Tnfaip3-targeted compositions and related methods

Abstract

Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting TNFAIP3 (e.g., hTNFAIP3); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the RNA agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing TNFAIP3 expression (e.g., mRNA expression), methods of treating TNFAIP3 associated diseases, and methods of treating proinflammatory (e.g., autoimmune) diseases (e.g., inflammatory bowel disease); and cancer.

Description

TNFAIP3-TARGETED COMPOSITIONS AND RELATED METHODSRELATED APPLICATIONS

[0001] This application claims priority to U.S. Serial No.: 63 / 640,317, filed April 30, 2024; the entire contents of each of which is incorporated herein by reference.1. FIELD

[0002] This disclosure relates to agents (e.g., RNA agents (e.g., double stranded RNAi agents comprising a sense strand and an antisense strand)) targeting TNF alpha induced protein 3 (TNFAIP3). The disclosure further relates to phaimaceutical compositions comprising the same; and methods of utilizing the same, including, e.g., methods of inhibiting expression of TNFAIP3, methods of treating TNFAIP3 associated diseases (e.g., pro-inflammatory diseases, autoimmune diseases, and cancer).2. BACKGROUND

[0003] The TNFAIP3 gene (also referred to as tumor necrosis factor alpha-induced protein 3) encodes a zinc finger ubiquitin-editing enzyme belonging to the peptidase C64 family. The TNFAIP3 protein contains seven A20-type finger motifs (E3 ubiquitin ligase domain) in its C- terminal region and a deubiquitinating enzyme domain, termed ovarian tumor (OTU) domain, in its N-terminal region. As such, the TNFAIP3 protein exhibits both ubiquitin ligase and deubiquitinase activities and is known to function in, e.g., cytokine-mediated immune and inflammatory responses. TNFAIP3 is generally expressed in both the cytoplasm and nucleus.3. SUMMARY

[0004] Provided herein are, inter alia, agents (e.g., RNA agents (e.g., RNAi agents, dsRNA agents, ssRNA agents, siRNA agents, antisense oligonucleotides, etc.)) targeting TNFAIP3 (e.g., hTNFAIP3); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein arc methods of utilizing the agents (e.g., RNA agents (e.g., RNAi agents, dsRNA agents, etc.)) including, e.g., methods of inhibiting or decreasing TNFAIP3 expression (e.g., mRNA expression), methods of treating TNFAIP3 associated diseases, and methods of treating proinflammatory (e.g., autoimmune) diseases (e.g., inflammatory bowel disease), and cancer.

[0005] Accordingly, in one aspect, provided herein are double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

[0006] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0007] In one aspect, provided herein are dsRNA agents for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

[0008] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3). In some embodiments, the region of complementarity comprises at least 15 contiguous nucleotides. In some embodiments, the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0009] In one aspect, provided herein are dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

[0010] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0011] In one aspect, provided herein are double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

[0012] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0013] In one aspect, provided herein are dsRNA agents for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

[0014] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3). In some embodiments, the region of complementarity comprises at least 15 contiguous nucleotides. In some embodiments, the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0015] In one aspect, provided herein are dsRNA agents for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

[0016] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0017] In one aspect, provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

[0018] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0019] In one aspect, provided herein are dsRNA agents for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

[0020] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3). In some embodiments, the region of complementarity comprises at least 15 contiguous nucleotides. In some embodiments, the region of complementarity comprises at least 15 contiguous nucleotides differing by no morethan 5 (e.g., 0, 1 , 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0021] In one aspect, provided herein are dsRNA agents for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

[0022] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0023] For the sake of clarity, it should be understood that each of the following embodiments are applicable to any of the foregoing aspects, as if recited directly after each of the foregoing aspects.

[0024] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide. In some embodiments, at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified. In some embodiments, substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified. In some embodiments, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety). In some embodiments, at least one of the modified nucleotides comprises a modified nucleobase. In some embodiments, the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

[0025] In some embodiments, each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length. In some embodiments, the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30 20- 30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30,18-30, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30, 29-30, 19-20, 19-21,19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, the antisense strand comprises or consists of about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides; and / or the antisense strand comprises or consist of about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides. In some embodiments, antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. In some embodiments, antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

[0026] In some embodiments, the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides. In some embodiments, the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides (e.g., 2 nucleotides).

[0027] In some embodiments, the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotide pairs in length. In some embodiments, the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length. In some embodiments, the double stranded region is about 21 nucleotide pairs in length.

[0028] In some embodiments, the sense strand and the antisense strand are pail of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule. In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

[0029] In one aspect, provided herein a e conjugates comprising a dsRNA agent described herein and a heterologous moiety. In some embodiments, the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule. In some embodiments, the heterologous moiety is attached to the dsRNA agent via a linker. In some embodiments, the heterologous moiety attached to the 3' end of the sense and / or antisense strand and / or the 5' end of the sense and / orantisense strand, and / or at an internal site of the sense and / or antisense strand.

[0030] In one aspect, provided herein arc vectors (e.g., a viral vector, a non-viral vector) encoding an antisense strand, a sense strand, or both the antisense and sense strand described herein, a dsRNA agent described herein, or a conjugate described herein.

[0031] In one aspect, provided herein are carriers comprising a dsRNA agent described herein, a conjugate described herein, or a vector described herein. In some embodiments, the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, as dendrimer, a cationic delivery system, or a hydrogel. In some embodiments, the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

[0032] In one aspect, provided herein is a cell (or population of cells) comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, or a carrier described herein.

[0033] In one aspect, provided herein are pharmaceutical compositions comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, or a cell (or population of cells) described herein, and a pharmaceutically acceptable excipient.

[0034] In one aspect, provided herein are kits comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0035] In one aspect, provided herein are diagnostic kits comprising one or more reagent for use in a method of detecting the presence or absence of one or more somatic TNFAIP3 e.g., hTNFAIP3) mutation (e.g., a TNFAIP3 somatic mutation set forth in Table 2 herein) in a sample from a subject.

[0036] In one aspect, provided herein are methods of treating, ameliorating, or preventing a TNFAIP3 associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, and (c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

[0037] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0038] In some embodiments, the therapeutic agent comprises an anti-inflammatory agent (e.g., an anti-inflammatory agent described herein). In some embodiments, the therapeutic agent inhibits expression of TNFAIP3. In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

[0039] In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0040] In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is a proinflammatory (e.g., autoimmune) diseases. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is an autoimmune disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is a cancer (e.g., a solid tumor).

[0041] In one aspect, provided herein are methods of treating, ameliorating, or preventing a proinflammatory (e.g., autoimmune) disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, and (c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

[0042] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0043] In some embodiments, the therapeutic agent is an anti-inflammatory agent (e.g.,described herein). In some embodiments, the therapeutic agent inhibits expression of TNFAIP3. In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3. In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0044] In some embodiments, the is an autoimmune disease. In some embodiments, the disease is inflammatory bowel disease, systemic lupus erythematosus, or rheumatoid arthritis. In some embodiments, the disease is inflammatory bowel disease.

[0045] In one aspect, provided herein are methods of treating, ameliorating, or preventing a cancer in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, and (c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

[0046] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0047] In some embodiments, the therapeutic agent is an anti-cancer agent (e.g., described herein). In some embodiments, the therapeutic agent inhibits expression of TNFAIP3. In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

[0048] In some embodiments, the inhibitory nucleic acid molecule a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0049] In some embodiments, the cancer is a solid tumor.

[0050] In one aspect, provided herein are methods of diagnosing a TNFAIP3 associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence ofone or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation e.g., a somatic mutation set forth in Table 2) indicates that the subject has a TNFAIP3 associated disease.

[0051] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0052] In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is a proinflammatory (e.g., autoimmune) disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is an autoimmune disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is a cancer (e.g., a solid tumor).

[0053] In one aspect, provided herein are methods of diagnosing a proinflammatory (e.g., autoimmune) disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) indicates that the subject has a proinflammatory (e.g., autoimmune).

[0054] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0055] In some embodiments, the proinflammatory disease is an autoimmune disease. In some embodiments, the proinflammatory disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma. In some embodiments, the proinflammatory disease is inflammatory bowel disease.

[0056] In one aspect, provided herein are methods of diagnosing a cancer in a subject, themethod comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) indicates that the subject has a cancer.

[0057] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0058] In some embodiments, the cancer is a solid tumor.

[0059] For the sake of clarity, it should be understood that the following embodiments are applicable to any of the foregoing aspects, as if recited directly after each of the foregoing aspects.

[0060] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic TNFAIP3 mutation in the DNA.

[0061] In some embodiments, the method further comprises administering to the subject a therapeutic agent if a TNFAIP3 somatic mutation is detected in the DNA, RNA, or protein. In some embodiments, the method further comprises administering to the subject a therapeutic agent that inhibits expression of TNFAIP3 if a TNFAIP3 somatic mutation is detected in the DNA, RNA, or protein.

[0062] In some embodiments, the method further comprises administering to the subject an inhibitory nucleic acid molecule that inhibits expression of TNFAIP3 if a TNFAIP3 somatic mutation is detected in the DNA, RNA, or protein.

[0063] In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0064] In one aspect, provided herein are methods of selecting a subject for administration of a therapeutic agent, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), froma sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the subject is selected for administration of the therapeutic agent if the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) is present.

[0065] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

[0066] In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth herein. In some embodiments, the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

[0067] In some embodiments, the method further comprises administering to the subject the therapeutic agent if the subject is selected. In some embodiments, the therapeutic agent is an antiinflammatory agent (e.g., described herein). In some embodiments, the therapeutic agent inhibits expression of TNFAIP3. In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

[0068] In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0069] In one aspect, provided herein are in vitro methods of screening a sample from a subject for one or more somatic TNFAIP3 mutation, the method comprising (a) isolating and purifying DNA, RNA, or protein from a sample obtained from the subject; and (b) detecting the presence or absence of one or more somatic TNFAIP3 mutation in the DNA, RNA, or protein.

[0070] For the sake of clarity, it should be understood that the following embodiments are applicable to any of the foregoing aspects, as if recited directly after each of the foregoing aspects.

[0071] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a bowel biopsy.

[0072] In some embodiments, the sample comprises B-cells and / or T cells (e.g., CD4+ T cells). In some embodiments, the sample comprises tumor infiltrating lymphocytes (e.g., tumor infiltrating B cells and / or tumor infiltrating T cells (e.g., CD4+ T cells)).

[0073] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation. In some embodiments, at least one of the one or more somatic mutation is a missense mutation. In some embodiments, at least one of the one or more somatic mutation is a nonsense mutation. In some embodiments, at least one of the one or more somatic mutation comprises the insertion of one or more nucleotide. In some embodiments, at least one of the one or more somatic mutation comprises the deletion of one or more nucleotide. In some embodiments, at least one of the one or more somatic mutation is synonymous. In some embodiments, at least one of the one or more somatic mutation is non-synonymous.

[0074] In some embodiments, the subject is a human.

[0075] In one aspect, provided herein are methods of delivering a dsRNA agent, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.

[0076] In one aspect, provided herein are methods of delivering a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition to the subject.

[0077] In one aspect, provided herein are methods of reducing or inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) in a cell, the method comprising delivering into the cell a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of TNFAIP3 (e.g., hTNFAIP3) in the cell.

[0078] In some embodiments, the cell is in vitro, ex vivo, or in vivo. In some embodiments, the cell is in vitro.

[0079] In one aspect, provided herein are methods of reducing or inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) in a cell in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein,a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of TNFAIP3 (e.g., hTNFAIP3) in the cell in the subject.

[0080] In one aspect, provided herein are methods of treating, ameliorating, or preventing a TNFAIP3 (e.g., hTNFAIP3) associated disease in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the TNFAIP3 (e.g., hTNFAIP3) associated disease in the subject.

[0081] In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is a proinflammatory (e.g., autoimmune) diseases. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is an autoimmune disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease. In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is a cancer (e.g., a solid tumor). In some embodiments, the TNFAIP3 (e.g., hTNFAIP3) associated disease is treated, ameliorated, or prevented through the reduction of inhibition of TNFAIP3 (e.g., hTNFAIP3) expression.

[0082] In one aspect, provided herein are methods of treating, ameliorate, or preventing a proinflammatory (e.g., autoimmune) disease in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the proinflammatory (e.g., autoimmune) disease in the subject.

[0083] In some embodiments, the is an autoimmune disease. In some embodiments, the disease is inflammatory bowel disease, systemic lupus erythematosus, or rheumatoid arthritis. In some embodiments, the disease is inflammatory bowel disease. In some embodiments, the proinflammatory (e.g., autoimmune) disease is treated, ameliorated, or prevented through the reduction of inhibition of TNFAIP3 (e.g., hTNFAIP3) expression.

[0084] In one aspect, provided herein are methods of treating, ameliorate, or preventing acancer in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the cancer in the subject. In some embodiments, the cancer is a solid tumor.

[0085] In one aspect, provided herein are populations of engineered immune cells comprising a chimeric antigen receptor (CAR) comprising an antigen binding domain, a transmembrane domain, and an intracellular’ domain; and an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 (or functional TNFAIP3) from the endogenous TNFAIP3 gene lacking the alteration).

[0086] In some embodiments, the population of immune cells exhibit enhanced cytolysis of cancer cells (e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

[0087] In some embodiments, the population of immune cells exhibit enhanced cytokine (e.g., IFNy) expression in the presence of cancer cells (e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

[0088] In some embodiments, the population of immune cells do not express TNFAIP3. In some embodiments, the population of immune cells do not express functional TNFAIP3. In some embodiments, the alteration in the endogenous TNFAIP3 gene effectively knocks TNFAIP3 such that there is no endogenous TNFAIP3 protein expression or a functional TNFAIP3 protein is not expressed. In some embodiments, the alteration in the endogenous TNFAIP3 gene completely inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration). In some embodiments, the alteration in the endogenous TNFAIP3 gene partially inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration). In some embodiments, the level of TNFAIP3 expression is reduced by at least 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%.

[0089] In some embodiments, the alteration in the endogenous TNFAIP3 gene comprises oneor more nucleotide substitution, deletion, or addition.

[0090] In some embodiments, the antigen binding domain of the CAR specifically binds to a molecule expressed on the surface of a cancer cell (e.g., a tumor associated antigen, a tumor specific antigen, etc.).

[0091] In some embodiments, the population of immune cells comprises tisagenlecleucel, idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel, brexueabtagene autoleucel, axicabtagene ciloleucel, or lifileucel.

[0092] In some embodiments, the population of immune cells comprises T cells (e.g., CD8+ T cells, CD4+ T cells). In some embodiments, the population of immune cells comprises tumor infiltrating lymphocytes (TILs).

[0093] In some embodiments, the population of immune cells have been obtained from the subject. In some embodiments, the population of immune cells are ex vivo. In some embodiments, the population of immune cells are autologous or allogenic to the subject.

[0094] In one aspect, provided herein are methods of making a population of engineered immune cells, the method comprising transfecting or transducing a population of immune cells with a nucleic acid molecule encoding a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; and introducing one or more agent (e.g., a nucleic acid molecule, a CRISPR / Cas system) into the population of immune cells that mediates an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration).

[0095] In one aspect, provided herein are methods of enhancing the cytolytic activity of a population of immune cells, the method comprising providing a population of CAR immune cells comprising a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; introducing one or more agent (e.g., a nucleic acid molecule, a CRISPR / Cas system) into the population of immune cells that mediates an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration), to thereby produce a population of engineered immune cells, wherein the cytolytic activity (e.g., against cancer cells) of the population of engineered immune cells is greater than the cytolytic activity (e.g., against cancer cells) of the population ofCAR immune cells (e.g., lacking the alteration in the endogenous TNFAIP3 gene) (e.g., assessed according to the methods described in Example 7).

[0096] In one aspect, provided herein are methods of treating a cancer in a subject in need thereof, the method comprising administering to the subject a population of engineered immune cells (or a pharmaceutical composition comprising the population of immune cells) comprising a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; and an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 (or functional TNFAIP3) from the endogenous TNFAIP3 gene lacking the alteration), to thereby treat the cancer in the subject in need thereof.

[0097] For the sake of clarity, it should be understood that the following embodiments are applicable to any of the foregoing aspects, as if recited directly after each of the foregoing aspects.

[0098] In some embodiments, the population of immune cells exhibit enhanced cytolysis of cancer cells (e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene). In some embodiments, the population of immune cells exhibit enhanced cytokine (e.g., IFNy) expression in the presence of cancer cells (e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

[0099] In some embodiments, the population of immune cells do not express TNFAIP3. In some embodiments, the population of immune cells do not express functional TNFAIP3. In some embodiments, the alteration in the endogenous TNFAIP3 gene effectively knocks TNFAIP3 such that there is no endogenous TNFAIP3 protein expression or a functional TNFAIP3 protein is not expressed. In some embodiments, the alteration in the endogenous TNFAIP3 gene completely inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration). In some embodiments, the alteration in the endogenous TNFAIP3 gene partially inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration). In some embodiments, the level of TNFAIP3 expression is reduced by at least 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%.

[0100] In some embodiments, the alteration in the endogenous TNFAIP3 gene comprises oneor more nucleotide substitution, deletion, or addition.

[0101] In some embodiments, the antigen binding domain of the CAR specifically binds to a molecule expressed on the surface of a cancer cell (e.g., a tumor associated antigen, a tumor specific antigen, etc.).

[0102] In some embodiments, the population of immune cells comprises tisagenlecleucel, idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel, brexueabtagene autoleucel, axicabtagene ciloleucel, or lifileucel.

[0103] In some embodiments, the population of immune cells comprises T cells (e.g., CD8+ T cells, CD4+ T cells). In some embodiments, the population of immune cells comprises tumor infiltrating lymphocytes (TILs). In some embodiments, the population of immune cells have been obtained from the subject. In some embodiments, the population of immune cells are ex vivo. In some embodiments, the population of immune cells are autologous or allogenic to the subject.

[0104] In some embodiments, the cancer is a hematopoietic cancer or a solid tumor.4. BRIEF DESCRIPTION OF THE FIGURES

[0105] FIG. 1A is a bar graph showing the concentration of IL- 10 expressed by CpG stimulated or control (PBS treated) B cells (CD40 knockout B cells, TNFAIP3 knockout B cells, or control B cells) 24 hours post CpG stimulation (or PBS treatment). FIG. IB is a bar graph showing the concentration of IL-6 expressed by CpG stimulated or control (PBS treated) B cells (CD40 knockout B cells, TNFAIP3 knockout B cells, or control B cells) 24 hours post CpG stimulation (or PBS treatment). FIG. 1C is a bar graph showing the concentration of IL-8 expressed by CpG stimulated or control (PBS treated) B cells (CD40 knockout B cells, TNFAIP3 knockout B cells, or control B cells) 24 hours post CpG stimulation (or PBS treatment).

[0106] FIG. 2A is a bar graph showing the concentration of IL- 10 expressed by CpG stimulated or control (PBS treated) B cells (CD40 knockout B cells, TNFAIP3 knockout B cells, or control B cells) 48 hours post CpG stimulation (or PBS treatment). FIG. 2B is a bar graph showing the concentration of IL-6 expressed by CpG stimulated or control (PBS treated) B cells (CD40 knockout B cells, TNFAIP3 knockout B cells, or control B cells) 48 hours post CpG stimulation (or PBS treatment). FIG. 2C is a bar graph showing the concentration of IL- 8 expressed by CpG stimulated or control (PBS treated) B cells (CD40 knockout B cells, TNFAIP3 knockout B cells, or control B cells) 48 hours post CpG stimulation (or PBS treatment).

[0107] FIG. 3 is a series of bar graphs showing the concentration of IL-2 (left), TNFa (middle), and IFNy (right) expressed by TCR stimulated T cells (CD28 knockout T cells, TNFAIP3 knockout T cells, or control T cells).

[0108] FIG. 4 is a series of bar graphs showing the concentration of IL-2 (left) and TNFa (right) expressed by T cells (CD28 knockout T cells, TNFAIP3 knockout T cells, or control T cells) co-cultured with EGFR expressing tumor cells in the presence of a bispecific antibody that binds CD3 and EGFR.

[0109] FIG. 5 is a bar graph showing the percent cytolysis of cancer cells by a population of CAR-T (CAR-T cells, CAR-T cells lacking TNFAIP3 expression) or control cells (untransduced, untransduced lacking TNFAIP3 expression) over the course of 5 days.

[0110] FIG. 6 is a bar graph showing the level of IFNy expression by a population of CAR-T (CAR-T cells, CAR-T cells lacking TNFAIP3 expression) or control cells (untransduced, untransduced lacking TNFAIP3 expression) after 24 hour co-culture with cancer cells.5. DETAILED DESCRIPTION

[0111] The inventors have, inter alia, discovered somatic mutations in TNFAIP3 associated, e.g., with particular diseases, including, e.g., proinflammatory diseases (e.g., autoimmune diseases) (e.g., inflammatory bowel disease) (e.g., in B-cells, T cells) and cancer (e.g., in tumor infiltrating lymphocytes (e.g., tumor infiltrating lymphocytes)). As such, a step of detecting (or having detected) one or more somatic mutation in TNFAIP3 is useful in methods of treating e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer; and agents capable of inhibiting TNFAIP3 expression (e.g., RNA agents described herein) are useful in e.g., methods of treating e.g., autoimmune diseases (e.g., inflammatory bowel disease)); and cancer. As such, the current disclosure provides, inter alia, methods of treating diseases associated with expression of TNFAIP3 (e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer) comprising detecting one or more somatic mutation in TNFAIP3; agents (e.g., RNA agents (e.g., RNAi agents, dsRNAi agents comprising a sense strand and an antisense strand, ssRNA agents)) capable of inhibiting TNFAIP3 expression (e.g., in a cell, in a cell in a subject); and their use in, inter alia, pharmaceutical compositions, and methods of treating diseases (e.g., proinflammatory diseases, autoimmune diseases, and cancer).TABLE OF CONTENTS5.1 Definitions5.2 RNA Agents5.2.1 RNAi Agents5.2.1.1 Antisense Strand5.2.1. l(i) Targeting Region5.2.1.1(H) Overall Length5.2.1. l(iii) Exemplary Antisense Strands5.2.1.2 Sense Strand5.2.1.2(i) Antisense Strand Complementarity5.2.1.2(H) Overall Length5.2.1.2(iii) Exemplary Sense Strands5.2.1.3 dsRNA Agents5.2.1.3(i) Single & Multiple Nucleic Acid Molecules5.2.1.3(H) Length of Double Stranded Region5.2.1.3(iii) Nucleotide Overhangs & Blunt Ends5.2.1.3(iv) Exemplary Structural Combinations of Sense & Antisense Strands5.2.1.3(v) Exemplary Antisense Strands & Sense Strands5.2.1.3(vi) Exemplary dsRNA Agents5.2.2 Antisense Oligonucleotide RNA Agents5.2.2.1 Targeting RegionS.2.2.2 Overall Length5.2.2.3 Exemplary Antisense Oligonucleotides5.3 Modified RNA Agents5.3.1 Nature of Nucleotide Modifications5.3.1.1 Modified Nucleosides5.3.1. l(i) Sugar Modifications5.3.1. l(i)(a) Non-Bicyclic Sugar Modifications5.3.1. l(i)(b) Bicyclic Sugar Modifications5.3.1.1(H) Nucleobase Modifications5.3.1.2 Internucleoside Linkage Modifications5.3.1.2(i) Modified Phosphorous Containing Internucleoside Linkages5.14 Exemplary Diseases5.15 Exemplary Therapeutic Agents5.16 Methods of Use5.16.1 Methods of Treating, Ameliorating, or Preventing a Disease in a Subject5.16.2 Methods of Diagnosing and / or Prognosticating a Disease in a Subject5.16.3 Methods of Screening, Identifying, and Selecting a Subject for Treatment with a Therapeutic Agent5.16.4 In Vitro Methods of Screening Samples for Somatic TNFAIP3 Mutations5.16.5 Methods of Delivery5.16.6 Methods of Reducing or Inhibiting TNFAIP3 Expression5.16.7 Methods of Making CAR Cells5.16.8 Methods of Enhancing Cytolytic Activity of CAR Cells5.16.9 Methods of Treating, Ameliorating, or Preventing Cancer in a Subject5.17 Kits5.1 Definitions

[0112] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0113] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the ail to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0114] In this application, the use of the singular includes the plural unless specifically stated otherwise. For example, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0115] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and “consisting essentially of’ are also provided and vice versa.

[0116] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0117] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0118] The term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of “about” should be assumed to be within an acceptable error range for that particular value or composition.

[0119] As used herein, the term “administering” refers to the physical introduction of an agent (e.g., an RNA agent (e.g., described herein)) e.g., a therapeutic agent (or a precursor of the therapeutic agent that is metabolized or altered within the body of the subject to produce the therapeutic agent in vivo) to a subject, using any of the various methods and delivery systems known to those skilled in the art. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0120] As used herein, the terms “agent” and “moiety” are used interchangeably herein and are used generically to describe any macro or micro molecule. Exemplary agents include, but are not limited polynucleotides (e.g., DNA, RNA (e.g., RNA)), proteins, peptides, small molecules, carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG).

[0121] The term “antigen” as used herein is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen.

[0122] As used herein, the term “autologous” is meant to refer to any material derived fromthe same individual to which it is later to he re-introduced into the individual.

[0123] As used herein, the term “allogeneic” refers to any material derived from a different animal of the same species.

[0124] As used herein, the term “antisense strand” refers to an RNA molecule (e.g., in some embodiments, pail of an RNAi agent (e.g., described herein), part of a dsRNA agent (e.g., described herein)) that comprises a region of complementarity comprising a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to a target nucleic acid sequence (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the antisense strand is part of a dsRNA molecule that further comprises a sense strand. In some embodiments, the antisense strand or antisense oligonucleotide is a ssRNA agent.

[0125] As used herein, the term “bicyclic sugar” refers to a modified sugar (e.g., ribose) moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In some embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In some embodiments, the furanosyl sugar moiety is a ribosyl moiety.

[0126] As used herein, the term “bicyclic nucleoside” (“BNA”) is a nucleoside comprising a bicyclic sugar.

[0127] As used herein, the term “blunt end” refers to a dsRNA molecule that does not contain any unpaired nucleotides at the end (e.g., 3' terminus, 5' terminus) of the dsRNA molecule (i.e., no nucleotide overhang(s)). The dsRNA molecule can have, for example, a blunt end at the 3' end, 5' end, or both the 3' and 5' end of the molecule.

[0128] The terms “cancer” and “tumor” are used interchangeably herein and refer to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that can invade neighboring tissues and may also metastasize to distant parts of the body through, e.g., the lymphatic system or bloodstream.

[0129] As used herein, the term “complementary” in reference to a first nucleotide sequence (e.g., a sense strand or a target mRNA) in relation to a second nucleotide sequence (e.g., an antisense strand), refers to the ability of a nucleic acid molecule comprising the first nucleotide sequence to hybridize to a nucleic acid molecule comprising the second nucleotide sequence andform a double stranded region (through base pair hydrogen bonds) under suitable in vivo or vitro conditions (e.g., under certain standard conditions, under mammalian (e.g., human) physiological conditions). A person of ordinary skill in the art would be able to select the set of conditions most appropriate for a hybridization test. Complementary sequences include, e.g., Watson-Crick base pairs. For example, complementary nucleobase pairs include adenine (A) and thymine (T); adenine (A) and uracil (U); and cytosine (C) and guanine (G). Complementary nucleobase pairs include natural and modified nucleotides, and nucleotide mimics, at least to the extent that the above hybridization requirements are fulfilled. As such, determinations of complementarity (as described herein) are independent of nucleotide chemical modifications (e.g., as described herein). For example, (C) and 5-methyl cytosine (mC) are both complementary to (G).

[0130] As used herein, the term “conjugation” refers to chemical conjugation of an RNA agent (e.g., a nucleic acid molecule) with another agent (e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer (e.g., polymers of polyethylene glycol (PEG)), etc.). The other agent can be directly connected to the RNA agent (e.g., nucleic acid molecule) or indirectly connected through a linker, e.g., as described herein. Chemical conjugation methods are well known in the ait, as are commercially available conjugation reagents and kits, with detailed instructions for their use readily available from the commercial suppliers.

[0131] As used herein, the term “differing by no more than X nucleotides” and the like (e.g., differing by not more than X nucleotides” in reference to a nucleotide sequence means that the nucleotide sequence comprises no more than X (wherein X is a specified number (e.g., 3, 2, 1, 0)) nucleotide variations (as defined herein) relative to a reference sequence. For example, the phrase “wherein the nucleotide sequence of the antisense strand differs by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: X” means that the nucleotide sequence comprises no more than 3 nucleotide variations relative to the nucleotide sequence set forth in the cited SEQ ID NO: X.

[0132] As used herein, the term “disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology. The term disease includes infection (e.g., a viral, bacterial, fungal, protozoal infection).

[0133] As used herein, the term “double stranded RNA agent” or “dsRNA agent” refers to acomplex of two RNA molecules comprising a double stranded region comprising two anti-parallel and at least partially (e.g., substantially, fully) complementary nucleic acid sequences that form the double stranded region. For example, in some embodiments, the dsRNA agent comprises a sense strand and an antisense strand.

[0134] The terms “DNA” and “polydeoxyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple deoxyribonucleotides that are polymerized via phosphodiester bonds. Deoxyribonucleotides are nucleotides in which the sugar is deoxyribose.

[0135] As used herein, the term “fully complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, 100% (all), of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of the first and / or second nucleic acid molecule.

[0136] As used herein, the term “heterologous,” when used to describe a first element in reference to a second element means that the first element and second element do not exist in nature disposed as described. For example, a nucleic acid molecule comprising a “heterologous moiety” means a nucleic acid molecule that is joined to a moiety (e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that is not joined to the nucleic acid molecule in nature.

[0137] As used herein, the term “isolated” with reference to a polypeptide, protein, or polynucleotide refers to a polypeptide, protein, or polynucleotide that is substantially free of other cellular components with which it is associated in the natural state.

[0138] As used herein, the term “nucleotide variation,” “variant nucleotide,” or use of the term “variation” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleic acid molecule that comprises at least one substitution, addition, or deletion of one or more nucleotide compared to a reference nucleic acid molecule. As used herein, the term “variant” or “variation” with reference to a peptide or protein refers to a peptide or protein that comprises at least one substitution, addition, or deletion of an amino acid residue compared to a reference peptide or protein.

[0139] As used herein, the term “modified RNA agent” and the like refers to any RNA agent (or any component thereof (e.g., any nucleic acid molecule thereof)) (e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) described herein thatcomprises one or more modified nucleotide (as defined herein).

[0140] As used herein, the term “modified nucleotide,” “nucleotide modification,” or use of the term “modification” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleotide comprising a chemical modification, e.g., a modified sugar moiety, a modified nucleobase, and / or a modified internucleoside linkage, or any combination thereof. Exemplary modifications are provided herein, see, e.g., §§ 5.3, 5.3.1. In certain embodiments of the instant disclosure, inclusion of a deoxynucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within an RNA agent (e.g., RNAi agent) or component thereof (e.g., described herein, e.g., a sense strand, an antisense strand, a dsRNA agent) is considered to constitute a modified nucleotide.

[0141] As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that extends from the double stranded region of a nucleic acid molecule (e.g., a dsRNA molecule (e.g., a dsRNA molecule described herein)). For example, when a 3'-end of one strand of a dsRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang.

[0142] As used herein, the term, “non-complementary nucleotide mismatch” refers to a nucleotide within a region of complementarity (as described herein) that is not complementary to the corresponding nucleotide in the target nucleic acid molecule.

[0143] As used herein, the term “obtaining a sample” refers to the acquisition of a sample. The term includes the direct acquisition from a subject and the indirect acquisition through one or more third parties wherein one of the third parlies directly acquired the sample from the subject.

[0144] As used herein, the term “operably connected” refers to the linkage of two moieties in a functional relationship. For example, a polypeptide is operably connected to another polypeptide when they are linked (either directly or indirectly via a peptide linker) in frame such that both polypeptides are functional (e.g., a fusion protein described herein). Or for example, a transcription regulatory polynucleotide e.g., a promoter, enhancer, or other expression control element is operably linked to a polynucleotide that encodes a protein if it affects the transcription of the polynucleotide that encodes the protein. The term “operably connected” can also refer to the conjugation of a moiety to e.g., a polynucleotide or polypeptide (e.g., the conjugation of a PEG polymer to a protein).

[0145] As used herein, “partially complementary” means that in a hybridized pair of a firstnucleic acid molecule and a second nucleic acid molecule, at least 70%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0146] The determination of “percent identity” between two sequences (e.g., protein (amino acid sequences) or polynucleotide (nucleic acid sequences)) can be accomplished using a mathematical algorithm. Determinations of identity (as described herein) are independent of nucleotide chemical modifications (e.g., as described herein). For example, (mC) is identical to (C) for the purposes of determining percent identity. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, the entire contents of each of which are incorporated herein by reference in their entirety for all purposes. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is incorporated herein by reference in its entirety for all purposes. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is incorporated herein by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CAB IOS 4:11-17, which is incorporated herein by reference in its entirety. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 canbe used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0147] As used herein, the term “pharmaceutical composition” means a composition that is suitable for administration to an animal, e.g., a human subject, and comprises a therapeutic agent and a pharmaceutically acceptable carrier or diluent.

[0148] As used herein, the term “pharmaceutically acceptable carrier or diluent” means a substance intended for use in contact with the tissues of human beings and / or non-human animals, and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable therapeutic benefit / risk ratio.

[0149] The terms “nucleic acid molecule,” “polynucleotide,” and “oligonucleotide” are used interchangeably herein and refer to a polymer of DNA or RNA. The nucleic acid molecule can be single- stranded or double-stranded; contain natural, non-natural, or modified nucleotides; and contain a natural, non-natural, or modified intemucleoside linkage, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule. Nucleic acid molecules include, but are not limited to, all nucleic acid molecules which are obtained by any means available in the art, including, without limitation, recombinant means, e.g., the cloning of nucleic acid molecules from a recombinant library or a cell genome, using ordinary cloning technology and polymerase chain reaction, and the like, and by synthetic means. The skilled artisan will appreciate that, except where otherwise noted, nucleic acid sequences set forth in the instant application will recite thymidine (T) in a representative DNA sequence but where the sequence represents RNA (e.g., mRNA), the thymidines (Ts) would be substituted for uracils (Us). Thus, any of the RNA polynucleotides encoded by a DNA identified by a particular sequence identification number may also comprise the corresponding RNA (e.g., mRNA) sequence encoded by the DNA, where each thymidine (T) of the DNA sequence is substituted with uracil (U).

[0150] As used herein, the term “plurality” means 2 or more (e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 9 or more, or 10 or more).

[0151] As used herein, the terms “protein” and “polypeptide” refers to a polymer of at least 2 (e.g., at least 5) amino acids linked by a peptide bond. The term “polypeptide” does not denote a specific length of the polymer chain of amino acids. It is common in the art to refer to shorterpolymers of amino acids (e.g., approximately 2-50 amino acids) as peptides; and to refer to longer polymers of amino acids (e.g., approximately over 50 amino acids) as polypeptides. However, the terms “peptide” and “polypeptide” and “protein” are used interchangeably herein. In some embodiments, the protein is folded into its three-dimensional structure. Where proteins are contemplated herein, it should be understood that proteins folded into their three-dimensional structure are also provided herein as well as polypeptides in the primary structure. Proteins can include more than one polypeptide (e.g., customarily referred to as the quaternary structure).

[0152] As used herein, the term “prognostication” and the like refers to the process of estimating / predicting the likely course and / or outcome of a disease in a subject, including, e.g., the chance that a subject has of recovering from the disease.

[0153] As used herein, the term “region of complementarity” refers to a portion of a first nucleic acid molecule comprising a nucleotide sequence that is at least partially complementary to the nucleotide sequence of at least a portion of a second nucleic acid molecule.

[0154] The terms “RNA” and “polyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple ribonucleotides that are polymerized via phosphodiester bonds. Ribonucleotides are nucleotides in which the sugar is ribose. RNA may contain modified nucleotides; and contain natural, non-natural, or modified internucleoside linkages, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule.

[0155] As used herein, the term “RNAi agent” refers to an RNA agent that contains one or more RNA molecules which can mediate the targeted cleavage of an RNA molecule (e.g., an mRNA molecule) via an RNA-induced silencing complex (RISC) pathway. The RNAi agent, is thereby capable of e.g., modulating, e.g., inhibiting, the expression of a target gene (e.g., TNFAIP3) in a cell, e.g., a cell within a subject, such as a mammalian subject. In some embodiments, the RNAi agent is a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, the sense strand and the antisense strand each independently comprise or consist of from about 19-23 nucleotides.

[0156] As used herein, the term “sample” encompasses a variety of biological specimens obtained from a subject. Exemplary sample types include, e.g., blood, red blood cells, and other liquid samples of biological origin (including, but not limited to, whole-blood, red blood cells (e.g., isolated from whole blood), peripheral blood mononuclear cells (PBMCs), serum, plasma, urine,saliva, amniotic fluid, stool, synovial fluid, etc.), nasopharyngeal swabs, solid tissue samples such as biopsies (or cells derived therefrom and the progeny thereof), tissue cultures (or cells derived therefrom and the progeny thereof), and cell cultures (or cells derived therefrom and the progeny thereof). The term also includes samples that have been manipulated in any way after their procurement from a subject, such as by centrifugation, filtration, washing, precipitation, dialysis, chromatography, lysis, treatment with reagents, enriched for certain cell populations, refrigeration, freezing, staining, etc.

[0157] As used herein, the term “sense strand” refers to an RNA molecule (e.g., pail of an RNAi agent (e.g., described herein), part of a dsRNA agent (e.g., described herein)) that comprises a region that is at least partially (e.g., substantially, fully) complementary to a region of the antisense strand (as defined herein). The sense strand is often referred to as such with reference to the orientation of the sequence of the sense strand being the same with respect to a target RNA (e.g., mRNA sequence).

[0158] As used herein, the term “somatic mutation” refers to one or more nucleotide alteration (e.g., variation, modification (e.g., variation)) in a genomic DNA sequence (e.g., of a gene) that is acquired during the lifetime of a subject. It is understood in the ail that somatic mutations are not present in the germline DNA of an individual and are therefore not inherited from a parent like germline polymorphisms. Somatic mutations may occur spontaneously due to e.g., the infidelity of DNA replication occurring at each cell division creating substitutions, deletions, or additions of nucleotides into the DNA of a cell. A somatic mutation may also be caused by environmental factors such as e.g., ultraviolet radiation, chemical exposure, or virial infections.

[0159] As used herein, the term “subject” includes any animal, such as a human or other animal. In some embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In some embodiments, the subject is a human. In some embodiments, the method subject is a non-human mammal. In some embodiments, the subject is a non-human mammal is such as a non-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse), or lagomorph (e.g., rabbit). In some embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus), Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots).

[0160] As used herein, “substantially complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, at least 85%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0161] In some embodiments, the term “substantially all” means at least 95%, 96%, 97%, 98% or 99%, e.g., of the subject of said sentence, but excluding 100% (i.e., all).

[0162] As used herein, the term “target nucleic acid sequence” refers to a contiguous portion of the nucleotide sequence of a nucleic acid sequence (e.g., an mRNA molecule formed during the transcription of a target gene (e.g., TNFAIP3)). In some embodiments, the target nucleic acid sequence is an mRNA molecule formed during the transcription of a target gene (e.g., TNFAIP3)). In some embodiments, the target nucleic acid molecule comprises an mRNA that is a product of RNA processing of a primary transcription product. In some embodiments, the target portion of the sequence (e.g., mRNA) will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near’ that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a TNFAIP3 gene. In one embodiment, the target sequence is within the protein coding region of TNFAIP3.

[0163] As used herein, the term “therapeutically effective amount” of a therapeutic agent refers to any amount of the therapeutic agent that, when used alone or in combination with another therapeutic agent, improves a disease condition, e.g., protects a subject against the onset of a disease; improves a symptom of disease, e.g., decreases severity of disease symptoms, decreases frequency or duration of disease symptoms, increases disease symptom- free periods; prevents or reduces impairment or disability due to the disease; or promotes disease (or infection) regression. The ability of a therapeutic agent to improve a disease condition can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the RNA agent in in vitro assays.

[0164] As used herein, the term “TNF alpha induced protein 3” or “TNFAIP3” refers to the zinc finger ubiquitin-editing enzyme belonging to the peptidase C64 family. The term TNFAIP3 includes human TNFAIP3 (hTNFAIP3). The mRNA sequence of reference hTNFAIP3 gene (isoform 1) is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_001270508.2). The amino acid sequenceof a reference hTNFAIP3 protein (isoform 1) is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_001257437.1). The mRNA sequence of reference hTNFAIP3 gene (isoform 2) is set forth in SEQ ID NO: 4 (NCBI Ref.: NM_001270507.2). The amino acid sequence of a reference hTNFAIP3 protein (isoform 2) is set forth in SEQ ID NO: 6 (NCBI Ref.: NP_001257436.1). The mRNA sequence of reference hTNFAIP3 gene (isoform 3) is set forth in SEQ ID NO: 7 (NCBI Ref.: NM_006290.4). The amino acid sequence of a reference hTNFAIP3 protein (isoform 3) is set forth in SEQ ID NO: 9 (NCBI Ref.: NP_006281.1). TNFAIP3 gene and mRNA sequences of e.g., human, mouse, rat, non-human primate (e.g., rhesus macaque, Macaca fascicularis (cynomolgus monkey)), are readily available through publicly available databases, including, e.g., GenBank, UniProt, OMIM, and the Macaca genome project web site.

[0165] As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disease and / or symptom(s) associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disease does not require that the disease, or symptom(s) associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a compositions as described herein.5.2 RNA Agents

[0166] Provided herein are inter alia, agents (e.g., RNA agents), useful in, inter alia, inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) (e.g., within a cell, e.g., within a cell in a subject, e.g., a mammalian subject, e.g., a human subject) (e.g., through the degradation of TNFAIP3 (e.g., hTNFAIP3) mRNA). Exemplary agents targeting TNFAIP3 include, e.g., ISIS- 124773, miR-29c, and DSL6A / C1-FOXP3-A20-DC.

[0167] As such provided herein are, inter alia, RNA agents (e.g., RNAi agents, dsRNA agents, ssRNA agents, siRNA agents, antisense oligonucleotides), useful in, inter alia, inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) (e.g., within a cell, e.g., within a cell in a subject, e.g., a mammalian subject, e.g., a human subject) (e.g., through the degradation of TNFAIP3 (e.g.,hTNFAIP3) mRNA).

[0168] The TNFAIP3 gene encodes a zinc finger ubiquitin-editing enzyme belonging to the peptidase C64 family. The TNFAIP3 protein contains seven A20-type finger motifs (E3 ubiquitin ligase domain) in its C-terminal region and a deubiquitinating enzyme domain, termed ovarian tumor (OTU) domain, in its N-terminal region. As such, the TNFAIP3 protein exhibits both ubiquitin ligase and deubiquitinase activities and is known to function in, e.g., cytokine-mediated immune and inflammatory responses. TNFAIP3 is generally expressed in both the cytoplasm and nucleus.

[0169] The mRNA sequence of a reference hTNFAIP3 gene (isoform 1) is set forth in SEQ ID NO: 1. The reverse complement sequence of the hTNFAIP3 mRNA (isoform 1) is set forth in SEQ ID NO: 2. The amino acid sequence of the hTNFAIP3 protein encoded by the hTNFAIP3 (isoform 1) reference gene is set forth in SEQ ID NO: 3. The mRNA sequence of a reference hTNFAIP3 gene (isoform 2) is set forth in SEQ ID NO: 4. The reverse complement sequence of the hTNFAIP3 mRNA (isoform 2) is set forth in SEQ ID NO: 5. The amino acid sequence of the hTNFAIP3 protein encoded by the hTNFAIP3 (isoform 2) reference gene is set forth in SEQ ID NO: 6. The mRNA sequence of a reference hTNFAIP3 gene (isoform 3) is set forth in SEQ ID NO: 7. The reverse complement sequence of the hTNFAIP3 mRNA (isoform 3) is set forth in SEQ ID NO: 8. The amino acid sequence of the hTNFAIP3 protein encoded by the hTNFAIP3 (isoform 3) reference gene is set forth in SEQ ID NO: 9. See Table 1, herein.Table 1. The mRNA and Amino Acid Sequence of a Reference hTNFAIP3 Protein.

[0170] In some embodiments, the RNA agent comprises one or more RNA molecule. In some embodiments, the RNA agent is an RNAi agent. In some embodiments, the RNAi agent is a dsRNA agent. In some embodiments, the RNA agent is an siRNA agent. In some embodiments, the RNA agent comprises a dsRNA agent. In some embodiments, the RNA agent comprises a dsRNA agent comprising a sense strand and an antisense strand. In some embodiments, the RNA agent comprises a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, the RNA agent comprises a dsRNA agent comprising a sense strand and an antisense strand that hybridize to form a double stranded region. In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., a single nucleic acid molecule comprising a hairpin loop). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules. In some embodiments, the RNA agent comprises an antisense strand. In some embodiments, the RNA agent comprises a sense strand. In some embodiments, the RNA agent comprises one or more single stranded RNA (ssRNA) molecule. In some embodiments, the RNA agent consists of an antisense strand. In some embodiments, the RNA agent is an antisense oligonucleotide agent.5.2.1 RNAi Agents

[0171] In some embodiments, the RNA agent is an RNAi agent. In some embodiments, the RNAi agent comprises an antisense strand and a sense strand. In some embodiments, the RNAi agent is a double stranded RNA (dsRNA) agent comprising a sense strand and an antisense strand. In some embodiments, the RNAi agent is an siRNA agent.5.2.1.1 Antisense Strand(i) Targeting Region

[0172] Antisense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)).

[0173] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 75% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)).In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% (e.g., in some embodiments, preferably at least 95%, more preferably at least 98%) complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)).

[0174] In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of one or more non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non- complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1 (e.g., 0) non-complementary nucleotide mismatch relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, hi some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non- complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleicacid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from cither the 5'- and / or 3'-cnd of the region of complementarity. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'- end of the region of complementarity. Methods known in the ail and described herein can be utilized to evaluate the effect of any non-complementary mismatches between an antisense strand and a target nucleic acid molecule on functional properties (e.g., inhibition of expression of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA))).

[0175] In some embodiments, the region of complementarity comprises from about 15-30 nucleotides, e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30,19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27,20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides. In some embodiments, the region of complementarity comprises from about18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 (e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity comprises about 19 nucleotides. In some embodiments, the region of complementarity comprises about 20 nucleotides. In some embodiments, the region of complementarity comprises about 21 nucleotides. In some embodiments, the region of complementarity comprises about 22 nucleotides. In someembodiments, the region of complementarity comprises about 23 nucleotides. In some embodiments, the region of complementarity consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity consists of about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity consists of about 19 nucleotides. In some embodiments, the region of complementarity consists of about 20 nucleotides. In some embodiments, the region of complementarity consists of about 21 nucleotides. In some embodiments, the region of complementarity consists of about 22 nucleotides. In some embodiments, the region of complementarity consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.

[0176] In some embodiments, the target nucleic acid molecule is part (e.g., a contiguous portion) of a larger nucleic acid molecule. For example, in some embodiments, the target nucleic acid molecule is a portion (e.g., a contiguous portion) of a target mRNA (e.g., a TNFAIP3 mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a TNFAIP3 mRNA) of sufficient length to allow it to be a substrate for cleavage directed by an RNAi agent (e.g., an RNAi agent described herein, e.g., a dsRNA agent (e.g., described herein)) (i.e., cleavage through a RISC pathway).

[0177] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., a TNFAIP3 mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a target mRNA (e.g., a TNFAIP3 mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA (e.g., a TNFAIP3 mRNA) formed in the expression of a target gene (e.g., a mammalian, primate, human, non-human primate, mouse, and / or rat gene) (e.g., a TNFAIP3 gene). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a TNFAIP3 (e.g., hTNFAIP3) mRNA. In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA formed in the expression of a TNFAIP3 (e.g., hTNFAIP3) gene. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of the nucleotide sequence set forth in SEQ ID NO: 1 (or a variant or fragment thereof). In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA encoding a target protein. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA encoding a TNFAIP3 (e.g., hTNFAIP3) protein. In some embodiments, the targetnucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA sequence encoding a protein comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant or fragment thereof).

[0178] In some embodiments, the target nucleic acid molecule comprises from about 19-30 nucleotides, e.g., 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20- 29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26,21-25, 21-24, 21-23, 21-22, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22-24, 22-23, 23-30, 23-29,23-28, 23-27, 23-26, 23-27, 23-26, 23-25, or 23-24 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 19-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 19-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 21-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 21-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 19, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 19 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 20 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 21 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 23 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 19, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 19 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 20 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 21 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 23 nucleotides.

[0179] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(ii) Overall Length

[0180] In some embodiments, the antisense strand comprises from about 15-30 nucleotides (e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17,18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28,19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25,20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22nucleotides). In some embodiments, the antisense strand comprises from about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20- 24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the antisense strand comprises from about 19-25 nucleotide (e.g., 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24, 21-25, 22-23, 22-24, 22-25, 23-24, 23-25, 24-25 nucleotides). In some embodiments, the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, the antisense strand comprises not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand comprises about 21 nucleotides. In some embodiments, the antisense strand comprises about 23 nucleotides. In some embodiments, the antisense strand consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand consists of about 21 nucleotides. In some embodiments, the antisense strand consists of about 23 nucleotides.

[0181] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(iii) Exemplary Antisense Strands

[0182] In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portionof a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0183] In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0184] In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27,28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28,29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0185] In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32,33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33,34, or 35) nucleotides from the nucleotide sequence of a portion of the reverse complement of aportion of a TNFAIP3 mRNA. Tn some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises at least 30 e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0186] In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0187] In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0188] In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisensestrand comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 19 contiguous nucleotides.

[0189] In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 20 contiguous nucleotides.

[0190] In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 21 contiguous nucleotides.

[0191] In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portionof a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 22 contiguous nucleotides.

[0192] In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand comprises 23 contiguous nucleotides.

[0193] In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0194] In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 1 , 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0195] In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 19 contiguous nucleotides.

[0196] In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 20 contiguous nucleotides.

[0197] In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 21 contiguous nucleotides.

[0198] In some embodiments, the antisense strand consists of 22 contiguous nucleotidesdiffering by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 22 contiguous nucleotides.

[0199] In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense strand consists of 23 contiguous nucleotides.

[0200] In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0201] In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In someembodiments, the antisense strand comprises at least 20 (e.g., at least 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0202] In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27,28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0203] In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0204] In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28,29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisensestrand comprises 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0205] In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0206] In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 19 contiguous nucleotides.

[0207] In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 20 contiguous nucleotides.

[0208] In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 21 contiguous nucleotidesdiffering by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 21 contiguous nucleotides.

[0209] In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 22 contiguous nucleotides.

[0210] In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand comprises 23 contiguous nucleotides.

[0211] In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0212] In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, theantisense strand consists of 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0213] In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 19 contiguous nucleotides.

[0214] In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 20 contiguous nucleotides.

[0215] In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 21 contiguous nucleotides.

[0216] In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 22 contiguous nucleotidesdiffering by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 22 contiguous nucleotides.

[0217] In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense strand consists of 23 contiguous nucleotides.

[0218] In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0219] In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 20 (e.g.,at least 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35) contiguous nucleotides.

[0220] In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27,28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0221] In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0222] In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0223] In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4,or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0224] In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 19 contiguous nucleotides.

[0225] In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 20 contiguous nucleotides.

[0226] In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 21 contiguous nucleotides.

[0227] In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence ofSEQ ID NO: 5. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 22 contiguous nucleotides.

[0228] In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand comprises 23 contiguous nucleotides.

[0229] In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0230] In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35contiguous nucleotides.

[0231] In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 19 contiguous nucleotides.

[0232] In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 20 contiguous nucleotides.

[0233] In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 21 contiguous nucleotides.

[0234] In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 22 contiguous nucleotides.

[0235] In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence ofSEQ ID NO: 5. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the antisense strand consists of 23 contiguous nucleotides.

[0236] In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0237] In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0238] In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from thenucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 25 e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0239] In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0240] In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0241] In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisensestrand comprises 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35 contiguous nucleotides.

[0242] In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 19 contiguous nucleotides.

[0243] In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 20 contiguous nucleotides.

[0244] In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 21 contiguous nucleotides.

[0245] In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 22 contiguous nucleotides.

[0246] In some embodiments, the antisense strand comprises 23 contiguous nucleotidesdiffering by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand comprises 23 contiguous nucleotides.

[0247] In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0248] In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0249] In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 19 contiguous nucleotidesdiffering by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 19 contiguous nucleotides.

[0250] In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 20 contiguous nucleotides.

[0251] In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 21 contiguous nucleotides.

[0252] In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 22 contiguous nucleotides.

[0253] In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the antisense strand consists of 23 contiguous nucleotides.

[0254] Ranges and lengths intermediate to the above recited ranges and lengths are alsocontemplated to be part of the disclosure.5.2.1.2 Sense Strand(i) Antisense Strand Complementarity

[0255] As described above, sense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of at least a portion of an antisense strand. As such, pairs of sense and antisense strands can hybridize to form a double stranded region (e.g., under conditions in which the pairs will be used).

[0256] In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0257] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 75% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0258] In some embodiments, the nucleotide sequence of the region of complementarity comprises one or more non-complcmcntary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 5 (e.g., 4, 3, 2, 1, or 0) non- complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 1 (e.g., 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non- complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand, wherein the one or more non- complementary nucleotide mismatch is within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 (e.g., 1, 2, or 3) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand, wherein the one or more non-complementary nucleotide mismatch is within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity.

[0259] In some embodiments, the region of complementarity comprises from about 15-30 nucleotides, e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30,19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27,20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides. In some embodiments, the region of complementarity comprises from about 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21 , 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 (e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises about 19, 20, or 21 nucleotides. In some embodiments, the region of complementarity comprises about 19 nucleotides. In some embodiments, the region of complementarity comprises about 20 nucleotides. In some embodiments, the region of complementarity comprises about 21 nucleotides. In some embodiments, the region of complementarity consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity consists of about 19, 20, or 21 nucleotides. In some embodiments, the region of complementarity consists of about 19 nucleotides. In some embodiments, the region of complementarity consists of about 20 nucleotides. In some embodiments, the region of complementarity consists of about 21 nucleotides.

[0260] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(ii) Overall Length

[0261] In some embodiments, the sense strand comprises from about 15-30 nucleotides (e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18- 30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28,19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25,20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides). In some embodiments, the sense strand comprises from about 18-25 nucleotides (e.g.,18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23,20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the sense strand comprises from about 19-25 nucleotide (e.g.,19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24,21-25, 22-23, 22-24, 22-25, 23-24, 23-25, 24-25 nucleotides). In some embodiments, the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30 20-30, 21-30, 22-30, 23-30, 24- 30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0262] In some embodiments, the sense strand comprises not more than about 15, 16, 17, 18,19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand comprises about 19, 20, 21, 22, 23 nucleotides. In some embodiments, the sense strand comprises about 19, 20, 21 nucleotides. In some embodiments, the sense strand comprises about 20 nucleotides. In some embodiments, the sense strand comprises about 21 nucleotides. In some embodiments, the sense strand comprises about 21 nucleotides. In some embodiments, the sense strand comprises about 23 nucleotides.

[0263] In some embodiments, the sense strand consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand consists of about 19, 20, 21, 22, 23 nucleotides. In some embodiments, the sense strand consists of about 19, 20, 21 nucleotides. In some embodiments, the sense strand consists of about 20 nucleotides. In some embodiments, the sense strand consists of about 21 nucleotides. In some embodiments, the sense strand consists of about 21 nucleotides. In some embodiments, the sense strand consists of about 23 nucleotides.

[0264] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(iii) Exemplary Sense Strands

[0265] In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0266] In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0267] In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28,29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29,30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0268] In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0269] In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3mRNA. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0270] In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0271] In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 19 contiguous nucleotides.

[0272] In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 20 contiguous nucleotides.

[0273] In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 21 contiguous nucleotides.

[0274] In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 22 contiguous nucleotides.

[0275] In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand comprises 23 contiguous nucleotides.

[0276] In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0277] In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0278] In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 19 contiguous nucleotides.

[0279] In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 20contiguous nucleotides.

[0280] In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 21 contiguous nucleotides.

[0281] In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 22 contiguous nucleotides.

[0282] In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a TNFAIP3 mRNA. In some embodiments, the sense strand consists of 23 contiguous nucleotides.

[0283] In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. Insome embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21 , 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0284] In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0285] In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0286] In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotidesequence of SEQ ID NO: 1 . In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0287] In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0288] In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0289] In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 19 contiguous nucleotides.

[0290] In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ IDNO: 1. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 20 contiguous nucleotides.

[0291] In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 21 contiguous nucleotides.

[0292] In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 22 contiguous nucleotides.

[0293] In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises 23 contiguous nucleotides.

[0294] In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3)nucleotides from the nucleotide sequence of SEQ ID NO: 1 . In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0295] In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0296] In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 19 contiguous nucleotides.

[0297] In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 20 contiguous nucleotides.

[0298] In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ IDNO: 1. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 21 contiguous nucleotides.

[0299] In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 22 contiguous nucleotides.

[0300] In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand consists of 23 contiguous nucleotides.

[0301] In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0302] In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0303] In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0304] In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0305] In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31 , 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 {e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0306] In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0307] In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 19 contiguous nucleotides.

[0308] In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 20 contiguous nucleotides.

[0309] In some embodiments, the sense strand comprises 21 contiguous nucleotides differingby no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 21 contiguous nucleotides.

[0310] In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 22 contiguous nucleotides.

[0311] In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises 23 contiguous nucleotides.

[0312] In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0313] In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31 , 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0314] In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 19 contiguous nucleotides.

[0315] In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 20 contiguous nucleotides.

[0316] In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 21 contiguous nucleotides.

[0317] In some embodiments, the sense strand consists of 22 contiguous nucleotides differingby no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 22 contiguous nucleotides.

[0318] In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand consists of 23 contiguous nucleotides.

[0319] In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0320] In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 20 (e.g., at least 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0321] In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28,29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0322] In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0323] In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0324] In some embodiments, the sense strand comprises 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0325] In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 19 contiguous nucleotides.

[0326] In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 20 contiguous nucleotides.

[0327] In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 21 contiguous nucleotides.

[0328] In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 22 contiguous nucleotides.

[0329] In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises 23 contiguous nucleotides.

[0330] In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0331] In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0332] In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 19 contiguous nucleotides.

[0333] In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 20 contiguous nucleotides.

[0334] In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 21 contiguous nucleotides.

[0335] In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 22 contiguous nucleotides.

[0336] In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand consists of 23 contiguous nucleotides.

[0337] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.5.2.1.3 dsRNA Agents

[0338] In some embodiments, the RNA agent (e.g., RNAi agent) comprises a dsRNA agent comprising an antisense strand (e.g., described herein, e.g., described in § 5.2.1.1) and a sense strand (e.g., described herein, e.g., described in § 5.2.1 .2) that hybridize to form a double stranded region (e.g., under conditions in which the dsRNA will be used (e.g., under physiological (e.g., mammalian, e.g., human) conditions within a cell)).

[0339] As described above, antisense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)); and the sense strands comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of at least a portion of an antisense strand.(i) Single & Multiple Nucleic Acid Molecules

[0340] As described herein, and known in the art, the sense strand and the antisense strand can be part of a single larger nucleic acid molecule (connected as a single stranded nucleic acid molecule) or separate nucleic acid molecules (only connected through the double stranded region). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules. In some embodiments, sense strand and the antisense strand are pail of a single larger nucleic acid molecule.

[0341] In embodiments wherein the sense and antisense strands are part of a single nucleic acid molecule, the nucleic acid molecule may comprise a hairpin loop between the antisense strandand the sense strand to allow for formation of the double stranded region. In some embodiments, the hairpin loop comprises at least 1 (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 23, 25 or more) unpaired nucleotides (non-complementary nucleotide mismatches). In some embodiments, the hairpin loop comprises at least one but less than 25, 23, 20, 10, 9, 8, 7, 6, 5, 4, 3, or 2 unpaired nucleotides (non-complementary nucleotide mismatches). In some embodiments, the hairpin loop comprises about 25, 23, 20, 9, 8, 7, 6, 5, 4, 3, or 1 unpaired nucleotide (non-complementary nucleotide mismatch). In some embodiments, the hairpin loop consists of about 25, 23, 20, 9, 8, 7, 6, 5, 4, 3, or 1 unpaired nucleotide (non-complementary nucleotide mismatch).

[0342] Without wishing to be bound by theory, in embodiments wherein the sense strand and the antisense strand are part of a single nucleic acid molecule, after introduction into a suitable cell (e.g., a mammalian cell, e.g., a human cell), the nucleic acid molecule may be cleaved into a dsRNA molecule wherein the two strands of the dsRNA molecule are no longer part of the same nucleic acid molecule e.g., by a Type III endonuclease (e.g., Dicer) (see, e.g., Sharp et al. (2001) Genes Dev. 15:485, the entire contents of which are incorporated herein by reference for all purposes).(ii) Length of Double Stranded Region

[0343] In some embodiments, the double stranded region is about 15-30 base pairs in length (e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17,18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28,19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25,20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length). In some embodiments, the double stranded region is about 18-25 base pairs in length (e.g., 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20,20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 base pairs in length (e.g., 19-21 base pairs in length)). In some embodiments, the double stranded region is about 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15- 20, 15-19, 15-18, 15-17, 15-16, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26,21-25, 21-24, 21-23, or 21-22 base pairs in length. In some embodiments, the double stranded region is about 19-21 (e.g., 19-20) base pairs in length.

[0344] In some embodiments, the double stranded region is not more than about 15, 16, 17,18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region is about 19, 20, or 21 base pairs in length. In some embodiments, the double stranded region is about 19 base pairs in length. In some embodiments, the double stranded region is about 20 base pairs in length. In some embodiments, the double stranded region is about 21 base pairs in length. In some embodiments, the double stranded region is about 23 base pairs in length.

[0345] In some embodiments, the double stranded region comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region comprises about 19, 20, or 21 base pairs in length. In some embodiments, the double stranded region comprises about 19 base pairs in length. In some embodiments, the double stranded region comprises about 20 base pairs in length. In some embodiments, the double stranded region comprises about 21 base pairs in length. In some embodiments, the double stranded region is about 23 base pairs in length.

[0346] In some embodiments, the double stranded region consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region consists of about 19, 20, or 21 base pairs in length. In some embodiments, the double stranded region consists of about 19 base pairs in length. In some embodiments, the double stranded region consists of about 20 base pairs in length. In some embodiments, the double stranded region consists of about 21 base pairs in length. In some embodiments, the double stranded region is about 23 base pairs in length.

[0347] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(iii) Nucleotide Overhangs & Blunt Ends

[0348] In some embodiments, the dsRNA agent comprises one or more nucleotide overhang. As is clear from the disclosure, but for the sake of clarity, the nucleotides of a nucleotide overhang can include one or more a modified (e.g., chemically modified) nucleotide (e.g., described herein, e.g., described in §§ 5.3, 5.3.1).

[0349] In some embodiments, the nucleotide overhang comprises from about 1-5 nucleotides, e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, 4-5 nucleotides. In some embodiments, the nucleotide overhang comprises about 1, 2, 3, 4, or 5 nucleotides. In some embodiments, the nucleotideoverhang comprises about 1 nucleotide. In some embodiments, the nucleotide overhang comprises about 2 nucleotides. In some embodiments, the nucleotide overhang consists of about 1, 2, 3, 4, or 5 nucleotides. In some embodiments, the nucleotide overhang consists of about 1 nucleotide. In some embodiments, the nucleotide overhang consists of about 2 nucleotides.

[0350] The nucleotide overhang(s) can be on the sense strand, the antisense strand, or both the sense strand and the antisense strand. In some embodiments, the sense strand comprises a nucleotide overhang. In some embodiments, the antisense strand comprises a nucleotide overhang. In some embodiments, the sense strand and the antisense strand both comprise a nucleotide overhang.

[0351] Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'- end, or both the 5'-end, 3'- end of an antisense and / or sense strand. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end and the 3 '-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5 '-end and the 3 '-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end; and the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end; and the sense strand comprises a nucleotide overhang at the 5'-end.

[0352] In some embodiments, the dsRNA agent comprises one or more blunt end. In some embodiments, the dsRNA agent comprises a blunt end at the end of the RNA agent comprising the 3 'end of the sense strand and the 5' end of the antisense strand. In some embodiments, the dsRNA agent comprises a blunt end at the end of the RNA agent comprising the 5 'end of the sense strand and the 3' end of the antisense strand. In some embodiments, both ends of the dsRNA agent are blunt ends.

[0353] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(iv) Exemplary Structural Combinations of Sense & Antisense Strands

[0354] In some embodiments, the antisense strand and the sense strand contain the same number of nucleotides. In some embodiments, the antisense strand and the sense strand containdifferent numbers of nucleotides. In some embodiments, the nucleotide sequence of the sense strand is from about 1-5, 1-3, or 1-2 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the sense strand is about 1, 2, 3, 4, or 5 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the sense strand is about 2 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the antisense strand is from about 1-5, 1-3, or 1-2 nucleotides shorter than the nucleotide sequence of the sense strand. In some embodiments, the nucleotide sequence of the antisense strand is about 1, 2, 3, 4, or 5 nucleotides shorter than the nucleotide sequence of the sense strand. In some embodiments, the nucleotide sequence of the antisense strand is about 2 nucleotides shorter than the nucleotide sequence of the sense strand.

[0355] In some embodiments, the sense strand comprises 21 nucleotides. In some embodiments, the antisense strand comprises 23 nucleotides. In some embodiments, the sense strand comprises 21 nucleotides; and the antisense strand comprises 23 nucleotides. In some embodiments, the double stranded region comprises 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3' end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand comprises 21 nucleotides; the antisense strand comprises 23 nucleotides; the double stranded region comprises 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0356] In some embodiments, the sense strand comprises 19 nucleotides. In some embodiments, the antisense strand comprises 21 nucleotides. In some embodiments, the sense strand comprises 19 nucleotides; and the antisense strand comprises 21 nucleotides. In some embodiments, the double stranded region comprises 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3' end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand comprises 19 nucleotides; the antisense strand comprises 21 nucleotides; the double stranded region comprises 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0357] In some embodiments, the sense strand comprises 21 nucleotides. In some embodiments, the antisense strand comprises 21 nucleotides. In some embodiments, the sensestrand comprises 21 nucleotides; and the antisense strand comprises 21 nucleotides. In some embodiments, the double stranded region comprises 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3 'end. In some embodiments, the sense strand comprises a 2-nucleotide overhang at the 3 'end. In some embodiments, the sense strand comprises 21 nucleotides; the antisense strand comprises 21 nucleotides; the double stranded region comprises 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the sense strand comprises a 2-nucleotide overhang at the 3' end.

[0358] In some embodiments, the sense strand comprises 20 nucleotides. In some embodiments, the antisense strand comprises 19 nucleotides. In some embodiments, the sense strand comprises 20 nucleotides; and the antisense strand comprises 19 nucleotides. In some embodiments, the double stranded region comprises 20 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5' end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand comprises 20 nucleotides; the antisense strand comprises 19 nucleotides; the double stranded region comprises 20 nucleotides; the sense strand comprises a 1-nucleotide overhang at the 5' end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0359] In some embodiments, the sense strand comprises 21 nucleotides. In some embodiments, the antisense strand comprises 19 nucleotides. In some embodiments, the sense strand comprises 21 nucleotides; and the antisense strand comprises 19 nucleotides. In some embodiments, the double stranded region comprises 19 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 3' end. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5' end. In some embodiments, the sense strand comprises 21 nucleotides; the antisense strand comprises 19 nucleotides; the double stranded region comprises 19 nucleotides; the sense strand comprises a 1-nucleotide overhang at the 3' end; and the sense strand comprises a 1-nucleotide overhang at the 5' end.

[0360] In some embodiments, the sense strand comprises 24 nucleotides. In some embodiments, the antisense strand comprises 23 nucleotides. In some embodiments, the sense strand comprises 24 nucleotides; and the antisense strand comprises 23 nucleotides. In some embodiments, the double stranded region comprises 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3 'end. In some embodiments, the sense strand comprises a 3-nucleotide overhang at the 3' end. In some embodiments, the sense strandcomprises 24 nucleotides; the antisense strand comprises 23 nucleotides; the double stranded region comprises 21 nucleotides; the antisense strand comprises a 2-nuclcotidc overhang at the 3' end; and the sense strand comprises a 3-nucleotide overhang at the 3' end.

[0361] In some embodiments, the sense strand comprises 19 nucleotides. In some embodiments, the antisense strand comprises 19 nucleotides. In some embodiments, the sense strand comprises 19 nucleotides; and the antisense strand comprises 19 nucleotides. In some embodiments, the double stranded region comprises 19 nucleotides. In some embodiments, the 5' end of the antisense strand (and 3' end of the sense strand) form a blunt end. In some embodiments, the 3' end of the antisense strand (and 5' end of the sense strand) form a blunt end. In some embodiments, the sense strand comprises 19 nucleotides; the antisense strand comprises 19 nucleotides; the double stranded region comprises 19 nucleotides; the 5' end of the antisense strand (and 3' end of the sense strand) form a blunt end; and the 3' end of the antisense strand (and 5' end of the sense strand) form a blunt end

[0362] In some embodiments, the antisense strand and the sense strand are part of the same larger nucleic acid molecule, wherein the nucleic acid molecule comprises 44 nucleotides, the antisense portion comprises 21 nucleotides, the sense strand portion of the nucleic acid molecule comprises 19 nucleotides, the double stranded region comprises 19 nucleotides, the antisense strand comprises a 2-nucleotide overhang at the 3 'end, and the intervening nucleotide sequence between the antisense strand and the sense strand comprises 4 unpaired nucleotides that create a hairpin loop.

[0363] In some embodiments, the sense strand consists of 21 nucleotides. In some embodiments, the antisense strand consists of 23 nucleotides. In some embodiments, the sense strand consists of 21 nucleotides; and the antisense strand consists of 23 nucleotides. In some embodiments, the double stranded region consists of 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3' end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand consists of 21 nucleotides; the antisense strand consists of 23 nucleotides; the double stranded region consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0364] In some embodiments, the sense strand consists of 19 nucleotides. In some embodiments, the antisense strand consists of 21 nucleotides. In some embodiments, the sensestrand consists of 19 nucleotides; and the antisense strand consists of 21 nucleotides. In some embodiments, the double stranded region consists of 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3 'end. In some embodiments, the 5’ end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand consists of 19 nucleotides; the antisense strand consists of 21 nucleotides; the double stranded region consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0365] In some embodiments, the sense strand consists of 21 nucleotides. In some embodiments, the antisense strand consists of 21 nucleotides. In some embodiments, the sense strand consists of 21 nucleotides; and the antisense strand consists of 21 nucleotides. In some embodiments, the double stranded region consists of 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the sense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the sense strand consists of 21 nucleotides; the antisense strand consists of 21 nucleotides; the double stranded region consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the sense strand comprises a 2-nucleotide overhang at the 3' end.

[0366] In some embodiments, the sense strand consists of 20 nucleotides. In some embodiments, the antisense strand consists of 19 nucleotides. In some embodiments, the sense strand consists of 20 nucleotides; and the antisense strand consists of 19 nucleotides. In some embodiments, the double stranded region consists of 20 nucleotides. In some embodiments, the sense strand comprises a 1 -nucleotide overhang at the 5' end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand consists of 20 nucleotides; the antisense strand consists of 19 nucleotides; the double stranded region consists of 20 nucleotides; the sense strand comprises a 1-nucleotide overhang at the 5' end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0367] In some embodiments, the sense strand consists of 21 nucleotides. In some embodiments, the antisense strand consists of 19 nucleotides. In some embodiments, the sense strand consists of 21 nucleotides; and the antisense strand consists of 19 nucleotides. In some embodiments, the double stranded region consists of 19 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 3' end. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5' end. In some embodiments, the sense strandconsists of 21 nucleotides; the antisense strand consists of 19 nucleotides; the double stranded region consists of 19 nucleotides; the sense strand comprises a 1-nuclcotidc overhang at the 3' end; and the sense strand comprises a 1 -nucleotide overhang at the 5' end.

[0368] In some embodiments, the sense strand consists of 24 nucleotides. In some embodiments, the antisense strand consists of 23 nucleotides. In some embodiments, the sense strand consists of 24 nucleotides; and the antisense strand consists of 23 nucleotides. In some embodiments, the double stranded region consists of 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3 'end. In some embodiments, the sense strand comprises a 3-nucleotide overhang at the 3'end. In some embodiments, the sense strand consists of 24 nucleotides; the antisense strand consists of 23 nucleotides; the double stranded region consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the sense strand comprises a 3-nucleotide overhang at the 3' end.

[0369] In some embodiments, the sense strand consists of 19 nucleotides. In some embodiments, the antisense strand consists of 19 nucleotides. In some embodiments, the sense strand consists of 19 nucleotides; and the antisense strand consists of 19 nucleotides. In some embodiments, the double stranded region consists of 19 nucleotides. In some embodiments, the 5' end of the antisense strand (and 3' end of the sense strand) form a blunt end. In some embodiments, the 3' end of the antisense strand (and 5' end of the sense strand) form a blunt end. In some embodiments, the sense strand consists of 19 nucleotides; the antisense strand consists of 19 nucleotides; the double stranded region consists of 19 nucleotides; the 5' end of the antisense strand (and 3' end of the sense strand) form a blunt end; and the 3' end of the antisense strand (and 5' end of the sense strand) form a blunt end

[0370] In some embodiments, the antisense strand and the sense strand are part of the same larger nucleic acid molecule, wherein the nucleic acid molecule consists of 44 nucleotides, the antisense portion consists of 21 nucleotides, the sense strand portion of the nucleic acid molecule comprises 19 nucleotides, the double stranded region consists of 19 nucleotides, the antisense strand comprises a 2-nucleotide overhang at the 3'end, and the intervening nucleotide sequence between the antisense strand and the sense strand consists of 4 unpaired nucleotides that create a hairpin loop.(v) Exemplary Antisense Strands & Sense Strands

[0371] In some embodiments, the antisense strand is an antisense strand described herein. Insome embodiments, the sense strand is a sense strand described herein. In some embodiments, the antisense strand is an antisense strand described in § 5.2.1.1. In some embodiments, the sense strand is a sense strand described in § 5.2.1.2. In some embodiments, the antisense strand is an antisense strand described in § 5.2.1.1; and the sense strand is a sense strand described in § 5.2.1.2. It is to be understood that any sense strand described herein (e.g., in § 5.2.1.2); and be utilized in combination with any antisense strand in a dsRNA agent described herein (e.g., in § 5.2.1.1). For the sake of clarity, the entire contents of in §§ 5.2.1.1 and § 5.2.1.2, are incorporated by reference into the instant section.(vi) Exemplary dsRNA Agents

[0372] The nucleotide sequence of exemplary unmodified and / or modified dsRNAi agents comprising a sense and antisense strand (e.g., suitable for targeting hTNFAIP3, suitable for inhibiting hTNFAIP3 expression)) are described in herein.

[0373] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) comprises a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

[0374] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprises a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from thenucleotide sequence of SEQ ID NO: 2.

[0375] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) comprises a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the region of SEQ ID NO: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

[0376] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprises a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 4. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the region of SEQ ID NO: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

[0377] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) comprises a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the region of SEQ ID NO: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

[0378] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of TNFAIP3(e.g., (hTNFAIP3) comprises a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 7. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the region of SEQ ID NO: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

[0379] Various salts, mixed salts and free acid forms of the dsRNA agents are also provided herein. In some embodiments, the dsRNA agent is in a free acid form. In some embodiments, the dsRNA agent is in a salt form. In some embodiments, the dsRNA agent is in a sodium salt form. In some embodiments, wherein the dsRNA agent is in the sodium salt form, sodium ions are present in the composition comprising the dsRNA agent as counterions for substantially all of the phosphodiester or phosphoro thioate groups present in the dsRNA agent. In some embodiments, wherein the dsRNA agent is in the sodium salt form, sodium ions are present in the RNA agent as counterions for all of the phosphodiester or phosphorothioate groups present in the dsRNA agent.5.2.2 Antisense Oligonucleotide RNA Agents

[0380] In some embodiments, the RNA agent comprises an antisense oligonucleotide. In some embodiments, the antisense oligonucleotide is single stranded. In some embodiments, the antisense oligonucleotide is single stranded and is not part of an RNAi agent.

[0381] Antisense oligonucleotides can mediate the inhibition or alteration of gene expression through, e.g., degradation of a target RNA (e.g., through the recruitment of endogenous enzymes (e.g., RNAses), inhibition of translation of a target RNA (e.g., through steric hinderance), and splicing modulation (e.g., leading to exon skipping, exon inclusion, etc.). See, e.g., Collotta, D et al. “Antisense oligonucleotides: a novel Frontier in pharmacological strategy.” Frontiers in pharmacology vol. 14 1304342. 17 Nov. 2023, doi:10.3389 / fphar.2023.1304342, the entire contents of which are incorporated herein by reference for all purposes.5.2.2.1 Targeting Region

[0382] As described herein, antisense oligonucleotides (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)).

[0383] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 75% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region ofcomplementarity is at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% (e.g., in some embodiments, preferably at least 95%, more preferably at least 98%) complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)).

[0384] In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of one or more non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises no more than 1 (e.g., 0) non-complementary nucleotide mismatch relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non- complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end ofthe region of complementarity. Tn some embodiments, the region of complementarity comprises at least one but not more than 3 non-complcmcntary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non- complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non -complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non- complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. Methods known in the art and described herein can be utilized to evaluate the effect of any non- complementary mismatches between an antisense strand and a target nucleic acid molecule on functional properties (e.g., inhibition of expression of the target nucleic acid molecule (e.g., a target mRNA (e.g., a TNFAIP3 mRNA), a portion of a target mRNA (e.g., a TNFAIP3 mRNA))).

[0385] In some embodiments, the region of complementarity comprises from about 15-30 nucleotides, e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30,19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27,20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides. In some embodiments, the region of complementarity comprises from about 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20- 24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 (e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity comprises about 19 nucleotides. In some embodiments, the region of complementarity comprises about 20 nucleotides. In someIllembodiments, the region of complementarity comprises about 21 nucleotides. In some embodiments, the region of complementarity comprises about 22 nucleotides. In some embodiments, the region of complementarity comprises about 23 nucleotides. In some embodiments, the region of complementarity consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity consists of about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity consists of about 19 nucleotides. In some embodiments, the region of complementarity consists of about 20 nucleotides. In some embodiments, the region of complementarity consists of about 21 nucleotides. In some embodiments, the region of complementarity consists of about 22 nucleotides. In some embodiments, the region of complementarity consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.

[0386] In some embodiments, the target nucleic acid molecule is part (e.g., a contiguous portion) of a larger nucleic acid molecule. For example, in some embodiments, the target nucleic acid molecule is a portion (e.g., a contiguous portion) of a target mRNA (e.g., a TNFAIP3 mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a TNFAIP3 mRNA) of sufficient length to allow it to be a substrate for cleavage directed by the antisense oligonucleotide.

[0387] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., a TNFAIP3 mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a target mRNA (e.g., a TNFAIP3 mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA (e.g., a TNFAIP3 mRNA) formed in the expression of a target gene (e.g., a mammalian, primate, human, non-human primate, mouse, and / or rat gene) (e.g., a TNFAIP3 gene). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a TNFAIP3 (e.g., hTNFAIP3) mRNA. In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA formed in the expression of a TNFAIP3 (e.g., hTNFAIP3) gene. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of the nucleotide sequence set forth in SEQ ID NO: 1 (or a valiant or fragment thereof). In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA encoding a target protein. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion)of an mRNA encoding a TNFAIP3 (e.g., hTNFAIP3) protein. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA sequence encoding a protein comprising the amino acid sequence set forth in SEQ ID NO: 1 (or a variant or fragment thereof).

[0388] In some embodiments, the target nucleic acid molecule comprises from about 19-30 nucleotides, e.g., 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20- 29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, 21-22, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22-24, 22-23, 23-30, 23-29, 23-28, 23-27, 23-26, 23-27, 23-26, 23-25, or 23-24 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 19-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 19-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 21-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises from about 21-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 19, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 19 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 20 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 21 nucleotides. In some embodiments, the target nucleic acid molecule comprises about 23 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 19, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 19 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 20 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 21 nucleotides. In some embodiments, the target nucleic acid molecule consists of about 23 nucleotides.

[0389] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.S.2.2.2 Overall Length

[0390] In some embodiments, the antisense oligonucleotide comprises from about 15-50 nucleotides e.g., 15-49, 15-48, 15-47, 15-46, 15-45, 15-44, 15-43, 15-42, 15-41, 15-40, 15-39, 15-38, 15-37, 15-36, 15-35, 15-34, 15-33, 15-32, 15-31, 15-30, 15-29, 15-28, 15-27, 15- 26, 15- 25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26,18-25, 18-24, 18-23, 18-22, 18-21 , 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23,19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30,21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides).

[0391] In some embodiments, the antisense oligonucleotide comprises from about 15-35 nucleotides (e.g., 15-34, 15-33, 15-32, 15-31, 15-30, 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24,18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21,19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28,21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides).

[0392] In some embodiments, the antisense oligonucleotide comprises from about 15-30 nucleotides (e.g., 15-29, 15-28, 15-27, 15- 26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30,19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27,20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides).

[0393] In some embodiments, the antisense oligonucleotide comprises from about 18-35 nucleotides (e.g., 18-34, 18-33, 18-32, 18-31, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22,20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the antisense oligonucleotide comprises from about 18-30 nucleotides (e.g.,18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22,19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the antisense oligonucleotide comprises from about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25,22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the antisense oligonucleotide comprises from about 19-25 nucleotide (e.g., 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24, 21-25, 22-23, 22-24, 22-25, 23-24,23-25, 24-25 nucleotides). In some embodiments, the antisense oligonucleotide comprises from about 15-30, 16-30, 17-30, 18-30, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0394] In some embodiments, the antisense oligonucleotide comprises not more than about 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 some embodiments, the antisense oligonucleotide comprises not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides. In some embodiments, the antisense oligonucleotide comprises not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides.

[0395] In some embodiments, the antisense oligonucleotide consists of not more than about 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 some embodiments, the antisense oligonucleotide consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides. In some embodiments, the antisense oligonucleotide consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides.

[0396] In some embodiments, the antisense oligonucleotide comprises about 18 nucleotides.In some embodiments, the antisense oligonucleotide comprises about 19 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 20 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 21 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 23 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 22 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 23 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 24 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 25 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 26 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 27 nucleotides. In someembodiments, the antisense oligonucleotide comprises about 28 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 29 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 30 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 31 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 32 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 33 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 34 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 35 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 36 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 37 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 38 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 39 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 40 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 41 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 42 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 43 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 44 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 45 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 46 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 47 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 48 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 49 nucleotides. In some embodiments, the antisense oligonucleotide comprises about 50 nucleotides.

[0397] In some embodiments, the antisense oligonucleotide consists of about 18 nucleotides.In some embodiments, the antisense oligonucleotide consists of about 19 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 20 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 21 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 23 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 22 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 23 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 24 nucleotides. In someembodiments, the antisense oligonucleotide consists of about 25 nucleotides. In some embodiments, the antisense oligonucleotide consists of about 26 nucleotides In some embodiments, the antisense oligonucleotide consists of about 27 nucleotides In some embodiments, the antisense oligonucleotide consists of about 28 nucleotides In some embodiments, the antisense oligonucleotide consists of about 29 nucleotides In some embodiments, the antisense oligonucleotide consists of about 30 nucleotides In some embodiments, the antisense oligonucleotide consists of about 31 nucleotides In some embodiments, the antisense oligonucleotide consists of about 32 nucleotides In some embodiments, the antisense oligonucleotide consists of about 33 nucleotides In some embodiments, the antisense oligonucleotide consists of about 34 nucleotides In some embodiments, the antisense oligonucleotide consists of about 35 nucleotides In some embodiments, the antisense oligonucleotide consists of about 36 nucleotides In some embodiments, the antisense oligonucleotide consists of about 37 nucleotides In some embodiments, the antisense oligonucleotide consists of about 38 nucleotides In some embodiments, the antisense oligonucleotide consists of about 39 nucleotides In some embodiments, the antisense oligonucleotide consists of about 40 nucleotides In some embodiments, the antisense oligonucleotide consists of about 41 nucleotides In some embodiments, the antisense oligonucleotide consists of about 42 nucleotides In some embodiments, the antisense oligonucleotide consists of about 43 nucleotides In some embodiments, the antisense oligonucleotide consists of about 44 nucleotides In some embodiments, the antisense oligonucleotide consists of about 45 nucleotides In some embodiments, the antisense oligonucleotide consists of about 46 nucleotides In some embodiments, the antisense oligonucleotide consists of about 47 nucleotides In some embodiments, the antisense oligonucleotide consists of about 48 nucleotides In some embodiments, the antisense oligonucleotide consists of about 49 nucleotides In some embodiments, the antisense oligonucleotide consists of about 50 nucleotides.

[0398] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.5.2.23 Exemplary Antisense Oligonucleotides

[0399] In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotidesdiffering by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0400] In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0401] In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differingby no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0402] In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from the nucleotide sequence of a portion of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0403] In some embodiments, the antisense oligonucleotide comprises 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0404] In some embodiments, the antisense oligonucleotide comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement ofa portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0405] In some embodiments, the antisense oligonucleotide comprises 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 19 contiguous nucleotides.

[0406] In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides.

[0407] In some embodiments, the antisense oligonucleotide comprises 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisenseoligonucleotide comprises 21 contiguous nucleotides.

[0408] In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides.

[0409] In some embodiments, the antisense oligonucleotide comprises 23 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 23 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide comprises 23 contiguous nucleotides.

[0410] In some embodiments, the antisense oligonucleotide consists of 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0411] In some embodiments, the antisense oligonucleotide consists of 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides.

[0412] In some embodiments, the antisense oligonucleotide consists of 19 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 19 contiguous nucleotides.

[0413] In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides.

[0414] In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotidesequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides.

[0415] In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides.

[0416] In some embodiments, the antisense oligonucleotide consists of 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a TNFAIP3 mRNA. In some embodiments, the antisense oligonucleotide consists of 23 contiguous nucleotides.

[0417] In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotidesequence of SEQ TD NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 15 (e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 15 e.g., at least 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0418] In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0419] In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 25 (e.g., at least 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) contiguous nucleotides.

[0420] In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) nucleotides from thenucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0421] In some embodiments, the antisense oligonucleotide comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucleotide comprises 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the antisense oligonucle...

Claims

CLAIMSWhat is claimed is:

1. A method of treating, ameliorating, or preventing a TNFAIP3 associated disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation set forth in Table 2 in the DNA, RNA, or protein, and(c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation set forth in Table 2 is detected in the DNA, RNA, or protein.

2. The method of claim 1, wherein the one or more somatic mutation comprises one or more of chr6: 137871360:C->T, chr6: 137871448:A->C, chr6:137874850:G->T, chr6:137875742:A- >G, chr6:137876019:T->G, chr6:137876101:C->T, chr6: 137877222:G->A, chr6:137878555:G- >T, chr6:137878568:C->A, chr6:137879108:C->T, chr6:137881192:G->A, chr6:137871481:GGTGTCGA->G, chr6:137874849:C->CA, chr6:137874875:CTCAGTACATGTGGG->C, chr6:137874920:AG->A, chr6:137874947:CAG- >C, chr6:137874984:GTC->G, chr6:137878961:GC->G, chr6:137879060:T->TG, chr6:137879109:TC->T, chr6: 137881054:A->AATTATTC, chr6: 137881129:G->GC, chr6:137874840:CT->C, chr6: 137871320:A->C, chr6:137871523:G->C, chr6:137876089:G->A, chr6:137876099:C->G, chr6:137876131:T->C, chr6:137878529:C->T, chr6: 137871356:GCACCGATA->G, or chr6:137874949:GAC->G.

3. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

4. The dsRNA agent of claim 3, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

5. The dsRNA agent of claim 3 or 4, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

6. A dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

7. The dsRNA agent of claim 6, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

8. The dsRNA agent of claim 6 or 7, wherein the region of complementarity comprises at least 15 contiguous nucleotides.

9. The dsRNA agent of any one of claims 6-8, wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

10. The dsRNA agent of any one of claims 6-9, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

11. The dsRNA agent of any one of claims 6-10, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

12. A dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

13. The dsRNA agent of claim 12, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

14. The dsRNA agent of claim 12 or 13, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

15. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

16. The dsRNA agent of claim 15, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

17. The dsRNA agent of claim 15 or 16, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

18. A dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

19. The dsRNA agent of claim 18, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

20. The dsRNA agent of claim 18 or 19, wherein the region of complementarity comprises at least 15 contiguous nucleotides.

21. The dsRNA agent of any one of claims 18-20, wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

22. The dsRNA agent of any one of claims 18-21, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

23. The dsRNA agent of any one of claims 18-22, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

24. A dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

25. The dsRNA agent of claim 24, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

26. The dsRNA agent of claim 24 or 25, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

27. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of TNFAIP3 (e.g., human TNFAIP3 (hTNFAIP3)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

28. The dsRNA agent of claim 27, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

29. The dsRNA agent of claim 27 or 28, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

30. A dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region,wherein the antisense strand comprises a region of complementarity to a portion of an mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

31. The dsRNA agent of claim 30, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding TNFAIP3 (e.g., (hTNFAIP3).

32. The dsRNA agent of claim 30 or 31, wherein the region of complementarity comprises at least 15 contiguous nucleotides.

33. The dsRNA agent of any one of claims 30-32, wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

34. The dsRNA agent of any one of claims 30-33, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

35. The dsRNA agent of any one of claims 30-34, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

36. A dsRNA agent for inhibiting expression of TNFAIP3 (e.g., (hTNFAIP3) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding TNFAIP3 (e.g., (hTNFAIP3), and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 2.

37. The dsRNA agent of claim 36, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 1.

38. The dsRNA agent of claim 36 or 37, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the region of SEQ ID NO: 1 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 2.

39. The dsRNA agent of any one of claims 3-38, wherein the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.

40. The dsRNA agent of any one of claims 3-39, wherein at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified.

41. The dsRNA agent of any one of claims 3-40, wherein substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.

42. The dsRNA agent of any one of claims 3-41, wherein at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).

43. The dsRNA agent of any one of claims 3-42, wherein at least one of the modified nucleotides comprises a modified nucleobase.

44. The dsRNA agent of any one of claims 3-43, wherein the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

45. The dsRNA agent of any one of claims 3-44, wherein each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length.

46. The dsRNA agent of any one of claims 3-45, wherein the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30 20-30, 21-30, 22-30, 23-30, 24- 30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

47. The dsRNA agent of any one of claims 3-46, wherein the antisense strand comprises or consists of about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides; and / or the antisense strand comprises or consist of about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides.

48. The dsRNA agent of any one of claims 3-47, wherein antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides.

49. The dsRNA agent of any one of claims 3-48, wherein antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

50. The dsRNA agent of any one of claims 3-49, wherein the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides.

51. The dsRNA agent of any one of claims 3-50, wherein the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides (e.g., 2 nucleotides).

52. The dsRNA agent of any one of claims 3-51, wherein the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23- 29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotide pairs in length.

53. The dsRNA agent of any one of claims 3-52, wherein the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length.

54. The dsRNA agent of any one of claims 3-53, wherein the double stranded region is about 21 nucleotide pairs in length.

55. The dsRNA agent of any one of claims 3-54, wherein the sense strand and the antisense strand are part of a single nucleic acid molecule e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule.

56. The dsRNA agent of any one of claims 3-55, wherein the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

57. A conjugate comprising the dsRNA agent of any one of claims 3-56 and a heterologous moiety.

58. The conjugate of claim 57, wherein the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

59. The conjugate of any one of claims 57-58, wherein the heterologous moiety is attached to the dsRNA agent via a linker.

60. The conjugate of any one of claims 57-59, wherein the heterologous moiety attached to the 3' end of the sense and / or antisense strand and / or the 5' end of the sense and / or antisense strand, and / or at an internal site of the sense and / or antisense strand.

61. A vector (e.g., a viral vector, a non-viral vector) encoding the antisense strand, the sense strand, or both the antisense and sense strand of any one of claims 3-56, the dsRNA agent of any one of claims 3-56, or the conjugate of any one of claims 57-60.

62. A carrier comprising the dsRNA agent of any one of claims 1-56, the conjugate of any one of claims 57-60, or the vector of claim 61.

63. The carrier of claim 62, wherein the carrier comprises a nanoparticle, a polymer, a lipid- based delivery system, as dendrimer, a cationic delivery system, or a hydrogel.

64. The carrier of claim 63, wherein the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

65. A cell (or population of cells) comprising the dsRNA agent of any one of claims 1-56, the conjugate of any one of claims 57-60, the vector of claim 61, or the carrier of any one of claims 62-64.

66. A pharmaceutical composition comprising the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, or the cell (or population of cells) of claim 65, and a pharmaceutically acceptable excipient.

67. A kit comprising the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the earner of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66.

68. A diagnostic kit comprising one or more reagent for use in a method of detecting the presence or absence of one or more somatic TNFAIP3 (e.g., hTNFAIP3) mutation (e.g., a TNFAIP3 somatic mutation set forth in Table 2 herein) in a sample from a subject.

69. A method of treating, ameliorating, or preventing a TNFAIP3 associated disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, and(c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

70. The method of claim 69, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

71. The method of any one of claims 69-70, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

72. The method of any one of claims 69-71 , wherein the therapeutic agent comprises an antiinflammatory agent (e.g., an anti-inflammatory agent described herein).

73. The method of any one of claims 69-72, wherein the therapeutic agent inhibits expression of TNFAIP3.

74. The method of any one of claims 69-73, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

75. The method of claim 74, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66.

76. The method of any one of claims 69-75, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is a proinflammatory (e.g., autoimmune) diseases.

77. The method of any one of claims 69-76, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is an autoimmune disease.

78. The method of any one of claims 69-77, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma.

79. The method of any one of claims 69-78, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease.

80. The method of any one of claims 69-79, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is a cancer (e.g., a solid tumor).

81. A method of treating, ameliorating, or preventing a proinflammatory (e.g., autoimmune) disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, and(c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Tabic 2) is detected in the DNA, RNA, or protein.

82. The method of claim 81, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

83. The method of any one of claims 81-82, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

84. The method of any one of claims 81-83, wherein the therapeutic agent is an antiinflammatory agent (e.g., described herein).

85. The method of any one of claims 81-84, wherein the therapeutic agent inhibits expression of TNFAIP3.

86. The method of any one of claims 81-85, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

87. The method of claim 86, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66.

88. The method of any one of claims 81-87, wherein the is an autoimmune disease.

89. The method of any one of claims 81-88, wherein the disease is inflammatory bowel disease, systemic lupus erythematosus, or rheumatoid arthritis.

90. The method of any one of claims 81-89, wherein the disease is inflammatory bowel disease.

91. A method of treating, ameliorating, or preventing a cancer in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, and(c) administering to the subject a therapeutic agent if the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

92. The method of claim 91 , wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

93. The method of any one of claims 91-92, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

94. The method of any one of claims 91-93, wherein the therapeutic agent is an anti-cancer agent (e.g., described herein).

95. The method of any one of claims 91-94, wherein the therapeutic agent inhibits expression of TNFAIP3.

96. The method of any one of claims 91-95, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

97. The method of claim 96, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66.

98. The method of any one of claims 91-97, wherein the cancer is a solid tumor.

99. A method of diagnosing a TNFAIP3 associated disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) indicates that the subject has a TNFAIP3 associated disease.

100. The method of claim 99, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

101. The method of any one of claims 99-100, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

102. The method of any one of claims 99-101, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is a proinflammatory (e.g., autoimmune) disease.

103. The method of any one of claims 99-102, wherein the TNFATP3 (e.g., hTNFAIP3) associated disease is an autoimmune disease.

104. The method of any one of claims 99-103, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma.

105. The method of any one of claims 99-104, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease.

106. The method of claim 99-105, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is a cancer (e.g., a solid tumor).

107. A method of diagnosing a proinflammatory (e.g., autoimmune) disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) indicates that the subject has a proinflammatory (e.g., autoimmune).

108. The method of claim 107, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

109. The method of any one of claims 107-108, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

110. The method of any one of claims 107-109, wherein the proinflammatory disease is an autoimmune disease.

111. The method of any one of claims 107-110, wherein the proinflammatory disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma.

112. The method of any one of claims 107-111, wherein the proinflammatory disease is inflammatory bowel disease.

113. A method of diagnosing a cancer in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) indicates that the subject has a cancer.

114. The method of claim 113, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

115. The method of any one of claims 113-114, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

116. The method of any one of claims 113-115, wherein the cancer is a solid tumor.

117. The method of any one of claims 69-116, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic TNFAIP3 mutation in the DNA.

118. The method of any one of claims 69-117, further comprising administering to the subject a therapeutic agent if a TNFAIP3 somatic mutation is detected in the DNA, RNA, or protein.

119. The method of any one of claims 69-118, further comprising administering to the subject a therapeutic agent that inhibits expression of TNFAIP3 if a TNFAIP3 somatic mutation is detected in the DNA, RNA, or protein.

120. The method of any one of claims 69-119, further comprising administering to the subject an inhibitory nucleic acid molecule that inhibits expression of TNFAIP3 if a TNFAIP3 somatic mutation is detected in the DNA, RNA, or protein.

121. The method of claim 120, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66.

122. A method of selecting a subject for administration of a therapeutic agent, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, wherein the subject is selected for administration of the therapeutic agent if the one or more somatic mutation (e.g., a somatic mutation set forth in Table 2) is present.

123. The method of claim 122, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified (e.g., from a cell or population of cells), from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic TNFAIP3 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

124. The method of any one of claims 122-123, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

125. The method of any one of claims 122-124, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

126. The method of any one of claims 122-125, further comprising administering to the subject the therapeutic agent if the subject is selected.

127. The method of any one of claims 122-126, wherein the therapeutic agent is an antiinflammatory agent (e.g., described herein).

128. The method of any one of claims 122-127, wherein the therapeutic agent inhibits expression of TNFAIP3.

129. The method of any one of claims 122-128, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets TNFAIP3.

130. The method of claim 129, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66.

131. An in vitro method of screening a sample from a subject for one or more somatic TNFAIP3 mutation, the method comprising(a) isolating and purifying DNA, RNA, or protein from a sample obtained from the subject; and(b) detecting the presence or absence of one or more somatic TNFAIP3 mutation in the DNA, RNA, or protein.

132. The method of any one of claims 69-131, wherein the sample is a blood, tissue, or cell sample.

133. The method of any one of claims 69-132, wherein the sample is biopsy.

134. The method of any one of claims 69-133, wherein the sample is a bowel biopsy.

135. The method of any one of claims 69-134, wherein the sample comprises B-cells and / or T cells (e.g., CD4+ T cells).

136. The method of any one of claims 69-135, wherein the sample comprises tumor infiltrating lymphocytes (e.g., tumor infiltrating B cells and / or tumor infiltrating T cells (e.g., CD4+ T cells)).

137. The method of any one of claims 69-136, wherein at least one of the one or more somatic mutation is a loss of function mutation.

138. The method of any one of claims 69-137, wherein at least one of the one or more somatic mutation is a gain of function mutation.

139. The method of any one of claims 69-138, wherein at least one of the one or more somatic mutation is a missense mutation.

140. The method of any one of claims 69-139, wherein at least one of the one or more somatic mutation is a nonsense mutation.

141. The method of any one of claims 69-140, wherein at least one of the one or more somatic mutation comprises the insertion of one or more nucleotide.

142. The method of any one of claims 69-141, wherein at least one of the one or more somatic mutation comprises the deletion of one or more nucleotide.

143. The method of any one of claims 69-142, wherein at least one of the one or more somatic mutation is synonymous.

144. The method of any one of claims 69-143, wherein at least one of the one or more somatic mutation is non- synonymous.

145. The method of any one of claims 69-144, wherein the subject is a human.

146. A method of delivering a dsRNA agent, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier ofany one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.

147. A method of delivering a dsRNA agent, conjugate, vector, carrier, or pharmaceutical composition to a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition to the subject.

148. A method of reducing or inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) in a cell, the method comprising delivering into the cell the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62- 64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby reduce or inhibit expression of TNFAIP3 (e.g., hTNFAIP3) in the cell.

149. The method of claim 148, wherein the cell is in vitro, ex vivo, or in vivo.

150. The method of claim 149, wherein the cell is in vitro.

151. A method of reducing or inhibiting expression of TNFAIP3 (e.g., hTNFAIP3) in a cell in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby reduce or inhibit expression of TNFAIP3 (e.g., hTNFAIP3) in the cell in the subject.

152. A method of treating, ameliorating, or preventing a TNFAIP3 (e.g., hTNFAIP3) associated disease in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby treat, ameliorate, or prevent the TNFAIP3 (e.g., hTNFAIP3) associated disease in the subject.

153. The method of claim 152, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is a proinflammatory (e.g., autoimmune) diseases.

154. The method of any one of claims 152- 153, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is an autoimmune disease.

155. The method of any one of claims 152-154, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, Sjogren’s syndrome, psoriatic arthritis, Celiac disease, scleroderma, or asthma.

156. The method of any one of claims 152-155, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is inflammatory bowel disease.

157. The method of any one of claims 152-156, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is a cancer (e.g., a solid tumor).

158. The method of any one of claims 152-157, wherein the TNFAIP3 (e.g., hTNFAIP3) associated disease is treated, ameliorated, or prevented through the reduction of inhibition of TNFAIP3 (e.g., hTNFAIP3) expression.

159. A method of treating, ameliorate, or preventing a proinflammatory (e.g., autoimmune) disease in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the carrier of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby treat, ameliorate, or prevent the proinflammatory (e.g., autoimmune) disease in the subject.

160. The method of claim 159, wherein the is an autoimmune disease.

161. The method of any one of claims 159-160, wherein the disease is inflammatory bowel disease, systemic lupus erythematosus, or rheumatoid arthritis.

162. The method of any one of claims 159-161, wherein the disease is inflammatory bowel disease.

163. The method of any one of claims 159-162, wherein the proinflammatory (e.g., autoimmune) disease is treated, ameliorated, or prevented through the reduction of inhibition of TNFAIP3 (e.g., hTNFAIP3) expression.

164. A method of treating, ameliorate, or preventing a cancer in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-56, the conjugate of any one of claims 57-60, the vector of claim 61, the earner of any one of claims 62-64, the cell (or population of cells) of claim 65, or the pharmaceutical composition of claim 66, to thereby treat, ameliorate, or prevent the cancer in the subject.

165. The method of claim 164, wherein the cancer is a solid tumor.

166. A population of engineered immune cells comprising a chimeric antigen receptor (CAR) comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; and an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 (or functional TNFAIP3) from the endogenous TNFAIP3 gene lacking the alteration).

167. The population of engineered immune cells of claim 166, wherein the population of immune cells exhibit enhanced cytolysis of cancer cells (e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

168. The population of engineered immune cells of any one of claims 166-167, wherein the population of immune cells exhibit enhanced cytokine (e.g., IFNy) expression in the presence of cancer cells (e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

169. The population of engineered immune cells of any one of claims 166-168, wherein the population of immune cells do not express TNFAIP3.

170. The population of engineered immune cells of any one of claims 166-169, wherein the population of immune cells do not express functional TNFAIP3.

171. The population of engineered immune cells of any one of claims 166-170, wherein the alteration in the endogenous TNFAIP3 gene effectively knocks TNFAIP3 such that there is no endogenous TNFAIP3 protein expression or a functional TNFAIP3 protein is not expressed.

172. The population of engineered immune cells of any one of claims 166-171, wherein the alteration in the endogenous TNFAIP3 gene completely inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration).

173. The population of engineered immune cells of any one of claims 166-172, wherein the alteration in the endogenous TNFAIP3 gene partially inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration).

174. The population of engineered immune cells of any one of claims 166-173, wherein the level of TNFAIP3 expression is reduced by at least 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%.

175. The population of engineered immune cells of any one of claims 166-174, wherein the alteration in the endogenous TNFAIP3 gene comprises one or more nucleotide substitution, deletion, or addition.

176. The population of engineered immune cells of any one of claims 166-175, wherein the antigen binding domain of the CAR specifically binds to a molecule expressed on the surface of a cancer cell (e.g., a tumor associated antigen, a tumor specific antigen, etc.).

177. The population of engineered immune cells of any one of claims 166-176, wherein the population of immune cells comprises tisagenlecleucel, idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel, brexueabtagene autoleucel, axicabtagene ciloleucel, or lifileucel.

178. The population of engineered immune cells of any one of claims 166-177, wherein the population of immune cells comprises T cells e.g., CD8+ T cells, CD4+ T cells).

179. The population of engineered immune cells of any one of claims 166-178, wherein the population of immune cells comprises tumor infiltrating lymphocytes (TILs).

180. The population of engineered immune cells of any one of claims 166-179, wherein the population of immune cells have been obtained from the subject.

181. The population of engineered immune cells of any one of claims 166-180, wherein the population of immune cells are ex vivo.

182. The population of engineered immune cells of any one of claims 166-181, wherein the population of immune cells are autologous or allogenic to the subject.

183. A method of making a population of engineered immune cells, the method comprising transfecting or transducing a population of immune cells with a nucleic acid molecule encoding a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; andintroducing one or more agent (e.g., a nucleic acid molecule, a CRTSPR / Cas system) into the population of immune cells that mediates an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration).

184. A method of enhancing the cytolytic activity of a population of immune cells, the method comprising providing a population of CAR immune cells comprising a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; introducing one or more agent (e.g., a nucleic acid molecule, a CRISPR / Cas system) into the population of immune cells that mediates an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration), to thereby produce a population of engineered immune cells, wherein the cytolytic activity (e.g., against cancer cells) of the population of engineered immune cells is greater than the cytolytic activity (e.g., against cancer cells) of the population of CAR immune cells (e.g., lacking the alteration in the endogenous TNFAIP3 gene) (e.g., assessed according to the methods described in Example 7).

185. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a population of engineered immune cells (or a pharmaceutical composition comprising the population of immune cells) comprising a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular domain; and an alteration in the endogenous TNFAIP3 gene that inhibits or reduces (e.g., completely or partially) expression of TNFAIP3 (or functional TNFAIP3) (e.g., relative to the level of expression of TNFAIP3 (or functional TNFAIP3) from the endogenous TNFAIP3 gene lacking the alteration), to thereby treat the cancer in the subject in need thereof.

186. The method of any one of claims 183-185, wherein the population of immune cells exhibit enhanced cytolysis of cancer cells (e.g., upon binding of the CAR to a moleculeexpressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

187. The method of any one of claims 183-186, wherein the population of immune cells exhibit enhanced cytokine e.g., IFNy) expression in the presence of cancer cells e.g., upon binding of the CAR to a molecule expressed on the surface of the cancer cells) (e.g., relative to a population of immune cells lacking the alteration in the endogenous TNFAIP3 gene).

188. The method of any one of claims 183-187, wherein the population of immune cells do not express TNFAIP3.

189. The method of any one of claims 183-188, wherein the population of immune cells do not express functional TNFAIP3.

190. The method of any one of claims 183-189, wherein the alteration in the endogenous TNFAIP3 gene effectively knocks TNFAIP3 such that there is no endogenous TNFAIP3 protein expression or a functional TNFAIP3 protein is not expressed.

191. The method of any one of claims 183-190, wherein the alteration in the endogenous TNFAIP3 gene completely inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration).

192. The method of any one of claims 183-191, wherein the alteration in the endogenous TNFAIP3 gene partially inhibits or reduces expression of TNFAIP3 (e.g., relative to the level of expression of TNFAIP3 from the endogenous TNFAIP3 gene lacking the alteration).

193. The method of any one of claims 183-192, wherein the level of TNFAIP3 expression is reduced by at least 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%.

194. The method of any one of claims 183-193, wherein the alteration in the endogenous TNFAIP3 gene comprises one or more nucleotide substitution, deletion, or addition.

195. The method of any one of claims 183-194, wherein the antigen binding domain of the CAR specifically binds to a molecule expressed on the surface of a cancer cell (e.g., a tumor associated antigen, a tumor specific antigen, etc.).

196. The method of any one of claims 183-195, wherein the population of immune cells comprises tisagenlecleucel, idecabtagene vicleucel, lisocabtagene maraleucel , ciltacabtagene autoleucel, brexueabtagene autoleucel, axicabtagene ciloleucel, or lifileucel.

197. The method of any one of claims 183-196, wherein the population of immune cells comprises T cells (e.g., CD8+ T cells, CD4+ T cells).

198. The method of any one of claims 183- 197, wherein the population of immune cells comprises tumor infiltrating lymphocytes (TILs).

199. The method of any one of claims 183-198, wherein the population of immune cells have been obtained from the subject.

200. The method of any one of claims 183-199, wherein the population of immune cells are ex vivo.

201. The method of any one of claims 183-200, wherein the population of immune cells are autologous or allogenic to the subject.

202. The method of any one of claims 183-201, wherein the cancer is a hematopoietic cancer or a solid tumor.

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