Treatment of angiopoietin-like 7 (ANGPTL7) related diseases

Abstract

The invention relates to the treatment of angiogenin-like 7 (ANGPTL7) related diseases. An oligonucleotide composition that inhibits ANGPTL7 and reduces intraocular pressure when administered to the eye is provided. The oligonucleotide composition contains a nucleoside modification.

Description

[0001] This application is a divisional application of the Chinese patent application with the application date of May 21, 2020, application number 202080053392.1, and invention name “Treatment of Angiopoietin-like 7 (ANGPTL7) Related Diseases” (the application date of the corresponding PCT application is May 21, 2020, and the application number is PCT / US2020 / 034063).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 852,813, filed May 24, 2019, and U.S. Provisional Application No. 62 / 881,906, filed August 1, 2019, the entire contents of which are incorporated herein by reference.

[0004] Sequence Listing

[0005] This application contains a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on May 15, 2020, is named 54462-709_601_SL.txt, and is 3,290 bytes in size. Background Art

[0006] Large-scale human genetic data provides a mechanism for leveraging natural experiments to improve the success rate of drug discovery and development.

[0007] A genome-wide association study (GWAS) is an experimental design that detects associations between genetic variants and traits in a population sample. The goal is to better understand the biology of the disease and develop treatments based on this understanding. GWAS can utilize genotyping and / or sequencing data and typically involves the evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is a case-control study, which involves comparing the frequencies of variants in cases with controls. If a variant has a significantly different frequency in cases and controls, the variant is said to be associated with the disease. The association statistics commonly reported for GWAS are the p-value as a measure of statistical significance and the odds ratio (OR), or the beta coefficient (β) as a measure of effect size. Researchers typically assume an additive genetic model and calculate the allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of the allele (compared to not carrying a copy of the allele). Another important concept in GWAS design and interpretation is linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can confound "causal" variants.

[0008] Functional annotation of variants and / or wet lab experiments can identify causal genetic variants identified by GWAS, and in many cases, this leads to the identification of disease-causing genes. In particular, understanding the functional impact of causal genetic variants (e.g., loss or gain of protein function, increase or decrease in gene expression) allows the variant to be used as a surrogate for therapeutic regulation of the target gene and provides insight into the potential therapeutic efficacy and safety of therapeutic agents that regulate the target.

[0009] The identification of such gene-disease associations provides fundamental insights into disease biology and is rapidly becoming an important means for the pharmaceutical industry to identify new therapeutic targets. In order to translate therapeutic insights derived from human genetics, the patient's disease biology must be exogenously "programmed" to replicate observations from human genetics. Today, there are more potential options for therapeutic modalities than ever before that can translate therapeutic targets identified through human genetics into new drugs. These include well-established therapeutic modalities such as small molecules and monoclonal antibodies, established modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality depends on multiple factors, including the location of the target (e.g., intracellular, extracellular, or secreted), the tissue of interest (e.g., lung, liver), and the indication of interest. Summary of the invention

[0010] Glaucoma is a heterogeneous group of diseases that affects more than 70 million people worldwide and is characterized by damage to the optic nerve leading to a progressive loss of retinal ganglion cells and resulting vision loss. The different subtypes of glaucoma are often stratified by the iridocorneal angle, with open-angle glaucoma accounting for approximately 75% of cases. Although the pathophysiology of glaucoma remains poorly understood, the major causal feature and risk factor is elevated intraocular pressure (IOP). IOP is determined by the balance between aqueous humor secretion from the ciliary body and its drainage through the trabecular meshwork and uveoscleral outflow pathways. Lowering IOP is the only strategy that has been shown to prevent the development of glaucoma or slow its progression, and therefore, treatment focuses on lowering IOP to target levels by either increasing aqueous humor outflow or decreasing aqueous humor production. Several classes of drugs that lower IOP are used, including prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, and more recently, rho-kinase inhibitors. Surgical approaches, such as laser trabeculoplasty, are also employed to improve drainage of aqueous humor through the trabecular meshwork. Despite the availability of medical and surgical therapies for glaucoma, it is the leading cause of irreversible blindness worldwide, and new treatment strategies are needed to further reduce the risk of significant morbidity and reduced quality of life associated with vision loss.

[0011] In one aspect, a composition is provided comprising an inhibitor or modulator of ANGPTL7 effective for treating glaucoma and ocular hypertension. In some embodiments, the inhibitor or modulator of ANGPTL7 is RNAi. In some embodiments, the RNAi is siRNA. In some embodiments, the siRNA comprises one or more sense strand and antisense strand sequences selected from SEQ ID NO: 1-4412. In some embodiments, the siRNA comprises a sequence comprising the reverse complement of a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90% or 95% homology with a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90% or 95% identity with a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the RNAi is miRNA. In some embodiments, the RNAi is an antisense oligonucleotide (ASO). In some embodiments, the ASO is double-stranded or single-stranded. In some embodiments, the inhibitor of ANGPTL7 is a small molecule. In some embodiments, the inhibitor of ANGPTL7 is an aptamer. In some embodiments, the aptamer is an oligonucleotide aptamer. In some embodiments, the aptamer is a peptide aptamer. In some embodiments, the inhibitor of ANGPTL7 is an antibody. In some embodiments, the antibody is a monoclonal antibody.

[0012] In another aspect, provided herein are molecules for inhibiting or modulating angiopoietin-like 7 (ANGPTL7) gene products, including dsRNA (dsRNA) agents, such as small interfering RNA (siRNA), or antisense oligonucleotides for therapeutic use. Also provided are methods for inhibiting the expression of a target gene by administering a dsRNA agent or an antisense oligonucleotide, for example, for treating various diseases involving ANGPTL7 gene products. Also provided is a method for modulating the expression of a target gene in a cell, comprising providing a dsRNA agent or an antisense oligonucleotide to the cell. In some embodiments, the target gene is ANGPTL7.

[0013] In another aspect, a method of treating one or more eye conditions in a subject in need thereof is provided, comprising editing an ANGPTL7 gene in the subject, wherein the one or more eye conditions comprise glaucoma or ocular hypertension. In some embodiments, editing of 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 according to the human protein sequence numbering. 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 according to the human protein sequence numbering. In some embodiments, CRISPR / cas9 is delivered systemically to the subject. In some embodiments, CRISPR / cas9 is delivered locally to the subject. In some embodiments, CRISPR / cas9 is delivered topically to the eye of the subject. In some embodiments, CRISPR / cas9 is delivered topically to the eye of the subject by intraocular injection. In some embodiments, CRISPR / cas9 is delivered topically to the eye of the subject by a topical solution. In some embodiments, editing of the ANGPTL7 gene is effective in treating one or more eye conditions. In some embodiments, one or more eye conditions are glaucoma. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, the subject has received first-line treatment including topical ocular prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors for one or more upper eyelid and eye conditions. In some embodiments, editing of the ANGPTL7 gene results in a reduction or regulation of the production of an ANGPTL7 gene product. In some embodiments, editing of the ANGPTL7 gene results in reduced intraocular pressure in the subject.

[0014] In another aspect, a composition comprising CRISPR / cas9 targeting ANGPTL7 is provided, which can effectively treat 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 includes a premature termination mutation. In some embodiments, the premature termination mutation occurs at amino acid position 177 according to the human protein sequence numbering. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to a missense mutation. In some embodiments, the missense mutation includes a mutation from glutamine to histidine. In some embodiments, the mutation from glutamine to histidine occurs at amino acid position 175 according to the human protein sequence numbering.

[0015] A non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is RNA interference (RNAi), where double-stranded RNAi (dsRNA) can be used to block gene expression. Short dsRNAs direct gene-specific post-transcriptional silencing in many organisms, including vertebrates, and provide a new tool for studying gene function. RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multicomponent nuclease that destroys messenger RNA homologous to the silencing trigger. RISC is known to contain a short RNA (approximately 21 nucleotides) derived from a double-stranded RNA trigger, but the protein component with this activity remains unknown.

[0016] Another non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is an antisense oligonucleotide. DNA-RNA and RNA-RNA hybridization are important for many aspects of nucleic acid function, including DNA replication, transcription, and translation. Hybridization is also at the heart of various technologies for detecting specific nucleic acids or altering their expression. For example, antisense nucleotides disrupt gene expression by hybridizing with target RNA, thereby interfering with RNA splicing, transcription, translation, and replication. Antisense DNA has the additional feature that the DNA-RNA hybrid acts as a substrate for ribonuclease H (RNaseH) digestion, an activity present in most cell types. Antisense molecules can be delivered into cells, as is the case with oligodeoxynucleotides (ODNs), or they can be expressed as RNA molecules from endogenous genes.

[0017] Another non-limiting example of a therapeutic molecule for inhibiting or modulating ANGPTL7 is a splice-switching antisense oligonucleotide (SSO). These are short, synthetic, antisense, modified nucleic acids that hybridize to pre-mRNA and disrupt the normal splicing repertoire of the transcript by blocking RNA-RNA base pairing or protein-RNA binding interactions that occur between components of the splicing machinery and the pre-mRNA. Proper expression of the vast majority of protein-coding genes requires splicing of pre-mRNA, and therefore, targeting this process provides a means of manipulating protein production from a gene. For example, splicing of pre-mRNA can also be used to alter the reading frame downstream of the splicing site, resulting in a truncated protein with impaired function.

[0018] The difference between splicing switching antisense oligonucleotides and mRNA cutting antisense oligonucleotides is that they do not recruit RNaseH to degrade the pre-mRNA-SSO complex, and are strictly steric blocking. This is achieved by using completely or almost completely 2'modified antisense oligonucleotides, which therefore lack the necessary DNA-RNA hybridization region recognized by RNaseH. Other types of modified oligonucleotides used to modify splicing are phosphoramidite morpholines (PMOs). PMO replaces the furanose ring found in natural nucleic acids with a morpholine ring, and replaces the negatively charged phosphodiester backbone with a neutral phosphorodiamidate backbone.

[0019] In some embodiments, the present disclosure provides methods for inhibiting or modulating the effects of a natural transcript by using antisense oligonucleotides (multiples) targeted to any region of the natural transcript. It is also contemplated herein that inhibition or modulation of a natural transcript can be achieved by siRNA, ribozymes, and small molecules. In an exemplary embodiment, the natural transcript encodes ANGPTL7.

[0020] One embodiment provides a method of modulating the function and / or expression of an ANGPTL7 polynucleotide in a patient's cell or tissue in vivo or in vitro, the method comprising contacting the cell or tissue with an antisense oligonucleotide of 5 to 30 nucleotides in length, wherein the antisense oligonucleotide has at least 50% sequence identity to the reverse complement of a polynucleotide comprising 5 to 30 consecutive nucleotides within nucleotides 1 to 6333 of SEQ ID NO: 11086 and any variants, alleles, homologs, mutants, derivatives, fragments, and complementary sequences thereof, thereby modulating the function and / or expression of an ANGPTL7 polynucleotide in a patient's cell 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 having at least about 80%, 85%, 90%, or 95% identity to a sequence selected from SEQ ID NOs: 4413-11084.

[0021] In some embodiments, the oligonucleotide targets a native sequence of an ANGPTL7 polynucleotide, such as 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 that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084.

[0022] In some embodiments, the oligonucleotide targets a native sequence of an ANGPTL7 polynucleotide, such as 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 that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084.

[0023] In some embodiments, the composition comprises one or more antisense oligonucleotides that bind to a sense ANGPTL7 polynucleotide. In some embodiments, the oligonucleotide comprises a sequence selected from SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to a sequence selected from SEQ ID NOs: 4413-11084. In some embodiments, the oligonucleotide comprises SEQ ID NO: 11087.

[0024] In some embodiments, the oligonucleotide comprises one or more modified or substituted nucleotides. In some embodiments, the oligonucleotide comprises one or more modified bonds. In some embodiments, the modified nucleotides include modified bases including phosphorothioate, methylphosphonate, peptide nucleic acid, 2'-0-methyl, methoxyethyl, fluoro- or carbon, methylene or other locked nucleic acid (LNA) molecules. In some embodiments, the modified nucleotides are locked nucleic acid molecules, including aL-LNA.

[0025] In some embodiments, the oligonucleotide is administered to the patient by topical administration, inhalation, intranasal, subcutaneous, intramuscular, intravenous, intraocular, or intraperitoneal administration.

[0026] In some embodiments, the oligonucleotide is administered in the form of a pharmaceutical composition. The treatment regimen includes administering an antisense compound to the patient at least once; however, this treatment can be modified to include multiple doses over a period of time. The treatment can be combined with one or more other types of treatment.

[0027] In some embodiments, the oligonucleotide is encapsulated in a liposome or attached to a carrier molecule (eg, cholesterol, TAT peptide).

[0028] On the one hand, the present invention provides an RNA interference (RNAi) agent capable of inhibiting or regulating the expression of angiopoietin-like 7 (ANGPTL7), wherein the RNAi agent comprises a double-stranded RNA (dsRNA) containing a sense strand and an antisense strand, each strand having 14 to 30 nucleotides. In some embodiments, the dsRNA has a length of 17-30 nucleotide pairs. In some embodiments, the sense strand and the antisense strand each have 17-30 nucleotides. In some embodiments, the sense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the antisense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to the reverse complementary sequence of the sense strand. In some embodiments, the antisense strand comprises a sequence having at least about 80%, 85%, 90%, 95%, or 100% identity to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the sequence of the sense strand comprises SEQ ID NO: 11089, and the sequence of the antisense strand comprises SEQ ID NO: 11090. In some embodiments, the RNAi agent comprises one or more nucleotide modifications selected from the group consisting of LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, and 2'-deoxy. In some embodiments, the nucleotides are replaced with 2'-OCH 3 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 connection. In some embodiments, the nucleotide at position 1 of the 5' end of the antisense strand of the dsRNA is selected from A, dA, dU, U, and dT. In some embodiments, the base pair at position 1 of the 5' end of the dsRNA is an AU base pair.

[0029] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or regulating the expression of ANGPTL7, wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the sense strand comprises at least two motifs having three identical modifications on three consecutive nucleotides, the first of the sense strand motifs occurring at the cleavage site in the sense strand, and the second of the sense strand motifs occurring at a different region of the sense strand separated from the first sense strand motif by at least one nucleotide; and wherein the antisense strand comprises at least two motifs having three identical modifications on three consecutive nucleotides, the first of the antisense strand motifs occurring at or near the cleavage site in the antisense strand, and the second of the antisense strand motifs occurring at a different region of the antisense strand separated from the first antisense strand motif by at least one nucleotide; wherein the modification in the first antisense strand motif is different from the modification in the second antisense strand motif. In some embodiments, at least one of the nucleotides occurring in the first sense strand motif forms a base pair with one of the nucleotides in the first antisense strand motif. In some embodiments, the dsRNA has 17-30 nucleotide base pairs. In some embodiments, the dsRNA has 17-19 nucleotide base pairs. In some embodiments, each strand has 17-23 nucleotides. In some embodiments, the modification on the nucleotides of the sense strand and / or antisense strand is selected from LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, 2'-deoxy and combinations thereof. In some embodiments, the modification on the nucleotides of the sense strand and / or antisense strand is 2'-OCH 3 Or 2'-F. In some embodiments, the RNAi agent further comprises a ligand attached to the 3' end of the sense strand.

[0030] In one aspect, provided herein is an RNA interference (RNAi) agent capable of inhibiting or regulating 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 having three 2'-F modifications on three consecutive nucleotides, one of which occurs at or near the cleavage site in the sense strand; and wherein the antisense strand comprises at least one motif having three 2'-0-methyl modifications on three consecutive nucleotides, one of which occurs at or near the cleavage site in the antisense strand. In some embodiments, the sense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the antisense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to the reverse complement of the sense strand. In some embodiments, the antisense strand comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0031] On the one hand, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of 5 to 30 nucleotides, wherein the at least one antisense oligonucleotide has at least 50% sequence identity with the reverse complementary sequence of a polynucleotide comprising 5 to 30 consecutive nucleotides within nucleotides 1 to 2224 of SEQ ID NO: 11085; thereby regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro.

[0032] On the one hand, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of 5 to 30 nucleotides, wherein the antisense oligonucleotide has at least 50% sequence identity with the antisense oligonucleotide of angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro.

[0033] On the one hand, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide targeting a region of a natural antisense oligonucleotide of angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro.

[0034] In one aspect, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) polynucleotides in patient cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of 5 to 30 nucleotides; thereby regulating the function and / or expression of ANGPTL7 polynucleotides in patient cells or tissues in vivo or in vitro.

[0035] In some embodiments, at least one antisense oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, 95% identical to SEQ ID NO: 11087. In some embodiments, the function and / or expression of Angiopoietin-like 7 (ANGPTL7) is increased in vivo or in vitro relative to a control oligonucleotide that does not target or does not specifically hybridize to ANGPTL7. In some embodiments, the function and / or expression of Angiopoietin-like 7 (ANGPTL7) is decreased in vivo or in vitro relative to a control oligonucleotide that does not target or does not specifically hybridize to ANGPTL7. In some embodiments, at least one antisense oligonucleotide targets a natural antisense sequence of an Angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, at least one antisense oligonucleotide targets a nucleic acid sequence that comprises 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 angiopoietin-like 7 (ANGPTL7) polynucleotides. In some embodiments, at least one antisense oligonucleotide comprises one or more modifications. In some embodiments, 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, one or more modifications comprise at least one modified sugar moiety selected from the following: 2'-0-methoxyethyl modified sugar moiety, 2'-methoxy modified sugar moiety, 2'-0-alkyl modified sugar moiety, bicyclic sugar moiety, and combinations thereof. In some embodiments, one or more modifications comprise at least one modified internucleoside linkage selected from the following: phosphorothioate, 2'-O methoxyethyl (MOE), 2'-fluoro, alkyl phosphonate, dithiophosphate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetamidate, carboxymethyl ester, and combinations thereof. In some embodiments, the one or more modifications include at least one modified nucleotide selected from the group consisting of peptide nucleic acid (PNA), locked nucleic acid (LNA), arabinose nucleic acid (FANA), analogs, derivatives, and combinations thereof.

[0036] In one aspect, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) gene in mammalian cells or tissues in vivo or in vitro, the method comprising: contacting the cells or tissues with at least one short interfering RNA (siRNA) oligonucleotide having a length of 5 to 30 nucleotides, the at least one siRNA oligonucleotide being specific to an antisense polynucleotide of angiopoietin-like 7 (ANGPTL7) polynucleotide, wherein the at least one siRNA oligonucleotide has at least 50% sequence identity with the complementary sequence of at least about five consecutive nucleic acids of the antisense and / or sense nucleic acid molecule of the angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) in mammalian cells or tissues in vivo or in vitro. In some embodiments, the oligonucleotide has at least 80% sequence identity with the sequence of at least about five consecutive nucleic acids complementary to the antisense and / or sense nucleic acid molecule of the angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, the at least one siRNA oligonucleotide comprises a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, at least one siRNA oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, 95%, or 100% identical to a sequence selected from SEQ ID NOs: 1-4412.

[0037] In one aspect, the present invention provides a method for regulating the function and / or expression of angiopoietin-like 7 (ANGPTL7) in mammalian cells or tissues in vivo or in vitro, the method comprising contacting the cells or tissues with at least one antisense oligonucleotide having a length of about 5 to 30 nucleotides, which is specific to the non-coding and / or coding sequence of the sense and / or natural antisense strand of angiopoietin-like 7 (ANGPTL7) polynucleotide, wherein the at least one antisense oligonucleotide has at least 50% sequence identity with at least one nucleic acid sequence shown in 1 to 2224 of SEQ ID NO: 11085 or its complementary sequence; thereby regulating the function and / or expression of angiopoietin-like 7 (AGNPTL7) in mammalian cells or tissues in vivo or in vitro. In some embodiments, at least one antisense oligonucleotide comprises the sequence of SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity with SEQ ID NO: 11087.

[0038] 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; wherein the oligonucleotide is an antisense compound that hybridizes to angiopoietin-like 7 (ANGPTL7) polynucleotides in vivo or in vitro and modulates their function and / or expression compared to a control oligonucleotide that does not specifically hybridize to an ANGPTL7 polynucleotide. In some embodiments, at least one modification comprises an internucleotide linkage selected from the following: phosphorothioates, alkylphosphonates, phosphorodithioates, alkylphosphonothioates, phosphoramidates, carbamates, carbonates, phosphotriesters, acetamidates, carboxymethyl esters, and combinations thereof. In some embodiments, the oligonucleotide comprises at least one phosphorothioate internucleotide linkage. In some embodiments, the oligonucleotide comprises a backbone of phosphorothioate internucleotide linkages. In some embodiments, the oligonucleotide comprises at least one modified nucleotide selected from: peptide nucleic acids, locked nucleic acids (LNAs), and analogs, derivatives, and combinations thereof. In some embodiments, the oligonucleotide includes multiple modifications, wherein the modification includes a modified nucleotide selected from the following: phosphorothioate, alkyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, acetoamic acid ester, carboxymethyl ester and combinations thereof. In some embodiments, the oligonucleotide includes multiple modifications, wherein the modification includes a modified nucleotide selected from the following: peptide nucleic acid, locked nucleic acid (LNA) and its analogs, derivatives and combinations. In some embodiments, the oligonucleotide includes at least one modified sugar moiety selected from the following: 2'-O-methoxyethyl modified sugar moiety, 2'-methoxy modified sugar moiety, 2-O-alkyl modified sugar moiety, bicyclic sugar moiety and combinations thereof. In some embodiments, the oligonucleotide includes multiple modifications, wherein the modification includes a modified sugar moiety selected from the following: 2'-O-methoxyethyl modified sugar moiety, 2'-methoxy modified sugar moiety, 2'-O-alkyl modified sugar moiety, bicyclic sugar moiety and combinations thereof. In some embodiments, the oligonucleotide is at least about 5 to 30 nucleotides in length and hybridizes to the antisense and / or sense strand of the Angiopoietin-like 7 (ANGPTL7) polynucleotide, wherein the oligonucleotide has at least about 20% sequence identity to the complement of at least about five consecutive nucleic acids of the antisense and / or sense coding and / or non-coding nucleic acid sequence of the Angiopoietin-like 7 (ANGPTL7) polynucleotide. In some embodiments, the oligonucleotide has at least about 80% sequence identity to the complement of at least about five consecutive nucleic acids of the antisense and / or sense coding and / or non-coding nucleic acid sequence of the Angiopoietin-like 7 (ANGPTL7) polynucleotide.In some embodiments, the oligonucleotide hybridizes to and modulates expression and / or function of at least one angiopoietin-like 7 (ANGPTL7) polynucleotide in vivo or in vitro compared to a control oligonucleotide. In some embodiments, the oligonucleotide comprises a sequence as set forth in SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises SEQ ID NO: 11087. In some embodiments, at least one antisense oligonucleotide comprises a sequence that is at least about 80%, 85%, 90%, or 95% identical to SEQ ID NO: 11087.

[0039] In one aspect, provided herein is a composition comprising one or more oligonucleotides specific for one or more angiopoietin-like 7 (ANGPTL7) polynucleotides, the one or more oligonucleotides comprising an antisense sequence, complementary sequence, allele, homolog, isoform, variant, derivative, mutant or fragment of the ANGPTL7 polynucleotide, or a combination thereof. In some embodiments, the one or more oligonucleotides have at least about 40% sequence identity compared to the nucleotide sequence as shown in SEQ ID NO: 11087. In some embodiments, the oligonucleotide comprises the nucleotide sequence as shown in SEQ ID NO: 11087. In some embodiments, the one or more oligonucleotides comprise a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the one or more oligonucleotides comprise a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NO: 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.

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

[0041] On the one hand, the present invention provides a method for preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one product encoded thereof, the method comprising: administering to a subject in need thereof a therapeutically effective dose of at least one antisense oligonucleotide that binds to the natural sense sequence of the at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and regulates the expression of the at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide; thereby preventing or treating a disease associated with at least one Angiopoietin-like 7 (ANGPTL7) polynucleotide and / or at least one product encoded thereof.

[0042] In some embodiments, the disease associated with at least one angiopoietin-like 7 (ANGPTL7) polynucleotide is selected from the group consisting of: diseases or conditions associated with abnormal function and / or expression of ANGPTL7, diseases or conditions associated with optic nerve damage, diseases or conditions associated with intraocular pressure, degenerative retinal diseases or conditions, inflammatory eye diseases or conditions, allergic eye diseases or conditions, diseases or conditions associated with joint degeneration or inflammation, diseases or conditions associated with abnormal lipid metabolism, cancer, Alzheimer's disease, dementia, stroke, and cerebral ischemia. In some embodiments, the diseases or conditions associated with optic nerve damage include primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, pigmentary glaucoma, exfoliation glaucoma, juvenile glaucoma, congenital glaucoma, inflammatory glaucoma, crystalline 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 diseases or conditions associated with joint degeneration or inflammation include osteoarthritis, osteoarthrosis, or a combination thereof. In some embodiments, cancer is selected from lung cancer, epidermoid carcinoma, breast cancer, or a combination thereof.

[0043] In one aspect, provided herein is a method for identifying and selecting at least one oligonucleotide for in vivo administration, comprising: identifying at least one oligonucleotide comprising at least five consecutive nucleotides complementary to ANGPTL7 or a polynucleotide antisense to ANGPTL7; measuring the thermal melting point of a hybrid of the antisense oligonucleotide and ANGPTL7 or a polynucleotide antisense to ANGPTL7 under stringent hybridization conditions; and selecting at least one oligonucleotide for in vivo administration based on the information obtained.

[0044] In one aspect, provided herein is a method of treating a disease or condition mediated by ANGPTL7, the method comprising administering to a subject in need thereof an oligonucleotide comprising a sequence having at least about 80%, 85%, 90%, 95%, or 100% identity to a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the oligonucleotide comprises a sequence selected from SEQ ID NOs: 1-4412. In some embodiments, the target is ANGPTL7. In some embodiments, the disease or condition comprises glaucoma (including primary open-angle glaucoma, primary angle-closure glaucoma, normal-tension glaucoma, pigmentary glaucoma, exfoliation glaucoma, juvenile glaucoma, congenital glaucoma, inflammatory glaucoma, crystalline glaucoma, glaucoma secondary to intraocular hemorrhage, traumatic glaucoma, neovascular glaucoma, drug-induced glaucoma, toxic glaucoma and absolute glaucoma), ocular hypertension, optic neuropathy or a combination thereof. In some embodiments, the oligonucleotide comprises dsRNA. In some embodiments, the oligonucleotide comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the oligonucleotide comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to SEQ ID NO: 11087.

[0045] In one aspect, provided herein is a method of treating one or more eye conditions in a subject in need thereof, comprising editing an ANGPTL7 gene in the subject, wherein the one or more eye conditions comprise glaucoma or ocular hypertension. In some embodiments, editing of 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 according to the human protein sequence numbering. 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 according to the human protein sequence numbering. In some embodiments, CRISPR / cas9 is delivered systemically to the subject. In some embodiments, CRISPR / cas9 is delivered locally to the subject. In some embodiments, CRISPR / cas9 is delivered topically to the eye of the subject. In some embodiments, editing of the ANGPTL7 gene is effective in treating one or more eye conditions. In some embodiments, the one or more eye conditions are glaucoma. In some embodiments, the subject suffers from ocular hypertension. In some embodiments, imaging from ocular hypertension in the subject shows optic nerve damage. In some embodiments, the subject has received first-line treatment including topical ocular prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors for one or more eye conditions. In some embodiments, editing of the ANGPTL7 gene results in a reduction or regulation of the production of an ANGPTL7 gene product in the subject. In some embodiments, editing of the ANGPTL7 gene results in reduced intraocular pressure in the subject.

[0046] On the one hand, the present invention provides a composition comprising CRISPR / cas9 targeting ANGPTL7, which can effectively treat 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 includes a premature termination mutation. In some embodiments, the premature termination mutation occurs at amino acid position 177 according to the human protein sequence numbering. In some embodiments, CRISPR / cas9 edits the ANGPTL7 gene to a missense mutation. In some embodiments, the missense mutation includes a mutation from glutamine to histidine. In some embodiments, the mutation from glutamine to histidine occurs at amino acid position 175 according to the human protein sequence numbering.

[0047] In some embodiments, disclosed herein are compositions comprising oligonucleotides targeting angiopoietin-like 7 (ANGPTL7), and when administered to a subject in an effective amount, reduce intraocular pressure, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides. In some embodiments, intraocular pressure is reduced by about 10% or more compared to before administration. In some embodiments, disclosed herein are compositions comprising oligonucleotides targeting angiopoietin-like 7 (ANGPTL7), and when administered to a cell, reduce the expression of ANGPTL7, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides. In some embodiments, the composition reduces the expression of ANGPTL7 compared to baseline ANGPTL7 measurements. In some embodiments, a baseline ANGPLT7 measurement is measured prior to administering the composition to the cell. In some embodiments, the composition reduces the expression of ANGPLT7 by at least 10% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces the expression of ANGPLT7 by at least 20% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces the expression of ANGPLT7 by at least 30% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces the expression of ANGPLT7 by at least 40% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces the expression of ANGPLT7 by at least 50% relative to the baseline ANGPTL7 measurement. In some embodiments, the composition reduces the expression of ANGPLT7 by at least 25% to 75% relative to the baseline ANGPTL7 measurement. In some embodiments, the baseline measurement is an ANGPLT7 protein measurement. In some embodiments, the baseline measurement is an ANGPLT7 mRNA measurement. In some embodiments, the expression of ANGPLT7 includes the expression of ANGPTL7 mRNA. In some embodiments, the expression of ANGPLT7 includes the expression of ANGPTL7 protein. In some embodiments, the siRNA binds to human ANGPTL7 mRNA with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not contain a SNP with a minor allele frequency (MAF) greater than or equal to 1% (positions 2-18). In some embodiments, the sense strand and the antisense strand each comprise a seed region that is not identical to a seed region of a human miRNA.In some embodiments, the sense strand comprises the same sequence as SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1 In some embodiments, the sense strand comprises a nucleotide sequence having at least 85% identity to any of SEQ ID NO: 434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943 ,948,1021,1092,1094,1097,1105,1107,1132,1198,1201,1424,1425,1429,1434,143 6, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 9 23, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1 The nucleotide sequence of any one of 2192, 229, 2434, 2436, 2438, 2537, 2541, 2639, 2654, 2691, 2693, 2762, 2764, 2765, 2794, 2796, 2797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192.In some embodiments, the antisense strand comprises the amino acid sequence of SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630 , 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 85% identity to any of SEQ ID NO: NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2 947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3 635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1 or 2 nucleosides substituted, added or deleted. In some embodiments, the antisense strand comprises SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 340 7. The nucleotide sequence of any one of 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398.In some embodiments, the oligonucleotide comprises one or more modified internucleosides connected. In some embodiments, one or more modified internucleosides are connected to include alkylphosphonates, phosphorothioates, methylphosphonates, phosphorodithioates, alkylthiophosphonates, phosphoramidates, carbamates, carbonates, phosphotriesters, acetamidates or carboxymethyl esters or combinations thereof. In some embodiments, one or more modified internucleosides are connected to include phosphorothioates. In some embodiments, the oligonucleotide comprises 2-6 modified internucleosides connected. In some embodiments, the oligonucleotide comprises one or more modified nucleosides. In some embodiments, one or more modified nucleosides include locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2',4' restricted ethyl, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro or 2'-deoxy, 2'-O-methyl nucleosides, 2'-deoxyfluoro nucleosides, 2'-ON-methylacetamido (2'-O-NMA) nucleosides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleosides, 2'-O-aminopropyl (2'-O-AP) nucleosides, 2'-ara-F or a combination thereof. In some embodiments, one or more modified nucleosides include 2'fluoro modified nucleosides. In some embodiments, one or more modified nucleosides include 2'O methyl modified nucleosides. In some embodiments, the oligonucleotide includes 15-23 modified nucleosides. In some embodiments, the oligonucleotide includes a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid includes cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, docosanoyl, docosahexenoyl, myristyl, palmityl stearyl or α-tocopherol, or a combination thereof. In some embodiments, the lipid includes cholesterol. In some embodiments, the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide includes cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid derived RGD, or a combination thereof. In some embodiments, the oligonucleotide includes an RGD peptide and a lipid attached to the 3' or 5' end of the oligonucleotide.In some embodiments, the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-lipid-3' (SEQ ID NO: 11384), or modification pattern 5S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsnN-lipid-3' (SEQ ID NO: 11385). NO:11385); wherein "Nf" is a 2' fluorine-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N includes the nucleoside. In some embodiments, the antisense strand includes modification pattern 1 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2 AS: 5'nsNfsnnnNfNfnNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388) or modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn3' (SEQ ID NO: 11389); wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to a sense strand sequence of a siRNA in any one of Tables 5-13. In some embodiments, the sense strand comprises a sense strand sequence of a siRNA in any one of Tables 5-13.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126, 111 27、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、11156、11157、1115 8. 11159, 11160, 11161, 11162, 11163, 11164, 11165, 11166, 11167, 11168, 11169, 11170, 11171, 11172, 11173, 11174, 11175, 11176, 11177, 11178, 11180, 11181, 11182, 11183, 11184, 1118 5, the nucleotide sequence of any one of 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 111 26、11127、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、111 56、11157、11158、11159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、111 In some embodiments, the antisense strand comprises a nucleotide sequence of any one of 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 85% identity to the antisense strand sequence of the siRNA in any one of Tables 5-13. In some embodiments, the antisense strand comprises the antisense strand sequence of the siRNA in any one of Tables 5-13.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247 47, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 11276, 11277, 1127 8. 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 1130 5. The nucleotide sequence of any one of 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or the antisense sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247, 11248, 11250, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 11263, 11264, 11265 46, 11247, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 112 76, 11277, 11278, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302 02, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332. In some embodiments, the sense strand or the antisense strand comprises a 3' overhang of at least 2 nucleosides. In some embodiments, the composition is in a solid composition. In some embodiments, the composition is sterile. Some embodiments include a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes water, a buffer solution or a saline solution.

[0048] In some embodiments, disclosed herein are methods of treating an eye condition in a subject in need thereof, the method comprising administering to the subject a composition comprising an oligonucleotide targeting ANGPTL7. In some embodiments, the eye condition comprises glaucoma. In some embodiments, the composition reduces intraocular pressure in the subject's eye relative to a baseline intraocular pressure measurement obtained from the subject prior to administering the composition to the subject. In some embodiments, the sense strand comprises a polypeptide having a sequence identical to SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1 In some embodiments, the sense strand comprises a nucleotide sequence having at least 85% identity to any of SEQ ID NO: 434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943 ,948,1021,1092,1094,1097,1105,1107,1132,1198,1201,1424,1425,1429,1434,143 6, a nucleotide sequence of 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, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the sense strand comprises SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1 429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the antisense strand comprises a nucleotide sequence corresponding to SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 294 6. 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630 , 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 85% identity to any of SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2 947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3 4305, 4306, 4397, 4411, 4429, 4430, 4444, 4466, 4471, 4480, 4491, 4502, 4503, 4504, 4512, 4524, 4536, 4540, 4551, 4562, 4570, 4581, 4592, 4604, 4605, 4606, 4607, 4608, 4610, 4611, 4612, 4613, 4614, 4625, 4630, 4631, 4632, 4633, 4634, 4640, 4642, 4644,In some embodiments, the antisense strand comprises SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3406, 7. The nucleotide sequence of any one of 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398. In some embodiments, the sense strand comprises modification pattern 1S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 11383), modification pattern 4S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfsnsnN-lipid-3' (SEQ ID NO: 11384), or modification pattern 5S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsnN-lipid-3' (SEQ ID NO: 11385). NO:11385); wherein "Nf" is a 2' fluorine-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N includes the nucleoside.In some embodiments, the antisense strand includes modification pattern 1 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386), modification pattern 2 AS: 5'-nsNfsnnnNfNfnNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), modification pattern 3 AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388) or modification pattern 4 AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn3' (SEQ ID NO: 11389); wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to a sense strand sequence of a siRNA in any one of Tables 5-13. In some embodiments, the sense strand comprises a sense strand sequence of a siRNA in any one of Tables 5-13.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126, 111 27、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、11156、11157、1115 8. 11159, 11160, 11161, 11162, 11163, 11164, 11165, 11166, 11167, 11168, 11169, 11170, 11171, 11172, 11173, 11174, 11175, 11176, 11177, 11178, 11180, 11181, 11182, 11183, 11184, 1118 5, the nucleotide sequence of any one of 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the sense strand comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 111 26、11127、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、111 56、11157、11158、11159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、111 In some embodiments, the antisense strand comprises a nucleotide sequence of any one of 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211, or 11212. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 85% identity to the antisense strand sequence of the siRNA in any one of Tables 5-13. In some embodiments, the antisense strand comprises the antisense strand sequence of the siRNA in any one of Tables 5-13.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247 47, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 11276, 11277, 1127 8. 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 1130 5. The nucleotide sequence of any one of 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.In some embodiments, the antisense strand comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247, 11248, 11250, 11251, 11252, 11253, 11254, 11255, 11256, 11257, 11258, 11259, 11260, 11261, 11262, 11263, 11264, 11265 46, 11247, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 112 76, 11277, 11278, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302 02, 11303, 11304, 11305, 11306, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331, or 11332. In some embodiments, the oligonucleotide includes a cholesterol moiety attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the oligonucleotide includes a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, lipids include cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl or alpha-tocopherol, or a combination thereof. In some embodiments, lipids include cholesterol. In some embodiments, the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide includes cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid derived RGD, or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figures 1A-1DAn empty plasmid construct used according to some embodiments is shown ( Figure 1A ), GFP-tagged plasmid construct ( Figure 1B ), representative ANGPTL7 pre-mRNA encoding constructs ( Figure 1C ) and representative ANGPTL7 CDS encoding constructs ( Figure 1D ).

[0050] Figure 2 Shown are fluorescence microscopy images of HEK293 cells transfected with pcDNA3.1(+)GFP vector.

[0051] Figure 3 Shown are the results of qPCR measuring ANGPTL7 mRNA expression in HEK293 cells transfected with WT and Q175H pre-mRNA expression constructs.

[0052] Figure 4 Shown are the results of qPCR measuring ANGPTL7 mRNA expression in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0053] Figure 5 Included are images of Western blots of ANGPTL7 in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0054] Figure 6 Included are the results of an ELISA assay measuring ANGPTL7 protein expression in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter pre-mRNA expression constructs.

[0055] Figure 7 Shown are the ratios of secreted protein compared to intracellular protein (measured by ELISA) in HEK293 cells transfected with WT, Q175H, R140H and R177Ter pre-mRNA expression constructs.

[0056] Figure 8 Included are images of Western blots of ANGPTL7 in HEK293 cells transfected with WT, Q175H, R140H, and R177Ter CDS expression constructs.

[0057] Fig. 9 The relative positions of protein-coding and noncoding ANGPTL7 transcripts and the Q175H missense variant are shown.

[0058] Fig.10Shown is an agarose gel with transcript-specific PCR products from HEK293 cells transfected with WT and Q175H pre-mRNA expression constructs.

[0059] Fig.11 Dexamethasone-induced ANGPTL7 and MYOC expression in HTM cells is shown.

[0060] Fig.12 Shown is an agarose gel with transcript-specific PCR products from dexamethasone-induced primary HTM cells. DETAILED DESCRIPTION

[0061] Glaucoma is the leading cause of irreversible blindness in the world, with a worldwide prevalence of approximately 1-2% of the population over the age of 40. There are multiple subtypes of glaucoma, but there are two main subtypes: 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 certain populations (i.e., Asian populations), most glaucoma occurs in the setting of normal intraocular pressure (normal-tension glaucoma, NTG).

[0062] The general characteristic of glaucoma is that the outflow of aqueous humor through the conventional outflow pathway is blocked. The conventional outflow pathway consists of the trabecular meshwork (TM) and Schlemm's canal at the base of the cornea. There is also an unconventional outflow pathway, which involves uveoscleral drainage and accounts for a portion of the aqueous humor outflow from the anterior compartment. Blockage of the TM / Schlemm's canal (conventional pathway) restricts the outflow of aqueous humor, resulting in increased anterior chamber pressure, which translates into increased posterior chamber pressure and optic nerve degeneration and damage.

[0063] Treatment of glaucoma aims to reduce intraocular pressure (IOP) to a target level (usually a 20-50% reduction in IOP). Treatment of NTG also revolves around lowering IOP, despite normal IOP. Several classes of medications are used to lower IOP, including prostaglandin analogs (usually first-line therapy), beta-adrenergic blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors. These medications are often ineffective, and surgical approaches (trabeculoplasty / trabeculotomy) are resorted to. However, the beneficial effects of trabeculoplasty / trabeculotomy diminish over time, resulting in a failure rate of approximately 10% per year.

[0064] Angiopoietin-like proteins (ANGPTLs) are a family of eight proteins that are structurally and functionally similar to 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.

[0065] ANGPTL7 was originally discovered in a human corneal cDNA library and named cornea-derived transcript 6 (CDT6). Immunohistochemistry shows ANGPTL7 staining in multiple tissues in the eye. ANGPTL7 is overexpressed in the aqueous humor of glaucoma patients and is upregulated by glaucomatous conditions such as TGFβ and dexamethasone exposure. Despite this, the molecular function of ANGPTL7 in ocular health and disease is unclear.

[0066] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. In addition, if the terms "including," "includes," "having," "has," "with," or variations thereof are used in the detailed description and / or claims, such terms are intended to be included in a manner similar to the term "comprising."

[0067] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined (i.e., the limitations of the measurement system). For example, in accordance with the practice in the art, "about" can mean within 1 or more than 1 standard deviation. In some cases, "about" can mean a range of up to 20%, up to 10%, up to 5%, and up to 1% of a given value. In some cases, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of a value, such as within 5-fold, or within 2-fold. Where specific values ​​are described in the application and claims, the term "about" should be assumed to mean that the specific value is within an acceptable error range unless otherwise indicated.

[0068] In some embodiments, the term "mRNA" refers to the currently known mRNA transcript(s) of a target gene, as well as any additional transcripts that may be elucidated.

[0069] In some embodiments, "dsRNA", "siRNA" and "siRNA agent" are used interchangeably as agents that can mediate the silencing of a target RNA, such as an mRNA, e.g., a transcript of a gene encoding a protein. In some cases, the target RNA is ANGPTL7. Such an mRNA may also be referred to herein as an mRNA to be silenced. Such a gene is also referred to as a target gene. In some cases, the RNA to be silenced is an endogenous gene or a pathogen gene. In addition, RNAs other than mRNAs, such as tRNAs and viral RNAs, may also be targeted.

[0070] In some embodiments, the phrase "mediates RNAi" refers to the ability to silence a target RNA in a sequence-specific manner. While not wishing to be bound by theory, it is believed that silencing uses RNAi machinery or processing and guide RNA, such as siRNA agents.

[0071] In some embodiments, "specifically hybridizable" and "complementary" are terms used to indicate a sufficient degree of complementarity to allow stable and specific binding to occur between a compound described herein and a target RNA molecule.

[0072] Specific binding may require a sufficient degree of complementarity to avoid non-specific binding of the oligomeric compound to non-target sequences under conditions where specific binding is desired, i.e., under physiological conditions in the case of an assay or therapeutic treatment, or under the conditions in which the assay is performed in the case of an in vitro assay. The non-target sequences may differ by at least 5 nucleotides.

[0073] In some embodiments, dsRNA reagent and target RNA, for example, target mRNA are "fully complementary", so that the dsRNA reagent silences the production of proteins encoded by the target mRNA. In some embodiments, dsRNA reagent and target RNA are "fully complementary", for example, the target RNA and dsRNA duplex reagent anneal, for example, in the fully complementary region, a hybrid consisting of Watson Crick base pairs is formed. The target RNA of "fully complementary" can include an internal region (for example, an internal region of at least 10 nucleotides) that is fully complementary to the target RNA. In addition, in some embodiments, dsRNA reagents specifically distinguish single nucleotide differences. In this case, if fully complementary is found in the region of single nucleotide differences (for example, within 7 nucleotides), the dsRNA reagent only mediates RNAi.

[0074] In some embodiments, the term "oligonucleotide" refers to a nucleic acid molecule (RNA or DNA) of less than 100, 200, 300, or 400 nucleotides in length.

[0075] 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 interaction and changes the activity of the target RNA. Antisense oligonucleotides can upregulate or downregulate the expression and / or function of a specific polynucleotide. This definition is intended to include any exogenous RNA or DNA molecule useful from a treatment, diagnosis or other perspective. Such molecules include, for example, antisense RNA and DNA molecules, interfering RNA (RNAi), microRNA, decoy RNA molecules, siRNA, enzymatic RNA, therapeutic editing RNA, and agonist and antagonist RNA, antisense oligomeric compounds, antisense oligonucleotides, external guide sequence (EGS) oligonucleotides, alternate splicing agents, primers, probes, and other oligomeric compounds that hybridize with at least a portion of a target nucleic acid. Therefore, these compounds can be introduced in the form of single-stranded, double-stranded, partially single-stranded or cyclic oligomeric compounds.

[0076] In some embodiments, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or its mimetics. The term "oligonucleotide" also includes natural and / or modified monomers or linked linear or cyclic oligomers, including deoxyribonucleosides, ribonucleosides, their substitutions and α-anomeric forms, peptide nucleic acids (PNA), locked nucleic acids (LNA), thiophosphates, methylphosphonates, etc. Oligonucleotides can specifically bind to target polynucleotides through regular patterns of monomer-to-monomer interactions, such as Watson Crick type base pairing, Hoogsteen or reverse Hoogsteen type base pairing, etc.

[0077] In some embodiments, oligonucleotide is "chimeric", i.e., composed of different regions. "Chimeric" oligonucleotide comprises two or more chemical regions, for example, DNA region (multiple), RNA region (multiple), PNA region (multiple) etc. Each chemical region is composed of at least one monomer unit, i.e., nucleotide in the case of oligonucleotide compounds. These oligonucleotides generally comprise at least one region, wherein the oligonucleotide is modified to show one or more desired characteristics. The desired characteristics of oligonucleotide include, but are not limited to, for example, an increase in resistance to nuclease degradation, an increase in cellular uptake and / or an increase in binding affinity to target nucleic acid. Therefore, different regions of oligonucleotide may have different characteristics. Chimeric oligonucleotide can be formed as a mixed structure of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and / or oligonucleotide analogs.

[0078] Oligonucleotides may comprise or consist of regions that may be linked in a "register", i.e. when the monomers are linked consecutively, as in natural DNA, or linked by spacers. Spacers are intended to constitute covalent "bridges" between regions and in some cases have a length of no more than about 100 carbon atoms. Spacers may have different functionalities, e.g., have a positive or negative charge, have special nucleic acid binding properties (intercalators, groove binders, toxins, fluorophores, etc.), be lipophilic, induce special secondary structures, such as, for example, alanine containing peptides that induce alpha helices.

[0079] In some embodiments, "ANGPTL7" and "Angiopoietin-like 7" include all family members, mutants, alleles, fragments, species, coding and non-coding sequences, sense and antisense polynucleotide strands, etc. of the ANGPTL7 transcript (NM_021146; SEQ ID NO: 11085). In some embodiments, "ANGPTL7" and "Angiopoietin-like 7" are used interchangeably in this application.

[0080] In some embodiments, an "oligonucleotide specific for..." or "oligonucleotide targeting..." refers to an oligonucleotide having a sequence that (i) can form a stable complex with a portion of a targeted gene, or (ii) can form a stable duplex with a portion of an mRNA transcript of a targeted gene. The stability of the complex and duplex can be determined by theoretical calculations and / or in vitro assays.

[0081] In some embodiments, the term "target nucleic acid" includes DNA, RNA (including, precursor mRNA and mRNA) transcribed from such DNA, and cDNA, coding sequence, non-coding sequence, sense and antisense polynucleotides derived from such RNA. The specific hybridization of oligomeric compounds with their target nucleic acids interferes with the normal function of nucleic acids. This regulation of target nucleic acid functions by compounds that specifically hybridize with them is generally referred to as "antisense". The functions of regulated DNA include, for example, replication and transcription. The functions of regulated RNA include all important functions, such as, for example, translocation of RNA to protein translation sites, translation of proteins from RNA, splicing of RNA to produce one or more mRNA species, and catalytic activity that can participate in RNA or promoted by RNA. The overall effect of this interference with the target nucleic acid function is the regulation of the expression of the encoded product or oligonucleotide.

[0082] RNA interference "RNAi" is mediated by double-stranded RNA (dsRNA) molecules with sequence-specific homology to its "target" nucleic acid sequence. In certain embodiments, the mediator is a "small interfering" RNA duplex (siRNA) of 5-25 nucleotides. siRNA is derived from the processing of dsRNA by the RNase enzyme called Dicer. The siRNA duplex product is recruited into a multiprotein siRNA complex called RISC (RNA-induced silencing complex). Without wishing to be bound by any particular theory, it is then believed that RISC is directed to the target nucleic acid (suitable mRNA), wherein the siRNA duplex interacts in a sequence-specific manner to mediate cutting in a catalytic manner. Small interfering RNA can be synthesized and used. The small interfering RNA used in the methods herein suitably comprises about 1 to about 50 nucleotides (nt). In the example of non-limiting embodiments, siRNA may comprise about 5 to about 40nt, about 5 to about 30nt, about 10 to about 30nt, about 15 to about 25nt or about 20-25 nucleotides.

[0083] In some embodiments, the selection of suitable oligonucleotides is promoted by using a computer program that automatically compares nucleic acid sequences and indicates identity or homology regions. Such programs are used to compare nucleic acid sequences obtained, for example, by searching databases such as GenBank or by sequencing PCR products. The comparison of nucleic acid sequences from a series of species allows the selection of nucleic acid sequences showing an appropriate degree of identity between species. In the case where the gene is not sequenced, Southern blotting is performed to allow determination of the degree of identity between the genes in the target species and other species. By performing Southern blotting under different stringencies, as known in the art, an approximate measurement of identity can be obtained. These programs allow selection to show a high degree of complementarity with the target nucleic acid sequence in the subject to be controlled and to show a relatively low degree of complementarity with the corresponding nucleic acid sequence in other species. Those skilled in the art will appreciate that there is considerable freedom of choice in selecting suitable gene regions.

[0084] In some embodiments, "enzymatic RNA" refers to an RNA molecule with enzymatic activity. Enzymatic nucleic acids (ribozymes) work by first binding to a target RNA. This binding occurs through the target binding portion of the enzymatic nucleic acid, which is kept in close proximity to the enzymatic portion of the molecule, which acts to cut the target RNA. Thus, the enzymatic nucleic acid first recognizes the target RNA, then binds to the target RNA through base pairing, and once bound to the correct site, acts enzymatically to cut the target RNA.

[0085] In some embodiments, "bait RNA" refers to an RNA molecule that simulates the natural binding domain of a ligand. Therefore, the bait RNA competes with the natural binding target for the binding of a specific ligand. For example, overexpression of HIV transactivation response (TAR) RNA can act as a "bait" and effectively bind to HIV tat protein, thereby preventing it from binding to the TAR sequence encoded in HIV RNA. This means a specific example. Those skilled in the art will recognize that this is just an example, and some embodiments can be easily generated using techniques known in the art.

[0086] In some embodiments, "monomer" generally refers to a monomer that is linked by a phosphodiester linkage or its analogs to form an oligonucleotide ranging in size from a few monomeric units, such as about 3-4, to about several hundred monomeric units. Phosphodiester-linked analogs include: phosphorothioates, phosphorodithioates, methylphosphonates, selenophosphates, phosphoramidates, etc., as described more fully below.

[0087] In some embodiments, "nucleotides" encompass naturally occurring nucleotides as well as non-naturally occurring nucleotides. It will be clear to those skilled in the art that various nucleotides previously considered to be "non-naturally occurring" were subsequently found in nature. Thus, "nucleotides" include not only known molecules containing purine and pyrimidine heterocycles, but also heterocyclic analogs and tautomers thereof. Illustrative examples of other types of nucleotides are "non-naturally occurring" nucleotides containing adenine, guanine, thymine, cytosine, uracil, purine, xanthine, diaminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanol cytosine, N6,N6-ethanol-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynyl cytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazole pvridin, isocytosine, isoguanine, inosine, and Benner et al., U.S. Pat. No. 5,432,272. The term "nucleotide" is intended to encompass each and all of these examples and their analogs and tautomers. Nucleotides of particular interest are those containing adenine, guanine, thymine, cytosine and uracil, which are considered to be the naturally occurring nucleotides relevant for human therapeutic and diagnostic applications. Nucleotides include the naturally occurring 2'-deoxy and 2'-hydroxy sugars, and their analogs.

[0088] In some embodiments, "analogs" with respect to nucleotides include synthetic nucleotides with modified base moieties and / or modified sugar moieties. Such analogs include synthetic nucleotides designed to enhance binding properties, such as duplex or triplex stability, specificity, etc.

[0089] In some embodiments, "hybridization" refers to the pairing of at least substantially complementary chains of oligomeric compounds. One mechanism of pairing involves hydrogen bonding between complementary nucleoside or nucleotide bases (nucleotides) of the chains of oligomeric compounds, which can be Watson-Crick, Hoogsteen or reverse Hoogsteen hydrogen bonding. For example, adenine and thymine are complementary nucleotides that pair by forming hydrogen bonds. Hybridization can occur under different circumstances.

[0090] In some embodiments, antisense compounds are "specifically hybridizable" when binding of the compound to a target nucleic acid interferes with the normal function of the target nucleic acid to cause modulation of function and / or activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target nucleic acid sequences under conditions where specific binding is desired, i.e., under physiological conditions for in vivo assays or therapeutic treatments, as well as under conditions where the assay is conducted in the context of an in vitro assay.

[0091] In some embodiments, "stringent hybridization conditions" or "stringent conditions" refer to conditions under which a compound will hybridize to its target sequence but hybridize to a minimum number of other sequences. Stringent conditions are sequence-dependent and will vary in different situations, and 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 they are studied. In some cases, stringent hybridization conditions include low concentrations (<0.15M) of salts containing inorganic cations such as Na+ or K+ (i.e., low ionic strength), temperatures above about 20°C to 25°C and below the Tm of the oligomeric compound / target sequence complex, and the presence of denaturants such as formamide, dimethylformamide, dimethyl sulfoxide, or detergent sodium dodecyl sulfate (SDS). For example, for every 1% of formamide, the hybridization rate is reduced by 1.1%. An example of high stringency hybridization conditions is 0.1 times sodium chloride-sodium citrate buffer (SSC) / 0.1% (w / v) SDS at 60°C for 30 minutes.

[0092] In some embodiments, "complementarity" refers to the ability of accurate pairing between two nucleotides on one or two oligomer chains. For example, if the core base at a certain position of antisense compounds can form hydrogen bonds with the core base at a certain position of target nucleic acid, and the target nucleic acid is DNA, RNA or oligonucleotide molecules, the position of the hydrogen bond between oligonucleotide and target nucleic acid can be considered as complementary position. When a sufficient number of complementary positions in each molecule are occupied by nucleotides that can hydrogen bond to each other, oligomeric compounds and other DNA, RNA or oligonucleotide molecules complement each other. Therefore, "specific hybridization" and "complementary" are terms that can be used to indicate the accurate pairing or complementarity of a sufficient degree on a sufficient number of nucleotides, thereby stabilizing and specifically binding between oligomeric compounds and target nucleic acids.

[0093] The sequence of the oligomeric compound does not need to be 100% complementary to the sequence of its target nucleic acid in order to specifically hybridize. In addition, the oligonucleotide can hybridize on one or more sections so that the inserted or adjacent sections do not participate in hybridization events (e.g., loop structures, mismatches or hairpin structures). In some embodiments, the oligomeric compounds disclosed herein include 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 with the target region in the target nucleic acid sequence they target. For example, 18 of the 20 nucleotides of the antisense compound are complementary to the target region and thus the antisense compound of specific hybridization represents 90% complementarity. In this example, the remaining non-complementary nucleotides can be clustered or interspersed with complementary nucleotides and do not need to be adjacent to each other or adjacent to complementary nucleotides. Therefore, an antisense compound with a length of 18 nucleotides and 4 (four) non-complementary nucleotides, which is flanked by two regions that are completely complementary to the target nucleic acid, has an overall complementarity of 77.8% with the target nucleic acid, and therefore will fall within the scope of the present disclosure. The complementarity percentage of antisense compounds and target nucleic acid regions can be determined routinely using BLAST programs (Basic Local Alignment Search Tool) and PowerBLAST programs known in the art. Percent homology, sequence identity or complementarity can be determined, for example, using default settings with the Gap program (Wisconsin Sequence Analysis Package, Unix Version 8, Genetics Computer Group, University Research Park, Madison Wis.), which uses the algorithm of Smith and Waterman.

[0094] In some embodiments, the term "thermal melting point (Tm)" refers to the temperature at which 50% of the oligonucleotides complementary to the target sequence hybridize to the target sequence in equilibrium under specified ionic strength, pH, and nucleic acid concentration. Typically, stringent conditions are those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3, and the temperature is at least about 30°C for short oligonucleotides (e.g., 10 to 50 nucleotides). Stringent conditions can also be achieved by adding destabilizing agents (e.g., formamide).

[0095] In some embodiments, "modulation" refers to an increase (stimulation) or decrease (inhibition) in gene expression.

[0096] In some embodiments, the term "variant" when used in the context of a polynucleotide sequence may include a polynucleotide sequence associated with a wild-type gene. The definition may also include, for example, "allele", "splicing", "species" or "polymorphic" variants. Splice variants may have significant identity with a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may have additional functional domains or no domains. Species variants are polynucleotide sequences that differ from one species to another. Particularly useful are variants of wild-type gene products. Variants may be produced by at least one mutation in a nucleic acid sequence and may result in an altered mRNA or a polypeptide whose structure or function may or may not be altered. Any given natural or recombinant gene may not have, have, or have one or more allele forms. Common mutational changes that cause variants are generally attributed to natural deletions, additions or substitutions of nucleotides. Each of these types of changes may occur alone or in combination with other changes, occurring one or more times in a given order.

[0097] The resulting polypeptides typically have significant amino acid identity relative to each other. Polymorphic variants are variations in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants may also include "single nucleotide polymorphisms" (SNPs) or single base mutations, in which the polynucleotide sequence changes by one base. The presence of a SNP may indicate, for example, that a population has a tendency toward a disease state, i.e., susceptibility versus resistance.

[0098] Derivatized polynucleotides include chemically modified nucleic acids, for example, hydrogens are replaced by alkyl, acyl or amino groups. Derivatives, such as derivative oligonucleotides, can contain non-naturally occurring moieties, such as altered sugar moieties or intersugar linkages. Examples thereof are phosphorothioates and other sulfur-containing substances known in the art. Derivatized nucleic acids can also contain labels, including radionucleotides, enzymes, fluorescent agents, chemiluminescent agents, color developers, substrates, cofactors, inhibitors, magnetic particles, etc.

[0099] In some embodiments, a "derivatized" polypeptide or peptide is one that has been modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction / alkylation, acylation, chemical coupling, or mild formalin treatment. Derivatives may also be modified to directly or indirectly include detectable labels, including but not limited to radioisotope, fluorescent, and enzyme labels.

[0100] 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.

[0101] "Mammal" encompasses warm-blooded mammals (e.g., humans and domestic animals) that are routinely receiving medical care. Examples include felines, canines, equines, bovines, and humans, as well as just humans.

[0102] "Treating" or "treatment" includes treating a disease state in a mammal, and includes: (a) preventing the mammal from developing a disease state, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed with the disease; (b) inhibiting the disease state, such as arresting its development; and / or (c) alleviating the disease state, for example, causing the disease state to regress until a desired endpoint is reached. Treatment also includes improvement of disease symptoms (e.g., relief of pain or discomfort), where such improvement may or may not directly affect the disease (e.g., cause, spread, expression, etc.). The term "treatment" is intended to also include prevention, treatment, and cure. Patients receiving such treatment are any animal in need, including primates, particularly humans, and other mammals, such as horses, cattle, pigs, and sheep; as well as poultry and pets.

[0103] All genes, gene names and gene products disclosed herein are intended to correspond to homologs of any species to which the compositions and methods disclosed herein are applicable. Therefore, these terms include, but are not limited to, genes and gene products from humans and mice. It should be understood that when disclosing genes or gene products from specific species, the disclosure is intended to be exemplary only and should not be construed as limiting unless the context in which it appears clearly indicates. Therefore, for example, for genes disclosed herein, it relates to mammalian nucleic acids in some embodiments, and amino acid sequences are intended to include 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 gene or nucleic acid sequence is human.

[0104] In some embodiments, the term "halogen" refers to any group of fluorine, chlorine, bromine or iodine. In some embodiments, the term "alkyl" refers to a saturated and unsaturated non-aromatic hydrocarbon chain, which can be a straight chain or branched chain, containing a specified number of carbon atoms (these include but are not limited to propyl, allyl or propargyl), which can optionally be inserted into N, O or S. For example, C1-C10 means that the group can have 1 to 10 (inclusive) carbon atoms therein. The term "alkoxy" refers to -O-alkyl. In some embodiments, the term "alkylene" refers to a divalent alkyl (i.e., -R-). The term "alkylenedioxo" refers to a divalent substance of the structure -ORO-, wherein R represents an alkylene. The term "aminoalkyl" refers to an alkyl substituted with an amino group. In some embodiments, the term "sulfhydryl" refers to a -SH group. The term "thioalkoxy" refers to -S-alkyl.

[0105] In some embodiments, the term "aryl" refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system, wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with a substituent. Examples of aryl include phenyl, naphthyl, etc. In some embodiments, the term "arylalkyl" or the term "aralkyl" refers to an alkyl substituted with an aryl group. In some embodiments, the term "arylalkoxy" refers to an alkoxy substituted with an aryl group.

[0106] In some embodiments, as used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, such as 3 to 8 carbons, and such as 3 to 6 carbons, wherein the cycloalkyl group may additionally be optionally substituted. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0107] In some embodiments, the term "heteroaryl" refers to an aromatic 5-8-membered monocyclic, 8-12-membered bicyclic, or 11-14-membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), 1-9 heteroatoms (if tricyclic), the heteroatoms being selected from O, N, or S (e.g., 1-3, 1-6, or 1-9 heteroatoms of carbon atoms and N, O, or S, respectively, if monocyclic, bicyclic, or tricyclic), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by substituents. Examples of heteroaryl include pyridyl, furfuryl, or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, phenylthio, or thienyl, quinolyl, indolyl, thiazolyl, and the like. In some embodiments, the term "heteroarylalkyl" or the term "heteroaralkyl" refers to an alkyl substituted with a heteroaryl. In some embodiments, the term "heteroarylalkoxy" refers to an alkoxy substituted with a heteroaryl.

[0108] In some embodiments, the term "heterocyclyl" refers to a non-aromatic 5-8-membered monocyclic, 8-12-membered bicyclic, or 11-14-membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 11-6 heteroatoms (if bicyclic), 1-9 heteroatoms (if tricyclic), the heteroatoms being selected from O, N, or S (e.g., 1-3, 1-6, or 1-9 heteroatoms of carbon atoms and N, O, or S, respectively, if monocyclic, bicyclic, or tricyclic), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclyl include triazolyl, tetrazolyl, piperazinyl, pyrrolidinyl, dioxane, morpholinyl, tetrahydrofuranyl, and the like.

[0109] In some embodiments, the term "oxo" refers to an oxygen atom, which when attached to carbon forms a carbonyl, when attached to nitrogen forms an N-oxide, and when attached to sulfur forms a sulfoxide or sulfone.

[0110] In some embodiments, the term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted with substituents.

[0111] In some embodiments, the term "substituted" refers to replacing one or more hydrogen groups in a given structure with a specified substituent group, including but not limited to: halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkyloxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkyloxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocycle and aliphatic. It should be understood that the substituent can be further substituted.

[0112] Oligonucleotide compounds and compositions

[0113] Some embodiments refer to nucleic acid sequence information. In some embodiments, any uracil (U) can be interchanged with any thymine (T), and vice versa. For example, in the siRNA with a nucleic acid sequence comprising one or more U, in some embodiments, any one of U can be replaced by T. Similarly, in the siRNA with a nucleic acid sequence comprising one or more T, in some embodiments, any one of T can be replaced by U. In some embodiments, oligonucleotides such as siRNA disclosed herein include RNA or consist of RNA. In some embodiments, oligonucleotides may include DNA or consist of DNA.

[0114] Some embodiments refer to a specific nucleic acid sequence comprising a modified nucleic acid. In some embodiments, the oligonucleotides described herein comprise or consist of a nucleic acid sequence comprising an unmodified version of a modified nucleic acid. In some embodiments, the oligonucleotides described herein comprise or consist of a nucleic acid sequence comprising a nucleic acid sequence comprising a modified nucleic acid, but with any one or more additional modifications or different modifications.

[0115] In some embodiments, oligonucleotide compounds targeting nucleic acid sequences of angiopoietin-like 7 (ANGPTL7) are provided herein, including but not limited to sense and / or antisense non-coding and / or coding sequences associated with ANGPTL7. In some embodiments, the target nucleic acid molecule is not limited to a single ANGPTL7 polynucleotide, but extends to any of the subtypes, receptors, homologs, non-coding regions, etc. of ANGPTL7.

[0116] In some embodiments, a composition is provided comprising 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 comprise two or more antisense oligonucleotides or dsRNA compounds targeting different regions of the same ANGPTL7 nucleic acid target. Many examples of antisense oligonucleotides or dsRNA compounds are illustrated herein and others may be selected from suitable compounds known in the art. Two or more combined compounds may be used together or sequentially.

[0117] In some embodiments, compositions comprising multiple antisense oligonucleotides or dsRNA reagent species are provided. In some embodiments, antisense oligonucleotides or dsRNA reagent species have sequences that are not overlapping and non-adjacent to another type of naturally occurring target sequence. In some embodiments, multiple antisense oligonucleotides or dsRNA reagent species have specificity to different natural target genes. In some embodiments, dsRNA reagents are allele-specific.

[0118] The present disclosure provides methods, compositions, and kits for administering and delivering the antisense oligonucleotide or dsRNA agents described herein.

[0119] Composition

[0120] In some embodiments, compositions comprising oligonucleotides are disclosed herein. In some embodiments, the compositions comprise oligonucleotides targeting ANGPTL7. In some embodiments, the compositions consist of oligonucleotides targeting ANGPTL7. In some embodiments, the compositions described herein are used in methods for treating a condition in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in methods for treating conditions as described herein. Some embodiments relate to the use of compositions comprising oligonucleotides in methods for treating conditions as described herein. The compositions (e.g., oligonucleotide compositions) may comprise or consist of dsRNA agents as described herein. The compositions (e.g., oligonucleotide compositions) may comprise or consist of siRNA as described herein. The compositions (e.g., oligonucleotide compositions) may comprise or consist of antisense oligonucleotides as described herein.

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

[0122] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7 and, when administered to a subject in an effective amount, reduces circulating ANGPTL7 protein levels. In some embodiments, ANGPTL7 protein levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by about 10% or more compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by no more than about 10% compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before administration. In some embodiments, the ANGPTL7 protein level is reduced by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% compared to before administration. In some embodiments, ANGPTL7 protein levels are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or a range defined by either of the foregoing two percentages.

[0123] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7 and, when administered to a subject in an effective amount, reduces symptoms of glaucoma. In some embodiments, the symptoms of glaucoma are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by about 10% or more compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the symptoms of glaucoma are reduced by no more than about 10% compared to before administration. In some embodiments, compared with before administration, glaucoma symptoms are reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90% or no more than about 100%. In some embodiments, glaucoma symptoms are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any of the above two percentages. In some embodiments, glaucoma symptoms are the incidence of glaucoma or a subtype of glaucoma. In some embodiments, glaucoma symptoms are the severity of glaucoma or a subtype of glaucoma. Examples of glaucoma subtypes include nonspecific glaucoma, primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG).

[0124] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7 and, when administered to a subject in an effective amount, reduces intraocular pressure. In some embodiments, the intraocular pressure is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the intraocular pressure is reduced by about 10% or more compared to before administration. In some embodiments, the intraocular pressure is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before administration. In some embodiments, the intraocular pressure is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the intraocular pressure is reduced by no more than about 10% compared to before administration. In some embodiments, compared to before administration, the intraocular pressure is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the intraocular pressure is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or a range defined by any one of the above two percentages.

[0125] Modifier Mode

[0126] In an embodiment, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a modification containing a modified nucleoside and / or a modified internucleoside connection, 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 connection. In some embodiments, the oligonucleotide comprises a modified internucleoside connection. In some embodiments, the modified internucleoside connection comprises an alkylphosphonate, a thiophosphate, a methylphosphonate, a dithiophosphate, an alkylthiophosphonate, an aminophosphate, a carbamate, a carbonate, a phosphotriester, an acetamidate, or a carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside connection comprises one or more thiophosphate connections. The benefits of the modified internucleoside connection may include reduced toxicity or improved pharmacokinetics. The composition (e.g., an oligonucleotide composition) may comprise or consist of a dsRNA agent as described herein. The composition (e.g., an oligonucleotide composition) may comprise or consist of an siRNA as described herein. A composition (eg, an oligonucleotide composition) may comprise or consist of an antisense oligonucleotide described herein.

[0127] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a series of modified internucleoside linkages defined by any two of the above numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, 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, 36 or more modified internucleoside linkages, 37 or more modified internucleoside linkages, 38 or more modified inter A plurality of modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

[0128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a modified nucleoside. In embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, 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' restricted 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. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl. In some embodiments, the modified nucleoside comprises a 2'-O-allyl. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2' fluorine-modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'O-alkyl modified nucleoside.Benefits of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0129] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 modified nucleosides, or a series of nucleosides defined by any two of the above numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0130] In some embodiments, the hydrophobic moiety is attached to an oligonucleotide (e.g., the sense strand and / or antisense strand of a siRNA, or an ASO). In some embodiments, the hydrophobic moiety is attached to the 3' end of the oligonucleotide. In some embodiments, the hydrophobic moiety is attached to the 5' end of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol.

[0131] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid is attached to the 3' end of the oligonucleotide. In some embodiments, the lipid is attached to the 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholyl, behenoyl, docosahexaenoyl, myristyl, palmitylstearyl or alpha-tocopherol, or a combination thereof. In some embodiments, the lipid comprises cholesterol.

[0132] In some embodiments, the composition comprises an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, the RGD peptide is attached to the 3' end of the oligonucleotide. In some embodiments, the RGD peptide is attached to the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to the 5' end of the sense strand, or attached to the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to the 5' end of the antisense strand, or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the oligonucleotide includes an RGD peptide and a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises a ring (-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises aminobenzoic acid derived RGD. In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises a plurality of such RGD peptides. For example, the RGD peptide may comprise 2, 3, or 4 RGD peptides.

[0133] In some embodiments, the oligonucleotide comprises a dsRNA agent as described herein. In some embodiments, the oligonucleotide comprises an siRNA as described herein. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide as described herein. In some embodiments, one or more nucleotides in the sense strand and / or antisense strand of an antisense oligonucleotide, a dsRNA agent or an siRNA are modified according to any modification or modification pattern as described herein.

[0134] In some embodiments, a modification or modification pattern disclosed herein includes a cholesterol moiety.

[0135] dsRNA reagents

[0136] 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 having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NO: 1-4412. In some cases, the antisense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to the reverse complement of the sense strand. In some cases, the antisense strand comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to a sequence selected from SEQ ID NO: 1-4412.

[0137] In some cases, the length of each strand of the dsRNA agent can be in the range of 12-30 nucleotides. For example, the length of each strand can be between 14-30 nucleotides, between 17-30 nucleotides, between 25-30 nucleotides, between 27-30 nucleotides, between 17-23 nucleotides, between 17-21 nucleotides, between 17-19 nucleotides, between 19-25 nucleotides, between 19-23 nucleotides, between 19-21 nucleotides, between 21-25 nucleotides, or between 21-23 nucleotides.

[0138] The sense strand and antisense strand form duplex dsRNA usually.The length of the duplex region of dsRNA reagent can be 12-30 nucleotide pairs.For example, the length of duplex region can be between 14-30 nucleotide pairs, length between 17-30 nucleotide pairs, length between 25-30 nucleotide pairs, length between 27-30 nucleotide pairs, length between 17-23 nucleotide pairs, length between 17-21 nucleotide pairs, length between 17-19 nucleotide pairs, length between 19-25 nucleotide pairs, length between 19-23 nucleotide pairs, length between 19-21 nucleotide pairs, length between 21-25 nucleotide pairs or length between 21-23 nucleotide pairs.In another example, the duplex region has a length of about 15,16,17,18,19,20,21,22,23,24,25,26 and 27.

[0139] In some embodiments, the dsRNA agent comprises one or more overhang regions and / or capping groups at the 3'-end or 5'-end or both ends of the chain. In some cases, the length of the overhang is about 1-6 nucleotides, for example, 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhang may be the result that one chain is longer than another, or the result that two chains of the same length are staggered. The overhang may form a mismatch with the target mRNA, or it may be complementary to the targeted gene sequence, or it may be other sequences. The first and second chains may also be connected, for example, by additional bases to form a hairpin, or by other non-base joints.

[0140] In some embodiments, described herein are compositions comprising RNA interference (RNAi) agents. In some embodiments, the RNAi agent is capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7). In some embodiments, the RNAi agent comprises an siRNA as described herein. In some embodiments, the RNAi agent comprises a double-stranded RNA (dsRNA). In some embodiments, the dsRNA comprises a sense strand and an antisense strand (e.g., a sense strand and / or antisense strand as described herein). In some embodiments, the antisense strand is complementary to a portion of a nucleic acid having a nucleoside sequence of SEQ ID NO: 11085. In some embodiments, the antisense strand is complementary to a portion of a nucleic acid having a nucleoside sequence of SEQ ID NO: 11086. In some embodiments, each strand has 14 to 30 nucleotides.

[0141] In some embodiments, described herein are compositions comprising an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7); wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides.

[0142] In some embodiments, described herein are compositions comprising an RNA interference (RNAi) agent capable of inhibiting or modulating the expression of angiopoietin-like 7 (ANGPTL7); wherein the RNAi agent comprises a double-stranded RNA (dsRNA) comprising a sense strand and an antisense strand, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11086, and each strand having 14 to 30 nucleotides.

[0143] In some embodiments, one or more modifications confer nuclease resistance to an oligonucleotide (e.g., an siRNA or an antisense oligonucleotide). In some embodiments, the modification pattern confer nuclease resistance to an oligonucleotide (e.g., an siRNA or an antisense oligonucleotide). For example, the modification pattern 1S, 2S, 3S, 4S, 5S, 1AS, 2AS, 3AS, 4AS, or ASO1 can confer nuclease resistance.

[0144] dsRNA modification

[0145] The modifications described herein with respect to dsRNA agents may be applicable to antisense oligonucleotides described elsewhere herein.The modifications described herein with respect to dsRNA agents may be applicable to siRNA oligonucleotides described elsewhere herein.

[0146] In some embodiments, one or more nucleotides in the sense strand and / or antisense strand of a dsRNA agent are modified. In some cases, each nucleotide in the sense strand and antisense strand of a dsRNA is modified. The modification of the sense strand and antisense strand can independently include at least two different modifications. In some cases, not each nucleotide in the sense strand and antisense strand is modified. In some cases, the nucleotides in the sense strand and / or antisense strand are not modified.

[0147] In some cases, the sense strand comprises at least one motif with three identical modifications on three consecutive nucleotides, wherein at least one of the motifs occurs at or near the cleavage site of the antisense strand. In some cases, the antisense strand comprises at least one motif with three identical modifications on three consecutive nucleotides. The modification pattern of the antisense strand can be shifted by one or more nucleotides relative to the modification pattern of the sense strand.

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

[0149] In some cases, the sense strand comprises at least two motifs with three identical modifications on three consecutive nucleotides, where at least one of the motifs occurs at the cleavage site of the strand and at least one of the motifs occurs at another portion of the strand that is at least one nucleotide away from the motif at the cleavage site. In some cases, the antisense strand comprises at least one motif with three identical modifications on three consecutive nucleotides, where at least one of the motifs occurs at or near the cleavage site of the strand and at least one of the motifs occurs at another portion of the strand that is at least one nucleotide away from the motif at or near the cleavage site. In some cases, the modification of the motif that occurs at the cleavage site in the sense strand is different from the modification of the motif that occurs at or near the cleavage site in the antisense strand.

[0150] In some cases, the sense strand comprises at least one motif of three 2'-F modifications on three consecutive nucleotides, wherein at least one of the motifs occurs at the cleavage site of the strand. In some cases, the antisense strand comprises at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides.

[0151] In some cases, the sense strand comprises one or more motifs having three identical modifications on three consecutive nucleotides, wherein one or more additional motifs occur at another portion of the strand that is at least one nucleotide away from the three 2'-F modifications at the cleavage site. The antisense strand may comprise one or more motifs having three identical modifications on three consecutive nucleotides, wherein one or more additional motifs occur at another portion of the strand that is at least one nucleotide away from the three 2'-O-methyl modifications. In some cases, at least one of the nucleotides having the 2'-F modification may form a base pair with one of the nucleotides having the 2'-O-methyl modification.

[0152] In some embodiments, if the dsRNA agent comprises an overhang, the nucleotides in the overhang region of the dsRNA agent can be each independently a modified or unmodified nucleotide. Non-limiting examples of modification include, but are not limited to, 2'-sugar modifications, such as 2-F 2'-O methyl, thymidine (T), 2'-0-methoxyethyl-5-methyluridine (Teo), 2'-0-methoxyethyladenosine (Aeo), 2'-0-methoxyethyl-5-methylcytidine (m5Ceo) and any combination thereof. For example, TT can be an overhang sequence at either end of either chain. The overhang can form a mismatch with the target mRNA, or it can be complementary to the targeted gene sequence, or it can be other sequences.

[0153] In some embodiments, if the dsRNA agent comprises an overhang, the 5'- and / or 3'-overhang on the sense strand, antisense strand or two strands of the dsRNA agent can be phosphorylated. In some embodiments, the overhang region comprises two nucleotides with a thiophosphate between the two nucleotides, wherein the two nucleotides can be the same or different. In some embodiments, the overhang is present at the 3'-end of the sense strand, antisense strand or two strands. In some embodiments, the 3'-overhang is present in the antisense strand. In some embodiments, the 3'-overhang is present in the sense strand.

[0154] 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, for example, 2'OMe-guanosine nucleotides, 2'OMe-uridine nucleotides, 2'OMe-adenosine nucleotides, 2'OMe-cytosine nucleotides, or combinations thereof. In some cases, the modified dsRNA agent does not comprise 2'OMe-cytosine nucleotides. In some embodiments, the modified dsRNA agent comprises a hairpin loop structure.

[0155] In certain aspects, the IC50 of the modified dsRNA agent is less than or equal to ten times the IC50 of the corresponding unmodified dsRNA (e.g., the IC50 of the modified dsRNA agent is less than or equal to ten times the IC50 of the corresponding unmodified dsRNA agent). In some embodiments, the IC50 of the modified dsRNA agent is less than or equal to three times the IC50 of the corresponding unmodified dsRNA agent. In some embodiments, the IC50 of the modified dsRNA agent is less than or equal to two times the IC50 of the corresponding unmodified dsRNA agent. It will be apparent to those skilled in the art that dose response curves can be generated and the IC50 values ​​of the modified dsRNA agent and the corresponding unmodified dsRNA agent can be easily determined using methods known to those skilled in the art.

[0156] The modified dsRNA agent may have 3' overhangs of 1, 2, 3, 4 or more nucleotides on one or both sides of the double-stranded region, or may not have overhangs (i.e., with flat ends). In some cases, the modified dsRNA agent has 3' overhangs of two nucleotides on each side of the double-stranded region. In some cases, the 3' overhang on the antisense strand is complementary to the target sequence, and the 3' overhang on the sense strand is complementary to the complementary strand of the target sequence. In some cases, the 3' overhang does not have complementarity with the target sequence or its complementary strand. In some embodiments, the 3' overhang comprises one, two, three, four or more nucleotides, such as 2'-deoxy (2'H) nucleotides. In some cases, the 3' overhang comprises deoxythymidine (dT) nucleotides.

[0157] In some embodiments, the 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 modified nucleotides in the double-stranded region of the dsRNA agent. In some embodiments, less than about 30% (e.g., less than about 30%, 25%, 20%, 15%, 10%, or 5%) or about 1% to about 30% (e.g., about 1%-30%, 5%-30%, 10%-30%, 15%-30%, 20%-30%, or 25%-30%) of the nucleotides in the double-stranded region of the dsRNA agent comprise modified nucleotides.

[0158] In some embodiments, the dsRNA agent does not include 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 include a 2'-deoxynucleotide, for example, in the sense strand and / or antisense strand of the double-stranded region. In some cases, the nucleotides at the 3'-end of the double-stranded region in the sense strand and / or antisense strand are not modified nucleotides. In some cases, the nucleotides near the 3'-end of the double-stranded region in the sense strand and / or antisense strand (for example, within one, two, three or four nucleotides at the 3'-end) are not modified nucleotides.

[0159] 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 not have an overhang (i.e., have a flat end). In some cases, the dsRNA agent has a 3' overhang of two nucleotides on each side of the double-stranded region. In some embodiments, the 3' overhang comprises one, two, three, four or more nucleotides, such as 2'-deoxy (2'H) nucleotides. In some cases, the 3' overhang comprises a deoxythymidine (dT) nucleotide.

[0160] The dsRNA agent may also have a blunt end, located at the 5'-end of the antisense strand (or the 3'-end of the sense strand), or vice versa. In some cases, the antisense strand of the dsRNA has a nucleotide overhang at the 3' end, and the 5' end is a blunt end. Although not being bound by theory, the asymmetric blunt end at the 5'-end of the antisense strand and the 3'-end overhang of the antisense strand may be conducive to the loading of the guide strand into the RISC process.

[0161] In some embodiments, the dsRNA agent may also have two blunt ends at both ends of the dsRNA duplex.

[0162] In some embodiments, each nucleotide in the sense and antisense strands of the dsRNA agent, including nucleotides that are part of the motif, can be modified. Each nucleotide can be modified with the same or different modifications, which can include one or more changes in one or both of the non-linked phosphate oxygens and / or one or more of the linked phosphate oxygens; changes in the composition of the ribose, such as changes in the 2' hydroxyl group on the ribose; wholesale replacement of the phosphate moiety with a "dephosphorylated" linker; modification or replacement of naturally occurring bases; and replacement or modification of the ribose-phosphate backbone. In some embodiments, less than all nucleotides in the sense and antisense strands are modified.

[0163] Because nucleic acid is a polymer of subunits, in some cases, many modifications occur in the position repeated in nucleic acid, such as the modification of base or phosphate moiety, or the non-connected O of phosphate moiety. In some cases, modification occurs in all tested positions in nucleic acid, but not in other cases. For example, modification may only occur in 3' or 5' terminal positions, may only occur in terminal regions, such as positions on terminal nucleotides or in the last 2,3,4,5 or 10 nucleotides of a chain. Modification may occur in double-stranded regions, single-stranded regions or both. Modification may only occur in the double-stranded regions of RNA or may only occur in the single-stranded regions of RNA. For example, the phosphorothioate modification of the non-connected O position may only occur in one or both ends, may only occur in the terminal regions, such as positions on terminal nucleotides or in the last 2,3,4,5 or 10 nucleotides of a chain, or may occur in double-stranded and single-stranded regions, particularly in the end. One or more 5' ends may be phosphorylated.

[0164] For example, stability can be improved to include specific bases in the overhang, or in the single-stranded overhang, such as in the 5' or 3' overhang, or in both, including modified nucleotides or nucleotide substitutes. For example, purine nucleotides can be included in the overhang. In some embodiments, all or some bases in the 3' or 5' overhang can be modified, for example, with modification as described herein. Modification can include, for example, the use of modifications known in the art at the 2' position of ribose, such as deoxyribonucleotides, 2'-deoxy-2'-fluoro (2'-F) or 2'-O-methyl modified rather than the ribose of the core base, and the modification in the phosphate group, such as the use of phosphorothioate modifications. In some cases, the overhang does not need to be homologous to the target sequence.

[0165] In some embodiments, each residue of 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 may contain more than one modification. In some embodiments, each residue of the sense strand and the antisense strand is independently modified with 2'-O-methyl or 2'-fluoro.

[0166] In some embodiments, there are at least two different modifications on the sense strand and the antisense strand. The two modifications can be 2'-O-methyl or 2'-fluoro modifications, etc.

[0167] In some embodiments, the sense strand and the antisense strand each contain two differently modified nucleotides selected from 2'-0-methyl or 2'-fluoro.

[0168] In some embodiments, each residue of the sense strand and the antisense strand is independently modified with 2'-0-methyl nucleotides, 2'-deoxyfluoro nucleotides, 2-ON-methylacetamide (2'-0-NMA) nucleotides, 2'-0-dimethylaminoethoxyethyl (2'-0-DMAEOE) nucleotides, 2'-0-aminopropyl (2'-0-AP) nucleotides, or 2'-ara-F nucleotides.

[0169] The types of modifications contained in the alternating motif can be the same or different. For example, if A, B, C, D each represent a type of modification on a nucleotide, the alternating pattern, i.e., the modification on every other nucleotide, can be the same, but each of the sense strand or antisense strand can select from several modification possibilities in the alternating motif, such as "ABABAB...", "ACACAC...", "BDBDBD...", or "CDCDCD...", etc.

[0170] In some embodiments, the dsRNA agent comprises a modification pattern of an alternating motif on the sense strand that is converted relative to the modification pattern of the alternating motif on the antisense strand. This conversion can be such that the modification groups of the nucleotides of the sense strand correspond to different modification groups of the nucleotides of the antisense strand, and vice versa. For example, when the sense strand is paired with the antisense strand in the dsRNA duplex, the alternating motif in the sense strand can start with "ABABAB" from the 5'-3' of the strand, and the alternating motif in the antisense strand can start with "BABABA" from the 3'-5 of the strand in the duplex region. As another example, the alternating motif in the sense strand can start with "AABBAABB" from the 5'-3' of the strand, and the alternating motif in the antisense strand can start with "BBAABBAA" from the 3'-5 of the strand in the duplex region, so that there is a complete or partial conversion of the modification pattern between the sense strand and the antisense strand.

[0171] In some embodiments, the dsRNA agent comprises a pattern of alternating motifs of 2'-0-methyl modification and 2'-F modification on the initial sense strand, with a switch relative to the pattern of alternating motifs of 2'-0-methyl modification and 2'-F modification on the initial antisense strand, i.e., 2'-0-methyl modified nucleotides on the sense strand are base paired with 2'-F modified nucleotides on the antisense strand, and vice versa. Position 1 of the sense strand may start with a 2'-F modification, and position 1 of the antisense strand may start with a 2'-O-methyl modification. Introducing one or more motifs of three identical modifications on three consecutive nucleotides into the sense strand and / or antisense strand interrupts the initial modification pattern present in the sense strand and / or antisense strand. This modification pattern of interrupting the sense strand and / or antisense strand by introducing one or more motifs of three identical modifications on three consecutive nucleotides of the sense strand and / or antisense strand can enhance the gene silencing activity of the target gene.

[0172] The dsRNA agent may comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or the antisense strand or both in any position of the strand. For example, the internucleotide linkage modification may occur on each nucleotide on the sense strand and / or the antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand or the antisense strand; or the sense strand or the antisense strand comprises two internucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may be switched relative to the alternating pattern of the internucleotide linkage modification on the antisense strand.

[0173] In some embodiments, dsRNA comprises phosphorothioate or methylphosphonate internucleotide connection modification in the overhang region.For example, the overhang region comprises two nucleotides, and there is phosphorothioate or methylphosphonate internucleotide connection between the two nucleotides.Internucleotide connection modification can also be carried out to connect the overhang nucleotide with the terminal pairing nucleotide in the duplex region.For example, at least 2,3,4 or all overhang nucleotides can be connected by phosphorothioate or methylphosphonate internucleotide connection connection, and optionally, there can be other phosphorothioate or methylphosphonate internucleotide connection that overhang nucleotide is connected with the pairing nucleotide adjacent to the overhang nucleotide.For example, there may be at least two phosphorothioate internucleotide connections between the three nucleotides at the end, wherein two of the three nucleotides are overhang nucleotides, and the third is the pairing nucleotide adjacent to the overhang nucleotide.In some cases, these three nucleotides at the end may be located at the 3'-end of the antisense strand.

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

[0175] In some embodiments, the antisense strand of the dsRNA agent comprises two blocks of two phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0176] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 3 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0177] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 4 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0178] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 5 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0179] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 6 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0180] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 7 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, 6, 7, or 8 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0181] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 8 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, 4, 5, or 6 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0182] In some embodiments, the antisense strand of the dsRNA agent comprises 2 blocks of 9 phosphorothioate or methylphosphonate internucleotide linkages separated by about 1, 2, 3, or 4 phosphate internucleotide linkages, wherein one of the phosphorothioate or methylphosphonate internucleotide linkages is located at any position in the oligonucleotide sequence, and the antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methylphosphonate, and phosphate internucleotide linkages or an antisense strand comprising either phosphorothioate or methylphosphonate and phosphate bonds.

[0183] In some embodiments, the dsRNA agent comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1-10 of the terminal position(s) of the sense strand and / or antisense strand. For example, at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides may be linked by phosphorothioate or methylphosphonate internucleotide linkages at one or both ends of the sense strand and / or antisense strand.

[0184] In some embodiments, the dsRNA agent comprises one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1-10 of the internal regions of the duplex of each sense strand and / or antisense strand. For example, at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides may be linked by phosphorothioate methylphosphonate internucleotide linkages at positions 8-16 of the duplex region counted from the 5'-end of the sense strand; the dsRNA may optionally further comprise one or more phosphorothioate or methylphosphonate internucleotide linkage modifications within 1-10 of the terminal position(s).

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

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

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

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

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

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

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

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

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

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

[0195] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1-5 and 1 phosphorothioate internucleotide linkage modification at positions 18-23 (counted from the 5'-end) of the sense strand, and 1 phosphorothioate internucleotide linkage modification at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 18-23 (counted from the 5'-end) of the antisense strand.

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

[0197] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 20 and 21 (counting from the 5'-end) of the antisense strand.

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

[0199] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counted from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 21 and 22 (counted from the 5'-end) of the antisense strand.

[0200] In some embodiments, the dsRNA agent comprises 2 phosphorothioate internucleotide linkage modifications within positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 22 and 23 of the sense strand (counted from the 5'-end), and 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 22 of the antisense strand (counted from the 5'-end).

[0201] In some embodiments, the dsRNA agent comprises 1 phosphorothioate internucleotide linkage modification at position 1 and 1 phosphorothioate internucleotide linkage modification at position 21 (counting from the 5'-end) of the sense strand, and 2 phosphorothioate internucleotide linkage modifications at positions 1 and 2 and 2 phosphorothioate internucleotide linkage modifications at positions 23 and 23 (counting from the 5'-end) of the antisense strand.

[0202] In some embodiments, the dsRNA agent comprises one or more mismatches or combinations thereof with the target in the duplex. Mismatches may occur in the overhang region or the duplex region. Base pairs can be ranked according to their tendency to promote dissociation or melting (e.g., according to the free energy of binding or dissociation of a specific pairing, the simplest method is to examine these pairs on the basis of a single pair, although the next neighbor or similar analysis can also be used). In some cases, in terms of promoting dissociation: A:U is better than G:C; G:U is better than G:C; and I:C is better than G:C (I = inosine). In some cases, mismatches, such as non-canonical or in addition to canonical pairing (as described elsewhere herein), are better than canonical (A:T, A:U, G:C) pairings; and the pairing comprising universal bases is better than canonical pairings. In some embodiments, the dsRNA agent comprises at least one of the first 1, 2, 3, 4, or 5 base pairs within the duplex region from the 5'-end of the antisense strand, which can be independently selected from: A:U, G:U, I:C, and mismatched pairs, such as non-canonical or in addition to canonical pairs or comprising universal bases, to promote dissociation of the antisense strand at the 5' end of the duplex.

[0203] In some embodiments, the nucleotide at position 1 from the 5'-end of the antisense strand in the duplex region is selected from A, dA, dU, U and dT. In some embodiments, at least one of the first 1, 2 or 3 base pairs from the 5'-end of the antisense strand in the duplex region is an AU base pair. For example, the first base pair from the 5' end of the antisense strand in the double-stranded region is an AU base pair.

[0204] In some embodiments, dsRNA agent is conjugated with one or more carbohydrate moieties, which can optimize one or more characteristics of dsRNA agent. In some cases, carbohydrate moieties are attached to the modified subunit of dsRNA agent. For example, the ribose of one or more ribonucleotide subunits of dsRNA agent can be replaced by another part, such as being attached to the non-carbohydrate (e.g., cyclic) carrier of carbohydrate ligand. The ribonucleotide subunit wherein the ribose of subunit is so replaced is referred to herein as ribose replacement modified subunit (RRMS). Annular carrier can be carbocyclic system, that is, all ring atoms are carbon atoms, or heterocyclic system, that is, one or more ring atoms can be heteroatoms, such as nitrogen, oxygen, sulfur. Annular carrier can be monocyclic system, or can include two or more rings, such as condensed ring. Annular carrier can be a fully saturated ring system, or it can contain one or more double bonds.

[0205] In some embodiments, the ligand is attached to the dsRNA through a carrier. In some cases, the carrier includes (i) at least one "main chain attachment point" or two "main chain attachment points" and (ii) at least one "tether attachment point". In some cases, a "main chain attachment point" refers to a functional group, such as a hydroxyl group, or is generally available for and suitable for incorporating the carrier into a main chain of ribonucleic acid, such as a phosphate, or a modified phosphate, such as a key of a sulfur-containing main chain. In some embodiments, a "tether attachment point" (TAP) refers to a constituent ring atom of a cyclic carrier, such as a carbon atom or a heteroatom (different from an atom providing a main chain attachment point), which connects a selected portion. The portion can be, for example, a carbohydrate, such as a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, and a polysaccharide. Optionally, the selected portion is connected by the insertion tether of the cyclic carrier. Therefore, the cyclic carrier can include a functional group, such as an amino group, or generally provides a key suitable for incorporating or tethering another chemical entity, such as a ligand constituting a ring.

[0206] In some embodiments, the dsRNA agent is conjugated to the ligand through a carrier, wherein the carrier can be a cyclic group or an acyclic group; for example, the cyclic group is selected from pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinone, tetrahydrofurfuryl and decahydronaphthalene; for example, the acyclic group is selected from a serinol backbone or a diethanolamine backbone. The dsRNA agent can be optionally conjugated to one or more ligands. The ligand can be attached to the sense strand, the antisense strand, or both strands at the 3'-end, the 5'-end, or both ends. For example, the ligand can be conjugated to the sense strand, particularly the 3'-end of the sense strand.

[0207] In some embodiments, dsRNA is modified to promote stability.Synthetic siRNA, such as dsRNA herein, stabilization for rapid nuclease degradation can be considered as a prerequisite for in vivo and therapeutic applications.This can be achieved using various stable chemicals previously developed for other nucleic acid drugs (such as ribozymes and antisense molecules).These include chemical modifications to natural 2'-OH groups in the ribose backbone, such as 2'-O-methyl (2'OMe) and 2'-fluorine (2'F) replacements, which can be easily introduced into siRNA, such as 2'-modified nucleotides in RNA synthesis.In some cases, introducing chemical modifications to natural siRNA duplexes can have a negative impact on RNAi activity, so the design of chemically modified siRNAs may require random screening methods to identify duplexes that retain effective gene silencing activity.

[0208] In some cases, endonucleolytic cleavage of the target mRNA is impaired when cleavage of the sense strand is inhibited. In some cases, incorporation of 2'-0-Me ribose into the Ago2 cleavage site in the sense strand inhibits RNAi. In some cases, for phosphorothioate modifications, effective RNAi may require cleavage of the sense strand.

[0209] In some cases, the dsRNA agent comprises a 2'-F modified residue, for example at the Ago2 cleavage site. The modification may or may not be motif specific, for example, one modification comprises a 2'-F modification of all pyrimidines on both the sense and antisense strands, as long as there are pyrimidine residues, without any selectivity.

[0210] In some cases, the dsRNA agent comprises two 2'-F modified residues, for example, at the Ago2 cleavage site, on the sense strand and / or the antisense strand. In some cases, for each particular strand, all pyrimidines or all purines are modified.

[0211] In some cases, the dsRNA agent comprises a 2'-OMe modification or various combinations of 2'-F, 2'-OMe and phosphorothioate modifications to stabilize the siRNA. In some cases, the residues at the cleavage site of the antisense strand are not modified with 2'-OMe to increase the stability of the siRNA.

[0212] siRNA

[0213] In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide targeting ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand. In some embodiments, the siRNA comprises a double-stranded agent described herein.

[0214] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 14-30 nucleosides in length. In some embodiments, the composition comprises a sense strand of at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the above two numbers. In some embodiments, the composition comprises an antisense strand of 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by either of the foregoing two numbers.

[0215] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11085. In some embodiments, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more consecutive nucleosides of one of SEQ ID NO: 11085.

[0216] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, each strand independently being about 14-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 14-30 consecutive nucleosides of a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11086. In some embodiments, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more consecutive nucleosides of one of SEQ ID NO: 11086.

[0217] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0218] In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, or a range of nucleotides defined by any two of the above numbers. In some embodiments, the 3' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, or a range of nucleotides defined by any two of the above numbers. In some embodiments, the 5' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0219] 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 nucleotide range defined by any two of the above numbers. In some embodiments, the 3' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, or a nucleotide range defined by any two of the above numbers. In some embodiments, the 5' overhang comprises 1, 2 or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

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

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

[0222] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 19-mer or a combination thereof in human ANGPTL7 mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer and 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer or 25-mer in human ANGPTL7 mRNA.

[0223] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to human ANGPTL7 mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 10 human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 20 human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 30 human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 40 human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human ANGPTL7 mRNA and less than or equal to 50 human off-targets with no more than 3 mismatches in the antisense strand.

[0224] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not contain a SNP, and the minor allele frequency (MAF) is greater than or equal to 1% (positions 2-18). In some embodiments, the MAF is greater than or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0225] In some embodiments, the siRNA binds to human ANGPTL7 mRNA with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds to a human ANGPTL7 mRNA target site that does not contain a SNP with a minor allele frequency (MAF) greater than or equal to 1% (positions 2-18). In some embodiments, the sense strand and the antisense strand each comprise a seed region that is not identical to a seed region of a human miRNA. In some embodiments, the sense strand comprises a seed region that is different from a seed region of a human miRNA. In some embodiments, the antisense strand comprises a seed region that is different from a seed region of a human miRNA.

[0226] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand. In some embodiments, the oligonucleotide comprises a nucleic acid sequence (e.g., a sense strand sequence or an antisense strand sequence). In some embodiments, the sense strand comprises a sense strand sequence. In some embodiments, the antisense strand comprises an antisense strand sequence. In some embodiments, the nucleic acid sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 1-4412, a sequence that is at least 80% identical to any one of SEQ ID NOs: 1-4412, a sequence that is at least 85% identical to any one of SEQ ID NOs: 1-4412, a sequence that is at least 90% identical to any one of SEQ ID NOs: 1-4412, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 1-4412. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 1-4412, or a nucleic acid sequence having 1, 2, 3 or 4 nucleoside substitutions, additions or deletions or consisting thereof. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 1-4412, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions or deletions or consisting thereof. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 1-4412 or consisting thereof. 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.

[0227] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset A or siRNAs having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset A. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset B or siRNAs having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset B. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset C or siRNAs having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset C. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset D or siRNAs having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset D. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset E or siRNAs thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs of siRNA subset E.

[0228] In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 1-2206, comprises or consists of a sequence that is at least 80% identical to any one of SEQ ID NOs: 1-2206, comprises or consists of a sequence that is at least 85% identical to any one of SEQ ID NOs: 1-2206, comprises or consists of a sequence that is at least 90% identical to any one of SEQ ID NOs: 1-2206, or comprises or consists of a sequence that is at least 95% identical to any one of SEQ ID NOs: 1-2206. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-2206, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-2206, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-2206. In some embodiments, the sense strand comprises an overhang as described herein. In some embodiments, the sense strand comprises one or more modifications or modification patterns as described herein.

[0229] In some embodiments, the sense strand sequence comprises the same sequence as SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192 have at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, or at least 95% identity. In some embodiments, the sense strand sequence comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 9 48, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 1436, 14 38, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having or consisting of 1, 2, 3 or 4 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises SEQ ID NO:7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192, or a sense strand sequence thereof having 1 or 2 nucleotide substitutions, additions or deletions, or consisting thereof.In some embodiments, the sense strand sequence comprises SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 14 29, 1434, 1436, 1438, 1537, 1541, 1639, 1654, 1691, 1693, 1762, 1764, 1765, 1794, 1796, 1797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099, or 2192. In some embodiments, the sense strand comprises an overhang described herein.

[0230] In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset A or a sense strand thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset A. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset B or a sense strand thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset B. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset C or a sense strand thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset C. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset D or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset D. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset E or a sense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises or consists of the sense strand of any one of the siRNAs of siRNA subset E.

[0231] In some embodiments, the sense strand sequence comprises or consists of a sequence in SEQ ID NO: 11089, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence in SEQ ID NO: 11089.

[0232] In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 2207-4412, a sequence that is at least 80% identical to any one of SEQ ID NOs: 2207-4412, a sequence that is at least 85% identical to any one of SEQ ID NOs: 2207-4412, a sequence that is at least 90% identical to any one of SEQ ID NOs: 2207-4412, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 2207-4412. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2207-4412, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises the sequence of any one of SEQ ID NO: 2207-4412, or an antisense strand sequence having 1 or 2 nucleoside substitutions, additions or deletions or consisting of them. In some embodiments, the antisense strand sequence comprises or consists of a sequence in SEQ ID NO: 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.

[0233] In some embodiments, the antisense strand sequence comprises the same sequence as SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3635, 3640, 364 2, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398 having at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, or at least 95% identity. In some embodiments, the antisense strand sequence comprises SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 294 7. 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1, 2, 3 or 4 nucleoside substitutions, additions or deletions, or consisting thereof.In some embodiments, the antisense strand sequence comprises SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 363 5, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305 or 4398, or an antisense strand sequence thereof having 1 or 2 nucleotide substitutions, additions or deletions, or consisting thereof. In some embodiments, the antisense strand sequence comprises SEQ ID NO:2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2 946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 3630, 3631, 3635, 3640, 3642, 3644, 3743, 3747, 3845, 3860, 3897, 3899, 3968, 3970, 3971, 4000, 4002, 4003, 4174, 4175, 4236, 4291, 4293, 4297, 4301, 4305, or 4398. In some embodiments, the antisense strand comprises an overhang as described herein. In some embodiments, the antisense strand comprises one or more modifications or modification patterns as described herein.

[0234] In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset A or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset A or consists of them. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset B or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset B or consists of them. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset C or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand comprises the antisense strand of any one of the siRNAs of siRNA subset C or consists of them. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset D, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset D. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset E, or an antisense strand thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises or consists of the antisense strand of any one of the siRNAs of siRNA subset E.

[0235] In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 11090, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 11090.

[0236] siRNA modification patterns

[0237] An oligonucleotide described herein (e.g., siRNA, antisense oligonucleotide, sense strand, antisense strand, siRNA agent, or dsRNA agent) may include any modification pattern disclosed herein, including but not limited to any one or more of modification patterns 1S-5S, 1AS-4AS, or ASO1.

[0238] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 11381), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5'nsnsnnNfnNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 11382), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 3S: 5'nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 11383), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises modification pattern 4S: 5'NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfnNfsnsnN-lipid-3' (SEQ ID NO: 11384), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises a nucleoside. In some embodiments, the sense strand comprises the modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-lipid-3' (SEQ ID NO: 11385), wherein "Nf" is a 2' fluoro modified nucleoside, "n" is a 2' O-methyl modified nucleoside, "s" is a phosphorothioate linkage, and N comprises the nucleoside.

[0239] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises a siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3' (SEQ ID NO: 11386), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5'nsNfsnnnNfnNfnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11387), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 3AS: 5'nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 11388), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5'nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn 3' (SEQ ID NO: 11389), wherein "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0240] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a pattern of 1S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a pattern of 2S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a pattern of 3S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a pattern of 4S and the antisense strand comprises a pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the sense strand comprises a modified pattern of 1AS, 2AS, 3AS, or 4AS. In some embodiments, the antisense strand comprises a modified pattern of 1S, 2S, 3S, 4S, or 5S. In some embodiments, the sense strand or the antisense strand comprises a modified pattern of AS01.

[0241] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and / or the antisense strand comprises one or more modifications or modification patterns. In some embodiments, the oligonucleotide comprises a nucleic acid sequence (e.g., a sense strand sequence or an antisense strand sequence) having one or more modifications or modification patterns.

[0242] In some embodiments, the nucleic acid sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11093-11332, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11093-11332, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11093-11332, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11093-11332, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11093-11332. In some embodiments, the nucleic acid sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11093-11332, or a sequence having 1, 2, 3, or 4 nucleotide substitutions, additions, or deletions thereof. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 11093-11332, or a sequence having 1 or 2 nucleoside substitutions, additions or deletions or consisting of them. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 11093-11332 or consisting of them. 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.

[0243] In some embodiments, the nucleic acid sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11333-11376, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11333-11376, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11333-11376, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11333-11376, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11333-11376. In some embodiments, the nucleic acid sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11376, or a sequence having 1, 2, 3, or 4 nucleotide substitutions, additions, or deletions thereof. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 11333-11376, or a sequence with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the nucleic acid sequence comprises a sequence of any one of SEQ ID NO: 11333-11376 or consists of them. 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.

[0244] In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any one of Tables 5-13 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any one of the siRNAs disclosed in any one of Tables 5-13. In some embodiments, the oligonucleotide comprises a nucleoside sequence having at least 85% identity to the sense strand sequence of the siRNA in any one of Tables 5-13.

[0245] In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 or siRNAs with 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1), or siRNAs with 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is less than the expression of the negative control in the table), or siRNAs with 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table). In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5), or siRNAs thereof with 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5). In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.25), or siRNAs thereof with 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the oligonucleotide comprises or consists of any of the siRNAs disclosed in any of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the oligonucleotide comprises or consists of an unmodified version of any of the siRNAs disclosed in any of Tables 5-10. In some embodiments, the oligonucleotide comprises or consists of a siRNA having a nucleic acid sequence of any of the siRNAs disclosed in any of Tables 5-10, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the nucleic acid sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0246] 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, a sequence at least 80% identical to any one of SEQ ID NOs: 11093-11212, a sequence at least 85% identical to any one of SEQ ID NOs: 11093-11212, a sequence at least 90% identical to any one of SEQ ID NOs: 11093-11212, or a sequence at least 95% identical to any one of SEQ ID NOs: 11093-11212. In some embodiments, the sense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11093-11212, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11093-11212, or a sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 a sense strand sequence described herein.

[0247] In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11333-11354, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11333-11354. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 11333-11354, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11333-11354, or a sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11333-11354. In some embodiments, the sense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0248] In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the sense strand sequences of any one of the siRNAs disclosed in any one of Tables 5-13, or a siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-13. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to the sense strand sequence of any one of the siRNAs in Table 513.

[0249] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10, or a siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1), or a siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table) or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5) or consisting thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10.In some embodiments, the sense strand sequence comprises or consists of a siRNA having a sense strand sequence of any of the siRNAs disclosed in any of Tables 5-10, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0250] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 0.67)), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 0.67)), or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is lower than 0.5) or consisting thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the sense strand sequence comprises or consists of an siRNA having the sense strand sequence of any one of the siRNAs disclosed in Table 5, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0251] In some embodiments, the sense strand sequence is incorporated into a siRNA that downregulates ANGPTL7. In some embodiments, the sense strand sequence comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126, 11127 、11128、11129、11130、11132、11133、11134、11135、11136、11139、11140、11143、11144、11145、11146、11147、11148、11149、11150、11151、11152、11153、11154、11155、11156、11157、11158、1 1159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、11182、11183、11184、11185、111 86, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof, or consisting of the sense strand sequence of any one of the above-mentioned sequences.In some embodiments, the sense strand sequence comprises SEQ ID NO: 11094, 11095, 11096, 11097, 11098, 11099, 11100, 11101, 11102, 11103, 11104, 11105, 11106, 11109, 11110, 11113, 11116, 11118, 11119, 11121, 11122, 11123, 11124, 11125, 11126 6. 11127, 11128, 11129, 11130, 11132, 11133, 11134, 11135, 11136, 11139, 11140, 11143, 11144, 11145, 11146, 11147, 11148, 11149, 11150, 11151, 11152, 11153, 11154, 11155, 11156, 11157、11158、11159、11160、11161、11162、11163、11164、11165、11166、11167、11168、11169、11170、11171、11172、11173、11174、11175、11176、11177、11178、11180、11181、11182、11 183, 11184, 11185, 11186, 11187, 11188, 11189, 11191, 11193, 11195, 11196, 11198, 11199, 11200, 11201, 11203, 11204, 11205, 11207, 11208, 11210, 11211 or 11212 sense strand sequence, or consisting thereof.

[0252] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 1.06)), or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 1.06)), or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is lower than 0.5), or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is lower than 0.5), or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the sense strand sequence comprises or consists of an siRNA having the sense strand sequence of any one of the siRNAs disclosed in Table 6, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0253] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1), or siRNAs having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.66)), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level of less than 0.66)), or consisting thereof. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM of the table is lower than 1), or an siRNA having 0.5 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 1 nM in the table is less than 0.5 (e.g., siRNAs having the sequence ETD00245, ETD00247, or ETD00252). In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 10 nM in the table is less than 1, or siRNAs thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 7, wherein the relative ANGPTL expression at 10 nM in the table is less than 1. In some embodiments, the sense strand sequence comprises or consists of an unmodified version of the sense strand sequence of any one of the siRNAs disclosed in Table 7.In some embodiments, the sense strand sequence comprises or consists of a siRNA having a sense strand sequence of any one of the siRNAs disclosed in Table 7, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to a sequence described herein.

[0254] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 8, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 8. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 9, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 9. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 10, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 10. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0255] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%). In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%) or consists of them. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the sense strand sequence comprises the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%) or consists of them. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%). 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 a siRNA having a sense strand sequence of any one of the siRNAs disclosed in Table 11, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the sense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0256] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 12, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 12. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 13, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of any one of the siRNAs disclosed in Table 13. In some embodiments, the sense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0257] In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00269 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNAETD00269. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00270 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00270. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00353 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00353. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00356 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNAETD00356. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00358 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00358. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00370 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00370. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00377 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNAETD00377. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00378 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00378. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00382 or its siRNA having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the sense strand sequence comprises or consists of the sense strand sequence of siRNA ETD00382.In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 11377, or a siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 11377. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 11378, or a siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 11387. In some embodiments, the sense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0258] 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, a sequence at least 80% identical to any one of SEQ ID NOs: 11093-11212, a sequence at least 85% identical to any one of SEQ ID NOs: 11093-11212, a sequence at least 90% identical to any one of SEQ ID NOs: 11093-11212, or a sequence at least 95% identical to any one of SEQ ID NOs: 11093-11212. In some embodiments, the antisense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11093-11212, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises a sequence of any one of SEQ ID NOs: 11093-11212, or a sequence having 1 or 2 nucleoside substitutions, additions or deletions or consisting thereof. In some embodiments, the antisense strand sequence comprises a sequence of any one of SEQ ID NOs: 11093-11212 or consisting thereof. In some embodiments, the antisense strand sequence is an unmodified version of the antisense strand sequence described herein. In some embodiments, the antisense strand sequence has more or different sequence modifications than the antisense strand sequence described herein.

[0259] In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 80% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 85% identical to any one of SEQ ID NOs: 11333-11354, a sequence that is at least 90% identical to any one of SEQ ID NOs: 11333-11354, or a sequence that is at least 95% identical to any one of SEQ ID NOs: 11333-11354. In some embodiments, the antisense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11333-11354, or a sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of a sequence of any one of SEQ ID NOs: 11333-11354, or a sequence having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of a 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.

[0260] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the antisense strand sequences of any one of the siRNAs disclosed in any one of Tables 5-13, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-13, or consists of it. In some embodiments, the antisense strand sequence comprises or consists of a sequence having at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, or at least 95% identity to the antisense strand sequence of any one of the siRNAs in Tables 5-13.

[0261] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control in the table) or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is lower than 0.5) or consists of them. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in any one of Tables 5-10.In some embodiments, the antisense strand sequence comprises or consists of an siRNA having an antisense strand sequence of any of the siRNAs disclosed in any of Tables 5-10, but has one or more additional or different modifications, or has 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.

[0262] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 0.67)), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 0.67)), or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is lower than 0.5) or consisting thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 5 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 5. In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 5, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0263] In some embodiments, the antisense sequence is incorporated into a siRNA that downregulates ANGPTL7. In some embodiments, the antisense sequence comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246, 11247 、11248、11249、11250、11252、11253、11254、11255、11256、11259、11260、11263、11264、11265、11266、11267、11268、11269、11270、11271、11272、11273、11274、11275、11276、11277、11278、1 1279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303, 11304, 11305, 11306 06, 11307, 11308, 11309, 11311, 11313, 11315, 11316, 11318, 11319, 11320, 11321, 11323, 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or an siRNA having 1 or 2 nucleotide substitutions, additions or deletions thereof, or consisting of the antisense strand sequence of any one of the above-mentioned sequences.In some embodiments, the antisense strand sequence comprises SEQ ID NO: 11214, 11215, 11216, 11217, 11218, 11219, 11220, 11221, 11222, 11223, 11224, 11225, 11226, 11229, 11230, 11233, 11236, 11238, 11239, 11241, 11242, 11243, 11244, 11245, 11246 6. 11247, 11248, 11249, 11250, 11252, 11253, 11254, 11255, 11256, 11259, 11260, 11263, 11264, 11265, 11266, 11267, 11268, 11269, 11270, 11271, 11272, 11273, 11274, 11275, 11276, 11277, 11278, 11279, 11280, 11281, 11282, 11283, 11284, 11285, 11286, 11287, 11288, 11289, 11290, 11291, 11292, 11293, 11294, 11295, 11296, 11297, 11298, 11300, 11301, 11302, 11303 11324, 11325, 11327, 11328, 11330, 11331 or 11332, or consists of the antisense strand sequence of any one of 11324, 11325, 11327, 11328, 11330, 11331 or 11332.

[0264] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 1.06)), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 1.06)), or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is lower than 0.5), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is lower than 0.5) or consisting thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25), or an siRNA thereof having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 6 (wherein the relative ANGPTL expression in the table is less than 0.25). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 6. In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 6, but having one or more additional or different modifications, or having a different modification pattern.In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0265] In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7, or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 1). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 0.66)), or an siRNA having 1 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM of the siRNA in the table is lower than the expression of the negative control siRNA in the table (e.g., a relative expression level lower than 0.66)), or consisting thereof. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is lower than 1), or an siRNA having 0.5 or 2 nucleoside substitutions, additions, or deletions thereof or consisting thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 1 nM in the table is less than 0.5 (e.g., siRNAs having the sequence ETD00245, ETD00247, or ETD00252)). In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 10 nM in the table is less than 1), or siRNAs thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 7 (wherein the relative ANGPTL expression at 10 nM in the table is less than 1). In some embodiments, the antisense strand sequence comprises or consists of an unmodified version of the antisense strand sequence of any one of the siRNAs disclosed in Table 7.In some embodiments, the antisense strand sequence comprises or consists of an siRNA having the antisense strand sequence of any one of the siRNAs disclosed in Table 7, but having one or more additional or different modifications, or having a different modification pattern. In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to a sequence described herein.

[0266] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 8, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 8, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 9, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 9, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 10, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions, or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 10, or consists of them. In some embodiments, the antisense strand sequence lacks a sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0267] 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 having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 11. 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 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%), or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions thereof. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 50%). In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 4 hours in the table is at least 75%) or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 50%) or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%), or it has 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of any one of the siRNAs disclosed in Table 11 (wherein the percentage of siRNA remaining at 24 hours in the table is at least 75%) or consists of them. 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 having an antisense strand sequence of any one of the siRNAs disclosed in Table 11, but has one or more additional or different modifications, or has a different modification pattern. In some embodiments, the antisense strand sequence lacks sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequence described herein.

[0268] 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 having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 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 having 1 or 2 nucleoside substitutions, additions or deletions. In some embodiments, the antisense strand sequence comprises or consists of the antisense strand sequence of any one of the siRNAs disclosed in Table 13. In some embodiments, the antisense strand sequence lacks sequence modification, or has a different or additional sequence modification, but is otherwise similar to the sequences described herein.

[0269] In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00269 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNAETD00269 or consists of it. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00270 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00270 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00353 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00353 or its antisense strand sequence with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00356 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNAETD00356 or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00358 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00358 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00370 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00370 or consists of it. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00377 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNAETD00377 or consists of it. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00378 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00378 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00382 or its siRNA with 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00382 or consists of it.In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNA ETD00752 or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the antisense strand sequence of siRNAETD00752 or consists of them. In some embodiments, the antisense strand sequence comprises the sequence of SEQ ID NO:11379, or an siRNA having 1 or 2 nucleoside substitutions, additions or deletions or consists of them. In some embodiments, the antisense strand sequence comprises the sequence of SEQ ID NO:11379 or consists of them. In some embodiments, the antisense strand sequence lacks sequence modifications, or has different or additional sequence modifications, but is otherwise similar to the sequences described herein.

[0270] Antisense compounds

[0271] In one aspect, provided herein are antisense compounds or oligonucleotides for modulating the activity and / or expression of a target nucleic acid, such as ANGPTL7. In some embodiments, the antisense compound inhibits the expression of ANGPTL7. In some cases, the antisense compound comprises a sequence having at least about 80%, 85%, 90%, 95%, or 100% identity to a sequence selected from SEQ ID NOs: 4413-11084. In some cases, the antisense compound comprises a sequence having at least about 80%, 85%, 90%, 95%, or 100% identity to SEQ ID NO: 11087.

[0272] In some embodiments, the antisense compound can specifically hybridize to the target nucleic acid, wherein the binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause, for example, loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target nucleic acid sequences under conditions where specific binding is required. Such conditions include physiological conditions in the case of in vivo assays or therapeutic treatments, as well as conditions where the assay is performed in the case of in vitro assays.

[0273] In some embodiments, antisense compounds include variants in which there are different bases at one or more nucleotide positions of the compound. For example, if the first nucleotide is adenine, a variant containing thymidine, guanosine, cytidine or other natural or non-natural nucleotides at that position can be produced. This can be done at any position of the antisense compound. These compounds are then tested using the methods described herein to determine their ability to inhibit the expression of the target nucleic acid.

[0274] 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%.

[0275] In some embodiments, antisense compounds, whether DNA, RNA, chimeric, substituted, etc., are specifically hybridizable, e.g., to cause loss of efficacy, when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA, and there is a sufficient degree of complementarity to avoid nonspecific binding of the antisense compound to non-target sequences under conditions where specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatments and under the conditions under which the assays are conducted in the case of in vitro assays.

[0276] In some embodiments, targeting of ANGPTL7 includes, but is not limited to, antisense sequences such as one or more of the sequences shown in SEQ ID NOs: 4413-11084, etc. (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, PCR, hybridization, etc., to modulate the expression or function of ANGPTL7. In some embodiments, expression or function is downregulated compared to a control oligonucleotide that does not specifically hybridize to ANGPTL7.

[0277] In some embodiments, the antisense oligonucleotide comprises one or more modified nucleotides, shorter or longer fragments, modified bonds, etc. Examples of modified bonds or internucleotide connections include phosphorothioates, phosphorodithioates, etc. In some embodiments, the nucleotide comprises a phosphorus derivative. The phosphorus derivative (or modified phosphate group) that can be attached to a sugar or sugar analog moiety in the modified oligonucleotide can be a monophosphate, a diphosphate, a triphosphate, an alkyl phosphate, an alkane phosphate, a thiophosphate, etc.

[0278] In embodiments, oligomeric antisense compounds, particularly oligonucleotides, bind to target nucleic acid molecules and regulate the expression and / or function of molecules encoded by target genes. The function of the DNA disturbed includes, for example, replication and transcription. The function of the RNA disturbed includes all important functions, such as, for example, RNA translocation to protein translation sites, protein translation from RNA, RNA splicing to produce one or more mRNA species, and the catalytic activity that can participate in RNA or promoted by RNA. Depending on the desired function, these functions can be raised or suppressed.

[0279] Antisense compounds include antisense oligomeric compounds, antisense oligonucleotides, external guide sequence (EGS) oligonucleotides, alternative splicing agents, primers, probes and other oligomeric compounds that hybridize to at least a portion of 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.

[0280] Targeting an antisense compound to a specific nucleic acid molecule can be a multi-step process. The process can begin with identifying a target nucleic acid whose function is to be modulated. The target nucleic acid can be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a specific condition or disease state. In some embodiments, the target nucleic acid encodes angiopoietin-like 7 (ANGPTL7).

[0281] The targeting process can include determining at least one target region, section or site in the target nucleic acid, so that antisense interactions occur, thereby producing a desired effect, such as the regulation of expression. In some embodiments, the term "region" is defined as a part of a target nucleic acid having at least one identifiable structure, function or feature. Within the target nucleic acid region is a section." Segment" can be defined as a smaller portion or sub-portion of a region in the target nucleic acid." Site" can be defined as a position in the target nucleic acid.

[0282] In some embodiments, the antisense oligonucleotide binds to the natural antisense sequence of angiopoietin-like 7 (ANGPTL7) and modulates the expression and / or function of ANGPTL7 (SEQ ID NO: 11085).

[0283] In some embodiments, the antisense oligonucleotide binds to one or more segments of angiopoietin-like 7 (ANGPTL7) polynucleotide and modulates the expression and / or function of ANGPTL7. In some cases, the segment comprises at least five consecutive nucleotides of an ANGPTL7 sense or antisense polynucleotide.

[0284] Since the translation start codon is usually 5'-AUG (in the transcribed mRNA molecule; 5-ATG in the corresponding DNA molecule), the translation start codon may be referred to as "AUG codon", "start codon" or "AUG start codon". A few genes have translation start codons whose RNA sequences are 5'-GUG, 5'-UUG or 5'-CUG; and 5'-AUA, 5'-ACG and 5'-CUG have been shown to function in vivo. Therefore, in some cases, the terms "translation start codon" and "start codon" may include many codon sequences, even though the starting amino acid is usually methionine (in eukaryotes) or formylmethionine (in prokaryotes) in each case. Eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially used for translation initiation in a particular cell type or tissue or under specific conditions. In some embodiments, "start codon" and "translation start codon" refer to one or more codons used in vivo to initiate translation of mRNA transcribed from a gene encoding angiopoietin like 7 (ANGPTL7), regardless of the sequence (s) of such codons. In some cases, the translation termination codon (or "stop codon") of a gene may have one of the following three sequences, namely 5'-UAA, 5'-UAG, and 5'-UGA (the corresponding DNA sequences are 5'-TAA, 5'-TAG, and 5'-TGA, respectively).

[0285] In some embodiments, the terms "start codon region" and "translation start codon region" refer to a portion of such an mRNA or gene that includes about 25 to about 50 consecutive nucleotides in either direction (i.e., 5' or 3') from the translation start codon. In some cases, the terms "stop codon region" and "translation stop codon region" refer to a portion of such an mRNA or gene that includes about 25 to about 50 consecutive nucleotides in either direction (i.e., 5' or 3') from the translation stop codon. Therefore, the "start codon region" (or "translation start codon region") and the "stop codon region" (or "translation stop codon region") are both regions that the antisense compounds described herein can effectively target.

[0286] Open reading frame (ORF) or "coding region", refers to the region between the translation start codon and the translation stop codon, and is also a region that can be effectively targeted. In some embodiments, the targeted region is an intragenic region containing the translation start or stop codon of the open reading frame (ORF) of the gene.

[0287] Another target region includes the 5' untranslated region (5'-UTR), which refers to the portion of the mRNA in the 5' direction starting from the translation start codon, and thus includes the nucleotides between the 5' cap site and the translation start codon of the mRNA (or the corresponding nucleotides on the gene). Another target region includes the 3' untranslated region (3'-UTR), which refers to the portion of the mRNA in the 3' direction starting from the translation stop codon, and 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 the mRNA contains an N7 methylated guanosine residue that is connected to the 5th most residue of the mRNA via a 5-5' triphosphate bond. The 5' cap region of the mRNA is believed to include the 5' cap structure itself and the first 50 nucleotides adjacent to the cap site. Another target region is the 5' cap region.

[0288] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions called "introns", which are excised from the transcript before it is transcribed. The remaining (thus translated) regions are referred to as "exons", which are spliced ​​together to form a continuous mRNA sequence. In some embodiments, targeted splice sites, i.e. intron-exon connections or exon-intron connections, are particularly useful in cases where abnormal splicing is associated with a disease, or where excessive production of a specific splicing product is associated with a disease. Abnormal fusion connections due to rearrangement or deletion are another embodiment of the target site. The mRNA transcript produced by the process of splicing two (or more) mRNAs from different gene sources is referred to as a "fusion transcript". Introns can be effectively targeted using antisense compounds targeting, for example, DNA or pre-mRNA.

[0289] In some embodiments, antisense oligonucleotides bind to coding and / or noncoding regions of a target polynucleotide and modulate the expression and / or function of the target molecule.

[0290] In some embodiments, antisense oligonucleotides bind to sense polynucleotides and modulate the expression and / or function of a target molecule.

[0291] Alternative RNA transcripts can be generated from the same genomic region of DNA. These alternative transcripts are often referred to as "variants". More specifically, "pre-mRNA variants" are transcripts produced by the same genomic DNA that differ from other transcripts produced by the same genomic DNA in the start or end position and contain intron and exon sequences.

[0292] After one or more exon or intron regions or parts thereof are removed during the splicing process, the pre-mRNA variants produce smaller "mRNA variants". Therefore, mRNA variants are processed pre-mRNA variants, and each unique pre-mRNA variant must always produce a unique mRNA variant through splicing. These mRNA variants are also called "alternative splice variants". If the pre-mRNA variant does not undergo splicing, the pre-mRNA variant is identical to the mRNA variant.

[0293] Variants can be produced by starting or stopping transcription using alternative signals. Pre-mRNA and mRNA can have more than one start codon or stop codon. Variants derived from pre-mRNA or mRNA using alternative start codons are referred to as "alternative start variants" of the pre-mRNA or mRNA. Transcripts using alternative stop codons are referred to as "alternative termination variants" of the pre-mRNA or mRNA. A specific type of alternative termination variant is a "poly A variant", in which the multiple transcripts produced are produced by the alternative selection of one of the "poly A termination signals" by the transcriptional mechanism, thereby producing transcripts that terminate at unique poly A sites. In some embodiments, the variant types described herein are also embodiments of target nucleic acids.

[0294] In some embodiments, the location on the target nucleic acid to which the antisense compound hybridizes is defined as a portion of the target region that is at least 5 nucleotides long that is targeted by the active antisense compound.

[0295] Although specific sequences of certain exemplary target segments are set forth herein, those skilled in the art will recognize that these are for illustration and description of specific embodiments. Additional target segments may be readily identified by one of ordinary skill in the art in view of the present disclosure.

[0296] Target segments of 5-100 nucleotides in length comprising a stretch of at least five (5) contiguous nucleotides selected from the exemplary target segments are also considered suitable for targeting.

[0297] In some embodiments, the target segment may include a DNA or RNA sequence comprising at least 5 consecutive nucleotides from the 5'-end of one of the target segments (the remaining nucleotides are a continuous segment of the same DNA or RNA starting from immediately upstream of the end of the target fragment and continuing until the DNA or RNA contains about 5 to about 100 nucleotides). In some cases, the target segment is represented by a DNA or RNA sequence comprising at least 5 consecutive nucleotides from the 3'-end of one of the target segments (the remaining nucleotides are a continuous segment of the same DNA or RNA starting from immediately downstream of the 3'-end of the target fragment and continuing until the DNA or RNA contains about 5 to about 100 nucleotides).

[0298] Once one or more target regions, segments or sites are identified, antisense compounds are selected that are sufficiently complementary to the target, ie, hybridize well enough and with sufficient specificity, to produce the desired effect.

[0299] Antisense compounds include antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, siRNA compounds, single-stranded or double-stranded RNA interference (RNAi) compounds, such as siRNA compounds, and other oligomeric compounds that hybridize with at least a portion of the target nucleic acid and regulate its function. Therefore, they can be DNA, RNA, DNA-like, RNA-like or a mixture thereof, or can be one or more of these analogs. These compounds can be single-stranded, double-stranded, circular or hairpin oligomeric compounds, and may include structural elements, such as internal or terminal protrusions, mispairings or loops. Antisense compounds are usually prepared linearly, but can be connected or otherwise prepared into circular and / or branched chains. Antisense compounds can include constructs, such as two chains that hybridize to form a complete or partial double-stranded compound or have enough self-complementarity to allow hybridization and form a complete or partial double-stranded compound. The two chains can be connected internally and leave free 3' or 5' ends, or can be connected to form a continuous hairpin structure or loop. The hairpin structure can include an overhang at the 5' or 3' end to produce an extension of single-stranded characteristics. Double-stranded compounds may optionally include an overhang at the end. Further modification may include a conjugate group attached to one of the ends, a selected nucleotide position, a sugar position, or an internucleoside connection. In some cases, the two chains may be connected by a non-nucleic acid portion or a linking group. When formed by only one chain, dsRNA can take the form of a self-complementary hairpin molecule, which folds itself in half to form a duplex. Therefore, dsRNA can be completely or partially double-stranded. Specific regulation of gene expression can be achieved by stably expressing dsRNA hairpins in transgenic cell lines, however, in some embodiments, gene expression or function is upregulated. When formed by two chains, or when a single strand adopts the form of a self-complementary hairpin molecule to fold itself in half to form a duplex, the two chains (or the duplex formation region of the single strand) are complementary RNA chains that are base-paired in a Watson-Crick manner.

[0300] Once introduced into the system, the compound may trigger the action of one or more enzymes or structural proteins to achieve cleavage or other modification of the target nucleic acid, or may act through an occupancy-based mechanism. In general, nucleic acids (including oligonucleotides) can be described as "DNA-like" (i.e., typically having one or more 2'-deoxy sugars, and typically having T instead of U bases) or "RNA-like" (i.e., typically having one or more 2'-hydroxyl or 2'-modified sugars, and typically having U bases instead of T bases). Nucleic acid helices can adopt more than one type of structure, the most common being type A and type B. It is generally believed that oligonucleotides with a type B structure are "DNA-like", and oligonucleotides with a type A structure are "RNA-like". In some (chimeric) embodiments, antisense compounds may contain both type A and type B regions.

[0301] In some embodiments, the desired oligonucleotide or antisense compound includes at least one of the following: antisense RNA, antisense DNA, chimeric antisense oligonucleotides, antisense oligonucleotides comprising a modified bond, interfering RNA (RNAi), short interfering RNA (siRNA); small interfering RNA (miRNA); small sequential RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activation (RNAa); small activating RNA (saRNA), or a combination thereof.

[0302] In some embodiments, the "target segments" identified herein can be used to screen for additional compounds that modulate the expression of angiopoietin-like 7 (ANGPTL7) polynucleotides. "Modulators" are those compounds that reduce or increase the expression of a nucleic acid molecule encoding ANGPTL7 and that comprise at least a 5 nucleotide portion that is complementary to the target segment. The screening method comprises the steps of 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 a nucleic acid molecule encoding an ANGPTL7 polynucleotide. Once one or more candidate modulators are shown to be able to modulate (e.g., reduce or increase) the expression of a nucleic acid molecule encoding an ANGPTL7 polynucleotide, the modulators can then be used for further investigation of the function of the ANGPTL7 polynucleotide, or as a research, diagnostic, or therapeutic agent.

[0303] Target segments can also be combined with their respective complementary antisense compounds to form stable double-stranded (duplex) oligonucleotides.

[0304] This double-stranded oligonucleotide portion regulates target expression and regulates translation and RNA processing through an antisense mechanism. In addition, the double-stranded portion may be chemically modified. For example, this double-stranded portion inhibits the target through classical hybridization of the antisense strand of the duplex with the target, thereby triggering enzymatic degradation of the target.

[0305] In some embodiments, the antisense oligonucleotide targets angiopoietin-like 7 (ANGPTL7) polynucleotide (eg, Accession No. NM_021146), variants, alleles, isoforms, homologs, mutants, derivatives, fragments, and sequences complementary thereto. In some cases, the oligonucleotide is an antisense molecule.

[0306] In some embodiments, the target nucleic acid molecule is not limited to ANGPTL7 alone, but extends to any of the subtypes, receptors, homologs, etc. of the ANGPTL7 molecule.

[0307] In some embodiments, the oligonucleotide is complementary to or binds to a nucleic acid sequence of an ANGPTL7 transcript and modulates the expression and / or function of an ANGPTL7 molecule.

[0308] 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.

[0309] Polynucleotide targets include ANGPTL7, including its family members, variants of ANGPTL7; mutants of ANGPTL7, including SNPs; non-coding sequences of ANGPTL7; ANGPTL7 alleles; species variants, fragments, etc. In some cases, the oligonucleotide is an antisense molecule.

[0310] In some embodiments, the oligonucleotides targeting ANGPTL7 polynucleotides include: antisense RNA, interfering RNA (RNAi), short interfering RNA (siRNA); small interfering RNA (miRNA); small sequential RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activation (RNAa); or small activating RNA (saRNA). In some embodiments, the siRNA comprises one or more sequences selected from SEQ ID NO: 1-4412. In some embodiments, the siRNA comprises a sequence comprising the reverse complement of a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90% or 95% homology with a sequence selected from SEQ ID NO: 1-4412. In some embodiments, the siRNA comprises a sequence having at least about 85%, 90% or 95% identity with a sequence selected from SEQ ID NO: 1-4412.

[0311] In some embodiments, targeting of angiopoietin-like 7 (ANGPTL7) polynucleotides, such as SEQ ID NO: 11085, modulates the expression or function of the target. In some embodiments, the expression or function is downregulated compared to a control.

[0312] In some embodiments, targeting of angiopoietin-like 7 (ANGPTL7) polynucleotides, such as SEQ ID NO: 11086, modulates the expression or function of the target. In some embodiments, the expression or function is downregulated compared to a control.

[0313] In some embodiments, antisense compounds are provided. These oligonucleotides may comprise one or more modified nucleotides, shorter or longer fragments, modified bonds, etc. In some embodiments, the antisense compounds comprise sequences as shown in SEQ ID NO:4413-11084. In some cases, the antisense compounds comprise sequences having at least about 80%, 85%, 90%, 95% or 100% identity to SEQ ID NO:11087.

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

[0315] In some embodiments, antisense compounds comprise one or more UNA nucleotides.

[0316] In some embodiments, the antisense compound comprises one or more GNA nucleotides.

[0317] Antisense compounds may comprise an antisense portion having a length of about 5 to about 80 nucleotides (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, a single-stranded antisense compound may comprise 5 to about 80 nucleotides, and a double-stranded antisense compound (e.g., dsRNA) may comprise a sense strand and an antisense strand or portion having a length of 5 to about 80 nucleotides. 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 nucleotides in length, or any range therein.

[0318] In some embodiments, the antisense compound has an antisense portion of 10 to 50 nucleotides in length. One of ordinary skill in the art will appreciate that this includes oligonucleotides having an antisense portion of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length, or any range therein. In some embodiments, the oligonucleotide has a length of 15 nucleotides.

[0319] In some embodiments, the antisense or oligonucleotide compounds have an antisense portion of about 12 or 13 to 30 nucleotides in length. One of ordinary skill in the art will appreciate that this includes 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 therein.

[0320] In some embodiments, oligomeric compounds also include variants in which there are different bases at one or more nucleotide positions of the compound. For example, if the first nucleotide is adenosine, a variant containing thymidine, guanosine or cytidine at that position can be produced. This can be done at any position of the antisense or dsRNA compound. These compounds are then tested using the methods described herein to determine their ability to inhibit the expression of the target nucleic acid.

[0321] In some embodiments, the homology, sequence identity or complementarity between the antisense compound and the target is about 40% to about 60%. In some embodiments, the homology, sequence identity or complementarity is about 60% to about 70%. In some embodiments, the homology, sequence identity or complementarity is about 70% to about 80%. In some embodiments, the homology, sequence identity or complementarity is about 80% to about 90%. In some embodiments, the homology, sequence identity or complementarity is about 90%, about 92%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%.

[0322] In some embodiments, antisense oligonucleotides, such as, for example, the nucleic acid molecules shown in SEQ ID NO: 4413-11084, comprise one or more substitutions or modifications. In some embodiments, nucleotides are replaced by locked nucleic acids (LNA). In some cases, the antisense compound comprises a sequence having at least about 80%, 85%, 90%, 95% or 100% identity to SEQ ID NO: 11087.

[0323] In some embodiments, the oligonucleotides target one or more regions of the coding and / or non-coding sequences associated with ANGPTL7 and the sense and / or antisense nucleic acid molecules of the sequence set forth in SEQ ID NO:11085.

[0324] In some embodiments, oligonucleotides disclosed herein are chimeric oligonucleotides. "Chimeric oligonucleotides" or "chimeras" are oligonucleotides comprising two or more chemically different regions, each region consisting of at least one nucleotide. These oligonucleotides typically include at least one modified nucleotide region (this region imparts one or more beneficial properties (such as, for example, increased nuclease resistance, increased cellular uptake, increased binding affinity to the target)) and a region as a substrate for an enzyme capable of cutting RNA:DNA or RNA:RNA hybrids. For example, RNase H is a cellular endonuclease that cuts the RNA strand of RNA:DNA duplexes. Therefore, the activation of RNase H leads to the cutting of RNA targets, thereby greatly improving the efficiency of antisense regulation of gene expression. Therefore, compared with phosphorothioate deoxy oligonucleotides that hybridize to the same target region, when using chimeric oligonucleotides, comparable results can usually be obtained with shorter oligonucleotides. The cutting of RNA targets can be routinely detected by gel electrophoresis and, if necessary, related nucleic acid hybridization techniques known in the art. In some embodiments, the chimeric oligonucleotide comprises at least one region modified to increase target binding affinity, and typically comprises a region that acts as a substrate for RNAse H. The affinity of an oligonucleotide for its target (in this case, a nucleic acid encoding ras) is typically determined by measuring the Tm of the oligonucleotide-target pair, which is the temperature at which the oligonucleotide and target dissociate; dissociation is detected spectrophotometrically. The higher the Tm, the greater the affinity of the oligonucleotide for the target.

[0325] Chimeric antisense compounds can be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and / or oligonucleotide mimetics as described above. Such compounds may also be referred to as hybrids or gapmers.

[0326] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleotides in length. In some embodiments, the ASO is 14-30 nucleotides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleosides in length, or a range defined by any of the above two numbers. In some embodiments, the ASO is 15-25 nucleotides in length. In some embodiments, the ASO is 20 nucleotides in length.

[0327] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO) of about 12-30 nucleosides in length and comprises a nucleoside sequence of about 12-30 consecutive nucleosides comprising a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11085; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0328] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an ASO of about 12-30 nucleosides in length and comprises a nucleoside sequence of about 12-30 consecutive nucleosides comprising a full-length human ANGPTL7 mRNA sequence, such as SEQ ID NO: 11086; wherein (i) the oligonucleotide comprises modifications comprising modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0329] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of ANGPTL7, wherein the oligonucleotide comprises an ASO. In some embodiments, the ASO comprises an ASO sequence. In some embodiments, the ASO sequence comprises or consists of a sequence of any one of SEQ ID NOs: 4413-11084, or a nucleic acid sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the ASO sequence comprises or consists of a sequence of any one of SEQ ID NOs: 4413-11084, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the ASO sequence comprises or consists of a sequence of any one of SEQ ID NOs: 4413-11084. In some embodiments, the ASO sequence comprises or consists of a sequence of SEQ ID NOs: 11087, or a nucleic acid sequence having 1 or 2 nucleoside substitutions, additions, or deletions thereof. In some embodiments, the ASO sequence comprises or consists of a sequence of SEQ ID NOs: 11087. In some embodiments, the ASO comprises one or more modifications or modification patterns described herein.

[0330] Antisense Compound Modification

[0331] In some embodiments, one or more nucleotides in the antisense compound are modified.The modifications described herein with respect to antisense compounds can be applicable to dsRNA agents or siRNAs.

[0332] In some embodiments, the modified oligonucleotide region comprises at least one nucleotide modified at the 2' position of the sugar, for example, 2'-O alkyl, 2,-O-alkyl-O-alkyl or 2'-fluoro-modified nucleotides. In some embodiments, RNA modifications include 2'-fluoro, 2'-amino and 2'O-methyl modifications on pyrimidine ribose, inverted bases at the 3' end of abasic residues or RNA. Such oligonucleotides may have a higher Tm (i.e., higher target binding affinity) than 2'-deoxy oligonucleotides for a given target. The effect of this increased affinity is to greatly enhance the inhibition of gene expression by RNAi oligonucleotides. RNAse H is a cellular endonuclease that cuts the RNA chain of the RNA:DNA duplex; therefore, activation of the enzyme results in the cutting of the RNA target, thereby greatly improving the efficiency of RNAi inhibition. The cutting of the RNA target can be routinely demonstrated by gel electrophoresis. In some embodiments, chimeric oligonucleotides are also modified to enhance nuclease resistance. Cells contain a variety of exo- and endonucleases that can degrade nucleic acids. Many nucleotide and nucleoside modifications make the oligonucleotides they are incorporated into more resistant to nuclease digestion than natural oligodeoxynucleotides. Nuclease resistance is measured routinely by incubating the oligonucleotides with cell extracts or isolated nuclease solutions and measuring the degree of intact oligonucleotides retained over time, usually by gel electrophoresis. Compared with unmodified oligonucleotides, oligonucleotides modified to enhance their nuclease resistance survive intact for longer periods of time. It has been demonstrated that a variety of oligonucleotide modifications can enhance or confer nuclease resistance. In some cases, oligonucleotides include at least one phosphorothioate modification. In some cases, oligonucleotide modifications that enhance target binding affinity can also independently enhance nuclease resistance.

[0333] The specific examples of some oligonucleotides include those oligonucleotides comprising modified main chains, such as phosphorothioate, phosphotriester, methylphosphonate, short chain alkyl or cycloalkyl sugar key or short chain heteroatom or heterocyclic sugar key. In some cases, oligonucleotides include phosphorothioate main chains. In some cases, oligonucleotides include heteroatom main chains, particularly CH2-NH-O--CH2, CH,-N (CH3)-O-CH2 [referred to as methylene (methylimino) or MM main chains], CH2-O-N (CH3)-CH2, CH2-N (CH3)-N (CH3)-CH2 and O-N (CH3)-CH2--CH2 main chains, wherein the natural phosphodiester main chain is expressed as OPO-CH,). In some cases, oligonucleotides include morpholine main chain structures. In some embodiments, such as peptide nucleic acid (PNA) main chains, the phosphodiester main chain of oligonucleotides is replaced by a polyamide main chain, and nucleotides are directly or indirectly attached to the aza nitrogen atoms of the polyamide main chain. The oligonucleotide may also include one or more substituted sugar moieties. In some cases, the oligonucleotide comprises one of the following at the 2' position: OH, SH, SCH3, F, OCN, OCH3, OCH3 O(CH2)n CH3, O(CH2)n NH2, or O(CH2)n CH3, wherein n is 1 to about 10; C1 to C10 lower alkyl, alkoxyalkoxy, substituted lower alkyl, alkaryl, or aralkyl; CI; Br; CN; CF3; OCF3; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; SOCH3; SO2 CH3; ONO2; NO2; N3; NH2; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; RNA cleavage group; reporter gene group; intercalator; a group for improving the pharmacokinetic properties of the oligonucleotide; or a group for improving the pharmacodynamic properties of oligonucleotides and other substituents with similar properties. Non-limiting exemplary modifications include 2'-methoxyethoxy [2-0-CH2 CH2 OCH3, also known as 2'-0-(2-methoxyethyl)]. Other exemplary modifications include 2'-methoxy (2'-0-CH3), 2'-propoxy (2'-OCH2 CH2CH3) and 2'-fluoro (2'-F). Similar modifications can also be made at other positions of the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide and the 5' position of the 5' terminal nucleotide. The oligonucleotide can also have a sugar mimetic, such as a cyclobutyl group instead of pentofuranosyl.

[0334] Oligonucleotides may also include modifications or substitutions of nucleobases (commonly referred to as "bases"). As used herein, "unmodified" or "natural" nucleotides include adenine (A), guanine (G), mymine (T), cytosine (C) and ura...

Claims

1. A composition comprising an oligonucleotide targeting angiopoietin-like 7 (ANGPTL7) and reducing 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, the antisense strand being complementary to a portion of a nucleic acid having a nucleotide sequence of SEQ ID NO: 11085, and each strand having 14 to 30 nucleotides.

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

3. The composition of claim 1, wherein the siRNA binds to human ANGPTL7 mRNA with no more than 2 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 contain a SNP with a minor allele frequency (MAF) greater than or equal to 1% (positions 2-18).

5. The composition of claim 1, wherein the sense strand and the antisense strand each comprise a seed region that is different from a seed region of a human miRNA.

6. The composition of claim 1, wherein the sense strand comprises the same sequence as SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1 any one of 2091, 2095, 2099, or 2192 having a nucleotide sequence that is at least 85% identical.

7. The composition of claim 1, wherein the sense strand comprises SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1429, 1434, 143 6, a nucleotide sequence of 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, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions or deletions.

8. The composition of claim 1, wherein the sense strand comprises SEQ ID NO: 7, 92, 93, 94, 115, 117, 118, 120, 206, 207, 256, 645, 646, 657, 740, 741, 743, 923, 943, 948, 1021, 1092, 1094, 1097, 1105, 1107, 1132, 1198, 1201, 1424, 1425, 1 The nucleotide sequence of any one of 2192, 229, 2434, 2436, 2438, 2537, 2541, 2639, 2654, 2691, 2693, 2762, 2764, 2765, 2794, 2796, 2797, 1968, 1969, 2030, 2085, 2087, 2091, 2095, 2099 or 2192.

9. The composition of claim 1, wherein the antisense strand comprises a residue corresponding to SEQ ID NO: 2213, 2298, 2299, 2300, 2321, 2323, 2324, 2326, 2412, 2413, 2462, 2851, 2852, 2863, 2946, 2947, 2949, 3129, 3149, 3154, 3227, 3298, 3300, 3303, 3311, 3313, 3338, 3404, 3407, 363 0, 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 has a nucleotide sequence at least 85% identical.

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

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