intragenic region encompassing the translation start codon or translation stop codon of the open reading frame (ORF) of a gene.

[0265] Another target region includes the 5' untranslated region (5'-UTR), which refers to the portion of the mRNA 5' from the translation start codon, and thus includes the nucleotides between the 5' cap site of the mRNA and the translation start codon (or the corresponding nucleotides on the gene). Yet another target region includes the 3' untranslated region (3'-UTR), which refers to the portion of the mRNA 3' from the translation stop codon, and thus includes the nucleotides between the translation stop codon and the 3' end of the mRNA (or the corresponding nucleotides on the gene). The 5' cap site of an mRNA contains an N7-methylated guanosine residue linked to the 5'-most residue of the mRNA via a 5-5' triphosphate bond. The 5' cap region of an mRNA is considered to include the 5' cap structure itself as well as the first 50 nucleotides adjacent to the cap site. Another target region is the 5' cap region.

[0266] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions known as "introns," which are excised from the transcript before translation. The remaining (hence translated) regions, known as "exons," are spliced ​​together to form a continuous mRNA sequence. In some embodiments, targeting splice sites, i.e., intron-exon or exon-intron junctions, is particularly useful in situations where aberrant splicing is associated with disease or where overproduction of a particular splice product is associated with disease. Aberrant fusion junctions due to rearrangements or deletions are another example of a target site. mRNA transcripts generated by the process of splicing two (or more) mRNAs from different gene sources are known as "fusion transcripts." Introns can be effectively targeted, for example, using antisense compounds targeted to DNA or pre-mRNA.

[0267] In some embodiments, antisense oligonucleotides bind to coding and / or non-coding regions of a target polynucleotide and modulate the expression and / or function of the target molecule.

[0268] In some embodiments, antisense oligonucleotides bind to sense polynucleotides and modulate the expression and / or function of target molecules.

[0269] Alternative RNA transcripts may be produced from the same genomic region of DNA. These alternative transcripts are generally known as "variants." More specifically, a "pre-mRNA variant" is a transcript produced from the same genomic DNA that differs from other transcripts produced from the same genomic DNA at either their start or stop positions and contains intron and exon sequences.

[0270] When one or more exon or intron regions, or portions thereof, are excised during splicing, the pre-mRNA variants produce smaller "mRNA variants." Consequently, mRNA variants are processed pre-mRNA variants, and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as "alternative splice variants." If splicing of the pre-mRNA variant does not occur, the pre-mRNA variant is identical to the mRNA variant.

[0271] Variants can be generated through the use of alternative signals to start or stop transcription. Pre-mRNAs and mRNAs can have more than one start or stop codon. Variants resulting from a pre-mRNA or mRNA that use alternative start codons are known as "alternative start variants" of that pre-mRNA or mRNA. These transcripts that use alternative stop codons are known as "alternative stop variants" of that pre-mRNA or mRNA. One particular type of alternative stop variant is a "polyA variant," in which multiple transcripts are generated resulting from alternative selection of one of the "polyA stop signals" by the transcription machinery, thereby producing transcripts that terminate at a unique polyA site. In some embodiments, the types of variants described herein are also embodiments of target nucleic acids.

[0272] In some embodiments, the location on a target nucleic acid to which an antisense compound hybridizes is defined as at least a 5-nucleotide long portion of the target region to which the active antisense compound is targeted.

[0273] While the specific sequences of certain exemplary target segments are set forth herein, those of skill in the art will recognize that these serve to illustrate and describe particular embodiments. Additional target segments are readily identifiable by those of skill in the art in light of the present disclosure.

[0274] Target segments between 5 and 100 nucleotides in length, comprising a stretch of at least 5 contiguous nucleotides selected from within the exemplary target segments, are also considered suitable for targeting.

[0275] In some embodiments, a target segment can comprise a DNA or RNA sequence comprising at least 5 contiguous nucleotides from the 5'-end of one of the target segments (the remaining nucleotides are a contiguous stretch of the same DNA or RNA beginning just upstream of the end of the target segment and continuing until the DNA or RNA comprises about 5 to about 100 nucleotides). In some cases, a target segment is represented by a DNA or RNA sequence comprising at least 5 contiguous nucleotides from the 3'-end of one of the target segments (the remaining nucleotides are a contiguous stretch of the same DNA or RNA beginning just downstream of the 3'-end of the target segment and continuing until the DNA or RNA comprises about 5 to about 100 nucleotides).

[0276] Once one or more target regions, segments, or sites are identified, antisense compounds are selected that are sufficiently complementary to the target, i.e., that they hybridize sufficiently favorably and with sufficient specificity, to produce the desired effect.

[0277] Antisense compounds include single- or double-stranded RNA interference (RNAi) compounds, such as antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, siRNA compounds, and other oligomeric compounds that hybridize to at least a portion of a target nucleic acid and modulate its function. As such, they may be DNA, RNA, DNA-like, RNA-like, or a mixture thereof, or may be mimetics of one or more of these. These compounds may be single-stranded, double-stranded, circular, or hairpin oligomeric compounds and may contain structural elements such as internal or terminal bulges, mismatches, or loops. Antisense compounds are traditionally linear, but may also be linked or otherwise configured to be circular and / or branched. Antisense compounds may include constructs such as double strands that hybridize to form fully or partially double-stranded compounds, or single strands that have sufficient self-complementarity to allow hybridization and formation of fully or partially double-stranded compounds. The double strands can be internally linked, leaving free 3' or 5' ends, or linked to form a continuous hairpin structure or loop. The hairpin structure can include an overhang on either the 5' or 3' end, resulting in an extension of the single-stranded characteristic. The double-stranded compound can optionally include an overhang on the end. Further modifications can include conjugate groups attached to the end, selected nucleotide positions, one of the sugar positions, or one of the internucleoside linkages. In some cases, the double strands can be linked via a non-nucleic acid moiety or linker group. When formed from only a single strand, the dsRNA can take the form of a self-complementary hairpin-type molecule that doubles back on itself to form a duplex. Thus, the dsRNA can be fully or partially double-stranded.Specific modulation of gene expression can be achieved by stable expression of dsRNA hairpins in transgenic cell lines, and in some embodiments, gene expression or function is upregulated. When formed from a double strand, or a single strand that takes the form of a self-complementary hairpin-shaped molecule that doubles back to form a duplex, the duplex (or the duplex-forming region of the single strand) is a complementary RNA strand that base-pairs in the Watson-Crick manner.

[0278] When introduced into a system, a compound can trigger the action of one or more enzymes or structural proteins that result in cleavage or other modification of the target nucleic acid, or can act through occupancy-based mechanisms. In general, nucleic acids (including oligonucleotides) may be described as "DNA-like" (i.e., generally having one or more 2'-deoxy sugars and generally T bases rather than U bases) or "RNA-like" (i.e., generally having one or more 2'-hydroxyl or 2'-modified sugars and generally U bases rather than T bases). Nucleic acid helices can adopt more than one type of structure, most commonly A- and B-forms. Generally, oligonucleotides with B-form-like structures are considered "DNA-like," and oligonucleotides with A-form-like structures are considered "RNA-like." In some (chimeric) embodiments, antisense compounds may contain regions of both A- and B-forms.

[0279] In some embodiments, the desired oligonucleotide or antisense compound comprises at least one of antisense RNA, antisense DNA, chimeric antisense oligonucleotides, antisense oligonucleotides containing modified linkages, interfering RNA (RNAi), short interfering RNA (siRNA); micro-interfering RNA (miRNA); small transient RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activator (RNAa); small activating RNA (saRNA), or a combination thereof.

[0280] In some embodiments, the "target segments" identified herein can be used in screens for additional compounds that modulate the expression of angiopoietin-like 7 (ANGPTL7). A "modulator" is a compound that reduces or increases the expression of a nucleic acid molecule encoding ANGPTL7 and includes at least a 5-nucleotide portion complementary to the target segment. Screening methods include contacting a 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 a candidate modulator is shown to be capable of modulating (e.g., reducing or increasing) the expression of a nucleic acid molecule encoding an ANGPTL7 polynucleotide, the modulator can be used in further research into the function of the ANGPTL7 polynucleotide or for use as a research, diagnostic, or therapeutic agent.

[0281] Target segments may also be combined with their respective complementary antisense compounds to form stabilized double-stranded (duplexed) oligonucleotides.

[0282] This double-stranded oligonucleotide portion regulates target expression and regulates translation and RNA processing through antisense mechanism.In addition, this double-stranded portion can be subjected to chemical modification.For example, this double-stranded portion inhibits target by the classical hybridization of the antisense strand of the double strand to target, thereby causing enzymatic degradation of target.

[0283] In some embodiments, the antisense oligonucleotide targets angiopoietin-like 7 (ANGPTL7) polynucleotides (e.g., accession number NM_021146), variants, alleles, isoforms, homologs, mutants, derivatives, fragments, and complementary sequences thereto. In some cases, the oligonucleotide is an antisense molecule.

[0284] 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.

[0285] In some embodiments, the oligonucleotide is complementary to or binds to a nucleic acid sequence of an ANGPTL7 transcript and modulates expression and / or function of the ANGPTL7 molecule.

[0286] 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.

[0287] Polynucleotide targets include ANGPTL7, including its family members, variants of ANGPTL7; mutants of ANGPTL7, including SNPs; non-coding sequences of ANGPTL7; alleles of ANGPTL7; species variants, fragments, etc. In some cases, the oligonucleotide is an antisense molecule.

[0288] In some embodiments, oligonucleotides targeting ANGPTL7 polynucleotides include antisense RNA, interfering RNA (RNAi), short interfering RNA (siRNA); micro-interfering RNA (miRNA); small transient RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activator (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.

[0289] In some embodiments, targeting angiopoietin-like 7 (ANGPTL7) polynucleotide, e.g., SEQ ID NO: 11085, modulates the expression or function of this target. In some embodiments, expression or function is downregulated compared to a control.

[0290] In some embodiments, targeting angiopoietin-like 7 (ANGPTL7) polynucleotide, such as SEQ ID NO: 11086, modulates the expression or function of this target. In some embodiments, the expression or function is downregulated compared to a control.

[0291] In some embodiments, antisense compounds are provided. These oligonucleotides may contain one or more modified nucleotides, shorter or longer fragments, modified linkages, etc. In some embodiments, the antisense compounds comprise the sequences set forth 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.

[0292] In some embodiments, the antisense compound comprises one or more LNA nucleotides.

[0293] In some embodiments, the antisense compound comprises one or more UNA nucleotides.

[0294] In some embodiments, the antisense compound comprises one or more GNA nucleotides.

[0295] Antisense compounds can contain antisense portions of about 5 to about 80 nucleotides in length (i.e., 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, single-stranded antisense compounds can contain 5 to about 80 nucleotides, and double-stranded antisense compounds (e.g., dsRNA, etc.) can contain sense and antisense strands or portions of 5 to about 80 nucleotides in length. Those skilled in the art will appreciate that this refers to the length of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 nucleotides in length, or any range of nucleotides therein.

[0296] In some embodiments, the antisense compound has an antisense portion of 10 to 50 nucleotides in length. Those skilled in the art will understand that this exemplifies oligonucleotides having an antisense portion of 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 is 15 nucleotides in length.

[0297] In some embodiments, antisense or oligonucleotide compounds have an antisense portion of about 12 or 13 to 30 nucleotides in length. One of skill in the art will recognize that this exemplifies antisense compounds having an antisense portion of 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 of nucleotides therein.

[0298] In some embodiments, oligomeric compounds comprise variants, where different bases are present at one or more of the nucleotide positions in the compound.For example, if the first nucleotide is adenosine, the variants that comprise thymidine, guanosine or cytidine at this position can be produced.This can be done at either the position of antisense compounds or dsRNA compounds.Then, these compounds are tested using the methods described herein to determine their ability to inhibit the expression of target nucleic acid.

[0299] In some embodiments, the homology, sequence identity, or complementarity is about 40% to about 60% between the antisense compound and the target. 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%.

[0300] In some embodiments, antisense oligonucleotides, such as, for example, nucleic acid molecules set forth in SEQ ID NOs: 4413-11084, contain one or more substitutions or modifications. In some embodiments, nucleotides are substituted with locked nucleic acids (LNAs). In some cases, the antisense compounds contain a sequence at least about 80%, 85%, 90%, 95%, or 100% identical to SEQ ID NO: 11087.

[0301] In some embodiments, oligonucleotides target one or more regions of the nucleic acid molecule sense and / or antisense of coding and / or non-coding sequences associated with ANGPTL7 and the sequence set forth in SEQ ID NO:11085.

[0302] In some embodiments, the oligonucleotides disclosed herein are chimeric oligonucleotides. A "chimeric oligonucleotide" or "chimera" is an oligonucleotide containing two or more chemically distinct regions, each of which is composed of at least one nucleotide. These oligonucleotides typically contain at least one region of modified nucleotides that confers one or more beneficial properties (e.g., increased nuclease resistance, increased cellular uptake, increased binding affinity for the target, etc.) and a region that is a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. As an example, RNAase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. Activation of RNAase H therefore results in cleavage of the RNA target, thereby greatly enhancing the efficiency of antisense modulation of gene expression. Consequently, chimeric oligonucleotides often allow for comparable results with shorter oligonucleotides compared to phosphorothioate deoxyoligonucleotides hybridized to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, by related nucleic acid hybridization techniques known in the art. In some embodiments, chimeric oligonucleotides contain at least one region modified to increase target binding affinity, typically a region that acts as a substrate for RNAse H. Oligonucleotide affinity for its target (in this case, a nucleic acid encoding ras) is conventionally determined by measuring the Tm of the oligonucleotide-target pair, the Tm being the temperature at which the oligonucleotide and target dissociate, as detected spectrophotometrically. The higher the Tm, the greater the affinity of the oligonucleotide for the target.

[0303] Chimeric antisense compounds may 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.

[0304] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-20 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or in a range defined by either of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0305] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO) of about 12-30 nucleosides in length comprising a nucleoside sequence comprising about 12-30 consecutive nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11085; wherein (i) the oligonucleotide comprises a modification including a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0306] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an ASO of about 12-30 nucleosides in length comprising a nucleoside sequence comprising about 12-30 consecutive nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11086; wherein (i) the oligonucleotide comprises a modification including a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0307] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide is 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 one, two, three, or four 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 one or two 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 NO: 11087, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the ASO sequence comprises or consists of the sequence of...

Claims

1. 1. A composition comprising an oligonucleotide that targets angiopoietin-like 7 (ANGPTL7) and reduces intraocular pressure when administered to a subject in an effective amount, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11085, and each strand has 14 to 30 nucleotides.

2. The composition of claim 1, wherein intraocular pressure is reduced by about 10% or more compared to before administration.

3. 2. The composition of claim 1, wherein the siRNA binds to human ANGPTL7 mRNA with no more than two mismatches in the antisense strand.

4. The composition of claim 1, wherein the siRNA binds to a human ANGPTL7 mRNA target site that does not carry a SNP and has a minor allele frequency (MAF) of 1% or more (positions 2-18).

5. The composition of claim 1 , wherein the sense strand and the antisense strand each comprise a seed region that is not identical to a seed region of a human miRNA.

6. The sense strand is selected from the group consisting of SEQ ID NOs: 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.

7. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 2. The composition of claim 1, comprising any one of the nucleoside sequences 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 one or two nucleoside substitutions, additions, or deletions.

8. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 143 2. The composition of claim 1, comprising any one of the following nucleoside sequences: 4, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192.

9. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 3633, 3634, 3635, 3636, 3637, 3638, 3639, 3640, 3641, 3642, 3643, 3644, 3645, 3646, 3647, 3648, 3649, 3650, 3651, 3652, 3653, 3654, 3655, 3656, 3657, 3658, 3659, 3660, 3661, 3662, 3663, 3664, 3665, 3666, 3667, 3668, 3669, 3670, 3671, 3672, 3673, 3674, 3675, 3676, 3677, 3678, 3679, 3680, 3681, 3682, 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.

10. The antisense strand is 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, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.

11. The antisense strand is selected from the group consisting of SEQ ID NOs: 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.

12. The composition of claim 1 , wherein the oligonucleotide comprises one or more modified internucleoside linkages.

13. 13. The composition of claim 12, wherein the one or more modified internucleoside linkages comprise an alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

14. 13. The composition of claim 12, wherein the one or more modified internucleoside linkages comprise a phosphorothioate linkage.

15. 13. The composition of claim 12, wherein the oligonucleotide comprises 2-6 modified internucleoside linkages.

16. The composition of claim 1 , wherein the oligonucleotide comprises one or more modified nucleosides.

17. 17. The composition of claim 16, wherein the one or more modified nucleosides comprise a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2',4'-constrained ethyl, a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, 2'-ara-F, or a combination thereof.

18. 17. The composition of claim 16, wherein the one or more modified nucleosides comprise a 2' fluoro-modified nucleoside.

19. 17. The composition of claim 16, wherein the one or more modified nucleosides comprise a 2'O-methyl modified nucleoside.

20. 17. The composition of claim 16, wherein the oligonucleotide comprises 15 to 23 modified nucleosides.

21. The composition of claim 1 , wherein the oligonucleotide comprises a lipid attached to the 3′ or 5′ end of the oligonucleotide.

22. 22. The composition of claim 21, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or alpha-tocopherol, or a combination thereof.

23. 22. The composition of claim 21, wherein the lipid comprises cholesterol.

24. 10. The composition of claim 1, wherein the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached at the 3' or 5' end of the oligonucleotide.

25. 25. The composition of claim 24, wherein the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys), cyclo(-Arg-Gly-Asp-D-Phe-Lys), cyclo(-Arg-Gly-Asp-D-Phe-Azide), aminobenzoic acid-derived RGD, or a combination thereof.

26. The composition of claim 1 , wherein the oligonucleotide comprises an RGD peptide and a lipid attached at the 3′ or 5′ end of the oligonucleotide.

27. The sense strand has modification pattern 1S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnnnnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'-nsnsnnNfnNfnNfnNfnnnnnnnnnnnnnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'-NfsnsNfnNfnNfNfNfN 2. The composition of claim 1, comprising: 5'-nsnsnnNfnNfnNfnNfnNfsnsnN-Lipid-3' (SEQ ID NO: 11384), or modification pattern 5S: 5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnnnnnnsnN-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 a nucleoside.

28. The antisense strand has modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2AS: 5'-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnnNfnNfnnns nsn-3' (SEQ ID NO: 11388), or modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11389), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

29. 2. The composition of claim 1, wherein the sense strand comprises a nucleoside sequence that is at least 85% identical to a sense strand sequence of any of the siRNAs in Tables 5-13.

30. The composition of claim 1, wherein the sense strand comprises a sense strand sequence of any of the siRNAs in Tables 5-13.

31. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 11131, 11132, 11133, 11134, 11135, 11136, 11137, 11138, 11139, 11140, 11141, 11142, 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, 1117 128, 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, 1116 1, 11162, 11163, 11164, 11165, 11166, 11167, 11168, 11169, 11170, 11171, 11172, 11173, 11174, 11175, 11176, 11177, 11178, 11180, 11181, 11182, 11183, 11184, 11185, 11186, 11187, 11188, 11189, 11191, 2. The composition of claim 1, comprising any one of the nucleoside sequences 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.

32. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 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, 11183, 11184, 111 11. The composition of claim 1, comprising any one of the nucleoside sequences: 11185, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212.

33. The composition of claim 1, wherein the antisense strand comprises a nucleoside sequence that is at least 85% identical to the antisense strand sequence of any of the siRNAs in Tables 5-13.

34. The composition of claim 1, wherein the antisense strand comprises an antisense strand sequence of any of the siRNAs in Tables 5-13.

35. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11279, 11280, 1128 1, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11 313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.

36. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 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, 112 1246, 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, 11304, 113 11327, 11328, 11330, 11331, or 11332.

37. The composition of claim 1 , wherein the sense strand or the antisense strand comprises a 3′ overhang of at least two nucleosides.

38. The composition of claim 1 , wherein the composition is a pharmaceutical composition.

39. 39. The composition of claim 38, wherein the composition is sterile.

40. 39. The composition of claim 38, further comprising a pharmaceutically acceptable carrier.

41. 41. The composition of claim 40, wherein the pharmaceutically acceptable carrier comprises water, a buffer solution, or saline.

42. 1. A method of treating an eye disorder in a subject, the method comprising: administering to the subject a composition comprising an oligonucleotide targeted to ANGPTL7, the oligonucleotide comprising a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to a portion of a nucleic acid having the nucleoside sequence of SEQ ID NO: 11085, and each strand has 14 to 30 nucleotides.

43. 43. The method of claim 42, wherein the eye disorder comprises glaucoma.

44. 43. The method of claim 42, wherein the composition reduces intraocular pressure in the subject's eye compared to a baseline intraocular pressure measurement obtained from the subject prior to administering the composition to the subject.

45. 45. The method of claim 44, wherein the composition reduces intraocular pressure in the subject's eye by at least 10% compared to a baseline intraocular pressure measurement obtained from the subject prior to administering the composition to the subject.

46. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 43. The method of claim 42, comprising a nucleoside sequence that is at least 85% identical to any one of 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192.

47. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 43. The method of claim 42, comprising the nucleoside sequence of any one of 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 one or two nucleoside substitutions, additions, or deletions.

48. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 143 43. The method of claim 42, comprising any one of the nucleoside sequences: 4, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192.

49. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 3633, 3634, 3635, 3636, 3637, 3638, 3639, 3640, 3641, 3642, 3643, 3644, 3645, 3646, 3647, 3648, 3649, 3650, 3651, 3652, 3653, 3654, 3655, 3656, 3657, 3658, 3659, 3660, 3661, 3662, 3663, 3664, 3665, 3666, 3667, 3668, 3669, 3670, 3671, 3672, 3673, 3674, 3675, 3676, 3677, 3678, 3679, 3680, 3681, 3682, 3 43. The method of claim 42, comprising a nucleoside sequence that is at least 85% identical to any one of: 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.

50. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 364 43. The method of claim 42, comprising the nucleoside sequence of any one of 4, 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 one or two nucleoside substitutions, additions, or deletions.

51. The antisense strand is selected from the group consisting of SEQ ID NOs: 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.

52. The sense strand has modification pattern 1S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnnnnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'-nsnsnnNfnNfnNfnNfnnnnnnnnnnnnnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'-NfsnsNfnNfnNfNfNfN 43. The method of claim 42, comprising the modification pattern 5S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnnsnN-Lipid-3' (SEQ ID NO: 11384), or the modification pattern 5S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnnnnsnN-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 a nucleoside.

53. The antisense strand has modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2AS: 5'-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnnNfnNfnnns nsn-3' (SEQ ID NO: 11388), or modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnnNfnNfnnnsnsn-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.

54. 43. The method of claim 42, wherein the sense strand comprises a nucleoside sequence that is at least 85% identical to a sense strand sequence of any of the siRNAs in Tables 5-13.

55. The method of claim 42, wherein the sense strand comprises a sense strand sequence of any of the siRNAs in Tables 5-13.

56. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 11131, 11132, 11133, 11134, 11135, 11136, 11137, 11138, 11139, 11140, 11141, 11142, 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, 1117 128, 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, 1116 1, 11162, 11163, 11164, 11165, 11166, 11167, 11168, 11169, 11170, 11171, 11172, 11173, 11174, 11175, 11176, 11177, 11178, 11180, 11181, 11182, 11183, 11184, 11185, 11186, 11187, 11188, 11189, 11191, 43. The method of claim 42, comprising the nucleoside sequence of any one of 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.

57. The sense strand is selected from the group consisting of SEQ ID NOs: 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, 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, 11183, 11184, 111 43. The method of claim 42, wherein the nucleoside sequence comprises any one of the following nucleoside sequences: 11185, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212.

58. 43. The method of claim 42, wherein the antisense strand comprises a nucleoside sequence that is at least 85% identical to the antisense strand sequence of any of the siRNAs in Tables 5-13.

59. The method of claim 42, wherein the antisense strand comprises an antisense strand sequence of any of the siRNAs in Tables 5-13.

60. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11279, 11280, 1128 1, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11 43. The method of claim 42, comprising the nucleoside sequence of any one of 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions.

61. The antisense strand is selected from the group consisting of SEQ ID NOs: 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, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 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, 112 1246, 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, 11304, 113 43. The method of claim 42, wherein the nucleoside sequence comprises any one of the following nucleoside sequences: 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332.

62. 43. The method of claim 42, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide.

63. 63. The method of claim 62, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or alpha-tocopherol, or a combination thereof.

64. 64. The method of claim 63, wherein the lipid comprises cholesterol.

65. 43. The method of claim 42, wherein the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached at the 3' or 5' end of the oligonucleotide.

66. 66. The method of claim 65, wherein the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys), cyclo(-Arg-Gly-Asp-D-Phe-Lys), cyclo(-Arg-Gly-Asp-D-Phe-Azide), aminobenzoic acid-derived RGD, or a combination thereof.

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