Immune cell 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 one or more genes expressed by one or more subsets of immune cells, e.g., T cells (e.g., tumor infiltrating T-cells), B-cells; 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 expression of one or more genes expressed by one or more subsets of immune cells, e.g., T cells (e.g., tumor infiltrating T-cells), B-cells expression (e.g., mRNA expression), methods of treating proinflammatory (e.g., autoimmune) diseases.

Description

IMMUNE CELL TARGETED COMPOSITIONS AND RELATED METHODSRELATED APPLICATIONS

[0001] This application claims priority to U.S. Serial No.: 63 / 632,335, filed April 10, 2024; U.S. Serial No.: 63 / 634,206, filed April 15, 2024; U.S. Serial No.: 63 / 636,512, filed April 19, 2024; U.S. Serial No.: 63 / 637,446, filed April 23, 2024; U.S. Serial No.: 63 / 638,958, filed April 26, 2024; the entire contents of each of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 4, 2025, is named 62801_60W001_SL.xml and is 52,915 bytes in size.1. FIELD

[0003] This disclosure relates to agents (e.g., RNA agents (e.g., double stranded RNAi agents comprising a sense strand and an antisense strand)) targeting one or more genes expressed by one or more subsets of immune cells, e.g., T cells, B-cells. The disclosure further relates to pharmaceutical compositions comprising the same; and methods of utilizing the same, including, e.g., methods of inhibiting expression of one or more target gene expressed by one or more subsets of immune cells e.g., T cells, B-cells, etc.), and methods of treating diseases associated with expression of one or more of said genes (e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer) comprising detecting one or more somatic mutation in a target gene expressed by one or more subsets of immune cells (e.g., T cells, B-cells, etc.).2. BACKGROUND

[0004] Somatic mutations are nucleotide alterations in a genomic DNA sequence (e.g., of a gene) that are acquired during the lifetime of a subject. Unlike germline mutations, 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 virialinfections.3. SUMMARY

[0005] Provided herein are, inter alia, agents (e.g., RNA agents (e.g., RNAi agents, dsRNA agents, ssRNA agents, siRNA agents, antisense oligonucleotides, etc.)) targeting one or more genes expressed by one or more subsets of immune cells, e.g., T cells, B-cells, tumor infiltrating lymphocytes (TILs) (e.g., tumor infiltrating T-cells); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNA agents (e.g., RNAi agents, dsRNA agents, etc.)) including, e.g., methods of inhibiting or decreasing gene expression (e.g., mRNA expression), methods of treating diseases associated with the one or more genes, and methods of treating diseases, including, e.g., proinflammatory diseases (e.g., autoimmune diseases); and cancer; and methods of treating diseases associated with expression of one or more of said genes (e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer) comprising detecting one or more somatic mutation in a target gene expressed by one or more subsets of immune cells (e.g., T cells, B-cells, etc.).

[0006] Accordingly, in one aspect, provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of BTG1 (e.g., human BTG1 (hBTGl)) 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.

[0007] 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.

[0008] In one aspect, provided herein are dsRNA agents for inhibiting expression of BTG1 (e.g., (hBTGl) 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 BTG1 (e.g., (hBTGl).

[0009] In some embodiments, the region of complementarity is fully complementary to theportion of the mRNA sequence encoding BTG1 (e.g., (hBTG1 ). 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.

[0010] In one aspect, provided herein are dsRNA agents for inhibiting expression of BTG1 (e.g., (hBTGl) 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 BTG1 (e.g., (hBTGl), 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.

[0011] 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.

[0012] In one aspect, provided herein are double stranded ribonucleic (dsRNA) agents for inhibiting expression of CDKN1B (e.g., human CDKN1B (hCDKNIB)) 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: 5.

[0013] 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: 4. 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: 4 that is complementary to the sequence of the antisense strand from the nucleotidesequence of SEQ ID NO: 5.

[0014] In one aspect, provided herein arc dsRNA agents for inhibiting expression of CDKN1B (e.g., (hCDKNIB) 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 CDKN1B (e.g., (hCDKNIB).

[0015] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding CDKN1B (e.g., (hCDKNIB). 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: 5. 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: 4. 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: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

[0016] In one aspect, provided herein are dsRNA agents for inhibiting expression of CDKN1B (e.g., (hCDKNIB) 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 CDKN1B (e.g., (hCDKNIB), 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: 5.

[0017] 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: 4. 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: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

[0018] In one aspect, provided herein are double stranded ribonucleic (dsRNA) agents for inhibiting expression of DUSP2 (e.g., human DUSP2 (hDUSP2)) 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) nucleotidesfrom the nucleotide sequence of SEQ ID NO: 8.

[0019] In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no more than 5 (e. ., 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 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: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

[0020] In one aspect, provided herein are dsRNA agents for inhibiting expression of DUSP2 (e.g., (hDUSP2) 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 DUSP2 (e.g., (hDUSP2), 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: 8.

[0021] 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: 7. 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: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

[0022] In one aspect, provided herein are dsRNA agents for inhibiting expression of DUSP2 (e.g., (hDUSP2) 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 DUSP2 (e.g., (hDUSP2).

[0023] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding DUSP2 (e.g., (hDUSP2)). 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: 8. 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: 7. In some embodiments, the sense strand comprises at least 15 contiguous nucleotides differing by no morethan 5 (e.g., 0, 1 , 2, 3, 4, or 5) 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.

[0024] In one aspect, provided herein are dsRNA agents for inhibiting expression of DUSP2 (e.g., (hDUSP2) 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 DUSP2 (e.g., (hDUSP2), 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: 8.

[0025] 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: 7. 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: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

[0026] In one aspect, provided herein are double stranded ribonucleic (dsRNA) agents for inhibiting expression of IGLL5 (e.g., human IGLL5 (hIGLL5)) 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: 11.

[0027] 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: 10. 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: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

[0028] In one aspect, provided herein are dsRNA agents for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5).

[0029] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding IGLL5 (e.g., (hIGLL5)). In some embodiments, theregion 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: 11. 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: 10. 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: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

[0030] In one aspect, provided herein are dsRNA agents for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5), 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: 11.

[0031] 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: 10. 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: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

[0032] In one aspect, provided herein are double stranded ribonucleic (dsRNA) agents for inhibiting expression of IGLL5 (e.g., human IGLL5 (hIGLL5)) 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: 14.

[0033] 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: 13. 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: 13 that is complementary to the sequence of the antisense strand from the nucleotidesequence of SEQ ID NO: 14.

[0034] In one aspect, provided herein arc dsRNA agents for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 e.g., (hIGLL5).

[0035] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding IGLL5 e.g., (hIGLL5)). 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: 14. 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: 13. 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: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

[0036] In one aspect, provided herein are dsRNA agents for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 sequence encoding IGLL5 (e.g., (hIGLL5), 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 region of SEQ ID NO: 14.

[0037] 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: 13. 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 sequence of SEQ ID NO: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

[0038] In one aspect, provided herein are double stranded ribonucleic (dsRNA) agents for inhibiting expression of KLHL6 (e.g., human KLHL6 (hKLHL6)) comprising a sense strand and an antisense strand that form a double stranded region, wherein the antisense strand comprises atleast 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: 17.

[0039] 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: 16. 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: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.

[0040] In one aspect, provided herein are dsRNA agents for inhibiting expression of KLHL6 (e.g., (hKLHL6) 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 KLHL6 (e.g., (hKLHL6).

[0041] In some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding KLHL6 (e.g., (hKLHL6)). 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: 17. 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: 16. 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: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.

[0042] In one aspect, provided herein are dsRNA agents for inhibiting expression of KLHL6 (e.g., (hKLHL6) 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 KLHL6 (e.g., (hKLHL6), 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: 17.

[0043] 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 ofSEQ ID NO: 16. 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: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.1n some embodiments, the region of complementarity is fully complementary to the portion of the mRNA sequence encoding IGLL5 (e.g., (hIGLL5)). 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: 14. 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: 13. 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: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

[0044] For the sake of clarity, it should be understood that the following exemplary embodiments, can be applied to any of the foregoing aspects.

[0045] In some embodiments, the send strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.

[0046] 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.

[0047] 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, 19-30 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. 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.

[0048] 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).

[0049] 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. In some embodiments, 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). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

[0050] In one aspect, provided herein are 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 / or antisense strand, and / or at an internal site of the sense and / or antisense strand.

[0051] In one aspect, provided herein are vectors (e.g., a viral vector, a non-viral vector) encoding an antisense strand, a sense strand, or both an antisense and sense strand of an RNA agent (e.g., dsRNA agent) described herein, or a conjugate described herein.

[0052] 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.

[0053] In one aspect, provided herein are cells comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, or a carrier described herein.

[0054] 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 described herein, and a pharmaceutically acceptable excipient.

[0055] 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 described herein, or a pharmaceutical composition described herein.

[0056] 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 BTG1 (e.g., hBTGl), CDKN1B, DUSP2, IGLL5, or KLHL6 mutation in a sample from a subject.

[0057] In one aspect, provided herein are methods of treating, ameliorating, or preventing a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

[0058] In some embodiments, the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6. 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.

[0059] In some embodiments, the gene associated disease is a BTG1 associated disease, a CDKN1B associated disease, DUSP2 associated disease, a ILL5 associated disease, or a KLHL6associated disease.

[0060] In some embodiments, (i) the gene associated disease is a BTG1 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic BTG1 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, (ii) the gene associated disease is a CDKN1B associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic CDKN1B mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, (iii) the gene associated disease is a DUSP2 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic DUSP2 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, (iv) the gene associated disease is a IGLL5 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic IGLL5 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, or (v) the gene associated disease is a KLHL6 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic KLHL6 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein.

[0061] In some embodiments, the therapeutic agent comprises an anti-inflammatory agent (e.g., an anti-inflammatory agent described herein).

[0062] In some embodiments, the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent as described herein, a conjugate as described herein, a vector as described herein, a carrier as described herein, a cell as described herein, a pharmaceutical composition as described herein.

[0063] In one aspect, provided herein are methods of treating, ameliorating, or preventing a proinflammatory disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

[0064] In some embodiments, the gene is BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6. 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.

[0065] In some embodiments, the therapeutic agent is an anti-inflammatory agent as described herein. In some embodiments, the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent as described herein, a conjugate as described herein, a vector as described herein, a carrier as described herein, a cell as described herein, a pharmaceutical composition as described herein.

[0066] In one aspect, provided herein are methods of diagnosing a gene e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease.

[0067] In some embodiments, the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6. 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. In some embodiments, the gene is associated disease is a BTG1 associated disease, a CD KN IB associated disease, DUSP2 associated disease, a IGLL5 associated disease, or a KLHL6 associated disease.

[0068] In some embodiments, (i) the gene associated disease is a BTG1 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic BTG1 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, (ii) the gene associated disease is a CDKN1B associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic CDKN1B mutation (e.g., a somaticmutation set forth in Table 2) in the DNA, RNA, or protein, (iii) the gene associated disease is a DUSP2 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic DUSP2 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, (iv) the gene associated disease is a IGLL5 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic IGLL5 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein, or (v) the gene associated disease is a KLHL6 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic KLHL6 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein.

[0069] In some embodiments, the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease is a proinflammatory (e.g., autoimmune) disease. In some embodiments, the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease is an autoimmune disease.

[0070] 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

[0071] In some embodiments, the method further comprises administering to the subject a therapeutic agent if a somatic mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

[0072] In some embodiments, the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent as described herein, a conjugate as described herein, a vector as described herein, a carrier as described herein, a cell as described herein, a pharmaceutical composition as described herein.

[0073] 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, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) inthe 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.

[0074] 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 gene e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA. In some embodiments, the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

[0075] 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.

[0076] 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 as described herein. In some embodiments, the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6). In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent as described herein, a conjugate as described herein, a vector as described herein, a carrier as described herein, a cell as described herein, a pharmaceutical composition as described herein.

[0077] In one aspect, provided herein are in vitro methods of screening a sample from a subject for one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2), 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein.

[0078] 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

[0079] In some embodiments, the sample is a blood, tissue, or cell sample. In someembodiments, the sample is biopsy. In some embodiments, the sample comprises a cell (e.g., a T- ccll) or a population of cells (e.g., a population of T-cclls).

[0080] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation, a gain of function mutation, a missense mutation, synonymous, and / or non- synonymous. In some embodiments, the one or more somatic mutation is a loss of function mutation. In some embodiments, the one or more somatic mutation truncates the protein encoded by the gene. 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.

[0081] In one aspect, provided herein are methods of reducing or inhibiting expression of a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in a cell, the method comprising delivering into the cell the a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in the cell.

[0082] In one aspect, provided herein are methods of reducing or inhibiting expression of a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in the cell in the subject.

[0083] In some embodiments, the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

[0084] In one aspect, provided herein are methods of treating, ameliorating, or preventing a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease in the subject.

[0085] In some embodiments, the gene associated disease is a BTG1 associated disease, a CDKN1B associated disease, a DUSP2 associated disease, an IGLL5 associated disease, or a KLHL6 associated disease.

[0086] In some embodiments, the gene (e.g., BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease associated disease is a proinflammatory disease (e.g., an autoimmune disease).

[0087] In some embodiments, the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease associated disease is an autoimmune disease.

[0088] In some embodiments, the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease is treated, ameliorated, or prevented through the reduction or inhibition expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

[0089] 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 described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the proinflammatory (e.g., autoimmune) disease in the subject.

[0090] In some embodiments, the proinflammatory (e.g., autoimmune) disease is treated, ameliorated, or prevented through a reduction or inhibition of expression of a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

[0091] In some embodiments, the subject is a human.4. DETAILED DESCRIPTION

[0092] The inventors have, inter alia, discovered somatic mutations in select genes expressed by subsets of immune cells (e.g., T cells, B-cells, TILs (e.g., tumor infiltrating T-cells), including BTG1, CDKN1B, DUSP2, IGLL5, and KLHL6, particularly within the context of certain diseases, including, e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer. As such, a step of detecting (or having detected) one or more somatic mutation in a target gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, and KLHL6) expressed by one or more subsets of immune cells (e.g., T cells, B-cells, etc.) is useful in methods of treating e.g., proinflammatory diseases (e.g., autoimmune diseases); and agents capable of inhibiting expression of one or more of these genes (BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) (e.g., RNA agents described herein) are useful in e.g., methods of treating e.g., proinflammatory diseases (e.g., autoimmune diseases). As such, the current disclosure provides, inter alia, methods of treating diseases associated with expression of one or more of said genes (e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer)comprising detecting one or more somatic mutation in a target gene expressed by one or more subsets of immune cells (e.g., T cells, B-cclls, etc.); agents (e.g., RNA agents (e.g., RNAi agents, dsRNAi agents comprising a sense strand and an antisense strand, ssRNA agents)) capable of inhibiting gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, and KLHL6) expression (e.g., in a cell, e.g., in a cell in a subject) and their use in, inter alia, pharmaceutical compositions, and methods of treating diseases (e.g., proinflammatory diseases (e.g., autoimmune diseases), cancer).TABLE OF CONTENTS4.1 Definitions4.2 RNA Agents4.2.1 RNAi Agents4.2.1.1 Antisense Strand4.2.1.1 (i) T argeting Region4.2.1.1(ii) Overall Length4.2.1.1(iii) Exemplary Antisense Strands4.2.1.2 Sense Strand4.2.1.2(i) Antisense Strand Complementarity4.2.1.2(ii) Overall Length4.2.1.2(iii) Exemplary Sense Strands4.2.1.3 dsRNA Agents4.2.1.3(i) Single & Multiple Nucleic Acid Molecules4.2.1.3(ii) Length of Double Stranded Region4.2.1.3(iii) Nucleotide Overhangs & Blunt Ends4.2.1.3(iv) Exemplary Structural Combinations of Sense & Antisense Strands4.2.1.3(v) Exemplary Antisense Strands & Sense Strands4.2.1.3(vi) Exemplary dsRNA Agents4.2.2 Antisense Oligonucleotide RNA Agents4.2.2.1 Targeting Region4.2.2.2 Overall Length4.2.2.3 Exemplary Antisense Oligonucleotides4.3 Modified RNA Agents4.3.1 Nature of Nucleotide Modifications4.13 Exemplary Diseases4.14 Exemplary Therapeutic Agents4.15 Methods of Use4.15.1 Methods of Treating, Ameliorating, or Preventing a Disease in a Subject4.15.2 Methods of Diagnosing and / or Prognosticating a Disease in a Subject4.15.3 Methods of Screening, Identifying, and Selecting a Subject for Treatment with a Therapeutic Agent4.15.4 In Vitro Methods of Screening Samples for Somatic Gene Mutations4.15.5 Methods of Delivery4.15.6 Methods of Reducing or Inhibiting Gene Expression4.16 Kits4.1 Definitions

[0093] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0094] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art 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.

[0095] 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.

[0096] 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.

[0097] 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).

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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).

[0102] As used herein, the term “antisense strand” refers to an RNA molecule (e.g., in some embodiments, part 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 BTG1 mRNA), a portion of a target mRNA (e.g., a BTG1 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.

[0103] 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.

[0104] As used herein, the term “bicyclic nucleoside” (“BNA”) is a nucleoside comprising a bicyclic sugar.

[0105] 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 (z.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.

[0106] 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 and form 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).

[0107] 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 art, as are commercially available conjugation reagents and kits, with detailedinstructions for their use readily available from the commercial suppliers.

[0108] 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.

[0109] 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).

[0110] As used herein, the term “double stranded RNA agent” or “dsRNA agent” refers to a complex 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.

[0111] As used herein, the term “BTG Anti-Proliferation Factor 1” or “BTG1” refers to the BTG / transducer of Erb family (Tob) member that functions, e.g., in the regulation of cell cycle progression, cell proliferation, and apoptosis. The term BTG1 includes human BTG1 (hBTGl). The mRNA sequence of reference hBTGl gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_001731.3). The amino acid sequence of a reference hBTGl protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_001722.1). The term BTGI includes naturally occurring variants of BTG1. BTG1 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.

[0112] As used herein, the term “ cyclin-dependent kinase inhibitor IB” or “CDKN1B” refers to the cyclin-dependent kinase inhibitor that belongs to the Cip / Kip family of cyclin dependentkinase inhibitor proteins. The term CDKN1B includes human CDKN1B (hCDKNIB). The mRNA sequence of reference hCDKNIB gene is set forth in SEQ ID NO: 4 (NCBI Ref.: NM_004064.5). The amino acid sequence of a reference hCDKNIB protein is set forth in SEQ ID NO: 6 (NCBI Ref.: NP_004055.1). The term CDKN1B includes naturally occurring variants of CDKN1B. CDKN1B 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.

[0113] As used herein, the term “dual specificity phosphatase 2” or “DUSP2” refers to the dual specificity protein phosphatase that functions, e.g., in the inactivation of ERK1 / 2 and p38 MAPK. The term DUSP2 includes human DUSP2 (hDUSP2). The mRNA sequence of reference hDUSP2 gene is set forth in SEQ ID NO: 7 (NCBI Ref.: NM_004418.4). The amino acid sequence of a reference hDUSP2 protein is set forth in SEQ ID NO: 9 (NCBI Ref.: NP_004409.1). The term DUSP2 includes naturally occurring variants of DUSP2. DUSP2 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.

[0114] As used herein, the term “ immunoglobulin lambda like polypeptide 5” or “IGLL5” refers to the gene (and encoded protein) located within the immunoglobulin lambda locus, wherein the first exon of the IGLL5 gene is unrelated to immunoglobulin variable genes; while the second and third exons are the immunoglobulin lambda joining 1 and the immunoglobulin lambda constant 1 gene segments. The term IGLL5 includes human IGLL5 (hIGLL5). The mRNA sequence of reference hIGLL5 gene (isoform 1) is set forth in SEQ ID NO: 10 (NCBI Ref.: NM_001178126.2). The amino acid sequence of a reference hIGLL5 protein (isoform 1) is set forth in SEQ ID NO: 12 (NCBI Ref.: NP_001171597.1). The mRNA sequence of reference hIGLL5 gene (isoform 2) is set forth in SEQ ID NO: 4 (NCBI Ref.: NM_001256296.2). The amino acid sequence of a reference hIGLL5 protein (isoform 2) is set forth in SEQ ID NO: 15 (NCBI Ref.: NP_001243225.1). The term IGLL5 includes naturally occurring variants of IGLL5. IGLL5 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.

[0115] As used herein, the term “kelch like family member 6” or “KLHL6” refers to the KLHL family member that functions, e.g., in B-lymphocytc antigen receptor signaling and germinal- center B-cell maturation. The mRNA sequence of reference hKLHL6 gene is set forth in SEQ ID NO: 16 (NCBI Ref.: NM_ 130446.4). The amino acid sequence of a reference hKLHL6 protein is set forth in SEQ ID NO: 18 (NCBI Ref.: NP_569713.2). The term KLHL6 includes naturally occurring variants of KLHL6. KLHL6 gene and mRNA sequences of e.g., human, mouse, rat, nonhuman 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 atleast one substitution, addition, or deletion of an amino acid residue compared to a reference peptide or protein.

[0121] 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 that comprises one or more modified nucleotide (as defined herein).

[0122] 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., §§ 4.3, 4.3.1. 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.

[0123] 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.

[0124] 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.

[0125] 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 parties directly acquired the sample from the subject.

[0126] 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 isoperably 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).

[0127] As used herein, “partially complementary” means that in a hybridized pair of a first nucleic 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.

[0128] 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 NBEAST and XBEAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is incorporated herein by reference in its entirety for all purposes. BEAST nucleotide searches can be performed with the NBEAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BEAST protein searches can be performed with the XBEAST 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 BEAST 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 amathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 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 can be 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.

[0129] 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.

[0130] 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.

[0131] 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).

[0132] 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).

[0133] 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 shorter polymers 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).

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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., BTG1) 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 eachindependently comprise or consist of from about 19-23 nucleotides.

[0138] 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.

[0139] As used herein, the term “sense strand” refers to an RNA molecule (e.g., part 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).

[0140] 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 art 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.

[0141] 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).

[0142] 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 pail of a first or second nucleic acid molecule.

[0143] 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).

[0144] 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., BTG1)). In some embodiments, the target nucleic acid sequence is an mRNA molecule formed during the transcription of a target gene (e.g., BTG1)). 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 BTG1 gene. In one embodiment, the target sequence is within the protein coding region of BTG1.

[0145] 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 RNAagent in in vitro assays.

[0146] 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.4.2 RNA Agents

[0147] Provided herein are inter alia, agents (e.g., RNA agents), useful in, inter alia, inhibiting expression of one or more target gene (e.g., expressed by one or more subsets of immune cells, e.g., T cells) (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 mRNA encoded by the target gene).

[0148] Target genes include, BTG1 (e.g., human BTG1 (hBTGl)); CDKN1B (e.g., human CDKN1B (hCDKNIB)); DUSP2 (e.g., human DUSP2 (hDUSP2)); IGLL5 (e.g., human IGLL5 (hIGLL5)); or KLHL6 (e.g., human KLHL6 (hKLHL6)).

[0149] 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: BTG1 (BTG1) (e.g., human BTG1 (hBTGl)) (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 BTG1 (e.g., hBTGl) mRNA); CDKN1B (e.g., hCDKNIB) (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 CDKN1B (e.g., hCDKNIB) mRNA); DUSP2 (e.g., hDUSP2) (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 DUSP2 (e.g., hDUSP2) mRNA); IGLL5 (e.g., hIGLL5) (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 IGLL5 (e.g., hIGLL5) mRNA); or KLHL6 (e.g., hKLHL6) (e.g., within a cell, e.g., within a cell in asubject, e.g., a mammalian subject, e.g., a human subject) (e.g., through the degradation of KLHL6 (e.g., hKLHL6) mRNA).

[0150] BTG1 is a member of the BTG / Tob family, generally regarded as an anti-proliferative gene family. The BTG / Tob family consists of six protein members; BTG1, BTG2 / Tis21 / PC3, BTG3 / ANA, BTG4 / PC3B, TOB1 / TOB, and TOB2. BTG1 functions in a wide range of cellular activities including, for example, proliferation, apoptosis, and cell growth. BTG1 expression is generally highest in the G0 / G1 phases of the cell cycle and downregulated as cells progress through Gl. BTG1 is expressed both in the nucleus and cytoplasm, and function influenced at least in part by the intracellular localization. In the nuclease BTG1 is known to interact with several nuclear receptors and can function as a coactivator of cell differentiation. See, e.g., Kim, Sang Hyeon et al. “Emerging role of anti-proliferative protein BTG1 and BTG2.” BMB reports vol. 55,8 (2022): 380-388. doi:10.5483 / BMBRep.2022.55.8.092. The mRNA sequence of a reference hBTGl gene is set forth in SEQ ID NO: 1. The reverse complement sequence of the hBTGl mRNA is set forth in SEQ ID NO: 2. The amino acid sequence of the hBTGl protein encoded by the hBTGl reference gene is set forth in SEQ ID NO: 3.

[0151] CDKN1B is a cyclin-dependent kinase inhibitor that belongs to the Cip / Kip family of cyclin dependent kinase inhibitor proteins. CDKN1B functions to, e.g., bind to and prevent the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus control the cell cycle progression at the Gl phase. CDKN1B degradation, which is triggered by, e.g., its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes (Skp, Cullin, F-box containing complex), is generally needed for the cellular transition from quiescence to a proliferative state. The mRNA sequence of a reference hCDKNIB gene is set forth in SEQ ID NO: 4. The reverse complement sequence of the hCDKNIB mRNA is set forth in SEQ ID NO: 5. The amino acid sequence of the hCDKNIB protein encoded by the hCDKNIB reference gene is set forth in SEQ ID NO: 6.

[0152] DUSP2 is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both phosphoserine / threonine and pho sphotyro sine residues. Members of the DUSP family exhibit distinct substrate specificities for various MAP kinases, different tissue distribution, different subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. DUSP2, for example, inactivates ERK1 / 2 and p38 MAPK. DUSP2 is expressed in, e.g., hematopoietic tissues, and islocalized in the nucleus. The mRNA sequence of a reference hDUSP2 gene is set forth in SEQ ID NO: 7. The reverse complement sequence of the hDUSP2 mRNA is set forth in SEQ ID NO: 8. The amino acid sequence of the hDUSP2 protein encoded by the hDUSP2 reference gene is set forth in SEQ ID NO: 9.

[0153] The IGLL5 gene is located within the immunoglobulin lambda locus but it does not require somatic rearrangement for expression. The first exon of the IGLL5 gene is unrelated to immunoglobulin variable genes; while the second and third exons are the immunoglobulin lambda joining 1 and the immunoglobulin lambda constant 1 gene segments. It is known that alternative splicing results in multiple transcript variants. The mRNA sequence of a reference hIGLL5 gene (isoform 1) is set forth in SEQ ID NO: 10. The reverse complement sequence of the hIGLL5 mRNA (isoform 1) is set forth in SEQ ID NO: 11. The amino acid sequence of the hIGLL5 protein encoded by the hIGLL5 (isoform 1) reference gene is set forth in SEQ ID NO: 12. The mRNA sequence of a reference hIGLL5 gene (isoform 2) is set forth in SEQ ID NO: 13. The reverse complement sequence of the hIGLLS mRNA (isoform 2) is set forth in SEQ ID NO: 14. The amino acid sequence of the hIGLL5 protein encoded by the hIGLL5 (isoform 2) reference gene is set forth in SEQ ID NO: 15.

[0154] KLHL6 is a member of the kelch-like (KLHL) family of proteins. Proteins of the KLHL family generally contain a BTB / POZ domain, a BACK domain, and five to six Kelch motifs. The KLHL6 protein contains an N-terminal broad-complex, tramtrack and brie a brae (BTB) domain that facilitates protein binding and dimerization, a BTB domain, C-terminal kelch (BACK) domain, and six C-terminal kelch repeat domains. KLHL6 functions, e.g., in B-lymphocyte antigen receptor signaling and germinal-center B-cell maturation. KLHL6 is expressed by lymphoid tissue, including, e.g., by germinal center B-cells. The mRNA sequence of a reference hKLHL6 gene is set forth in SEQ ID NO: 16. The reverse complement sequence of the hKLHL6 mRNA is set forth in SEQ ID NO: 17. The amino acid sequence of the hKLHL6 protein encoded by the hKLHL6 reference gene is set forth in SEQ ID NO: 18.Table 1. The mRNA and Amino Acid Sequence of a Reference hBTGl, hCDKN 1 B, hDUSP2, hIGLL5, and hKLHL6,

[0155] 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.4.2.1 RNAi Agents

[0156] 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.4.2.1.1 Antisense Strand(i) Targeting Region

[0157] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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., aBTGl, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, 1GLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA)).

[0158] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN IB, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA)).

[0159] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 4, 3, 2, 1 , or 0) non-complementarynucleotide 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. ., 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. 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 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 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 targetmRNA (e.g., a BTGl , CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA))).

[0160] 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 some embodiments, 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.

[0161] 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 BTG1, CDKN1B,DUSP2, IGLL5, or KLHL6 mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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).

[0162] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 gene).

[0163] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a BTG1 (e.g., hBTGl) 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 BTG1 (e.g., hBTGl) 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 BTG1 (e.g., hBTGl) 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: 3 (or a variant or fragment thereof).

[0164] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a CDKNIB (e.g., hCDKNIB) 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 CDKNIB (e.g., hCDKNIB) 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: 4 (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 aCDKN1B e.g., hCDKNIB) 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: 6 (or a variant or fragment thereof).

[0165] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a DUSP2 (e.g., hDUSP2) 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 DUSP2 (e.g., hDUSP2) 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: 7 (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 DUSP2 (e.g., hDUSP2) 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: 9 (or a variant or fragment thereof).

[0166] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a IGLL5 (e.g., hIGLL5) 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 IGLL5 (e.g., hIGLL5) 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: 10 (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 IGLL5 (e.g., hIGLL5) 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: 12 (or a variant or fragment thereof). 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: 13 (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 IGLL5 (e.g., hIGLL5) protein. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA sequence encodinga protein comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant or fragment thereof).

[0167] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a KLHL6 (e.g., hKLHL6) 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 KLHL6 (e.g., hKLHL6) 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: 16 (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 KLHL6 (e.g., hKLHL6) 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: 18 (or a variant or fragment thereof).

[0168] 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 consistsof about 21 nucleotides. Tn some embodiments, the target nucleic acid molecule consists of about 23 nucleotides.

[0169] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(ii) Overall Length

[0170] 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 21-22 nucleotides). 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.

[0171] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(iii) Exemplary Antisense Strands

[0172] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0173] 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 aportion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0174] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strandcomprises 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 aportion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0175] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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 the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0176] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2,IGLL5, or KLHL6 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.

[0177] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 aportion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0178] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises 19 contiguous nucleotides.

[0179] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2,IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises 20 contiguous nucleotides.

[0180] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises 21 contiguous nucleotides.

[0181] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises 22 contiguous nucleotides.

[0182] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises 23 contiguousnucleotides differing by no more than 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand comprises 23 contiguous nucleotides.

[0183] 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 aportion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CD KN IB, DUSP2, IGLL5, or KLHL6 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.

[0184] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0185] 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 ofthe reverse complement of a portion of a BTG1 , CDKN IB, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand consists of 19 contiguous nucleotides.

[0186] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN IB, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand consists of 20 contiguous nucleotides.

[0187] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand consists of 21 contiguous nucleotides.

[0188] 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 the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA.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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand consists of 22 contiguous nucleotides.

[0189] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense strand consists of 23 contiguous nucleotides.

[0190] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0191] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0192] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0193] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0194] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0195] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0196] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 19contiguous nucleotides.

[0197] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 20 contiguous nucleotides.

[0198] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 21 contiguous nucleotides.

[0199] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 22 contiguous nucleotides.

[0200] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strandcomprises 23 contiguous nucleotides differing by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand comprises 23 contiguous nucleotides.

[0201] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0202] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of20, 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0203] 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 ofany one of SEQ ID NOS: 2, 5, 8, 11 , 14, or 17. 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) {e.g., by no more than 3 {e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 19 contiguous nucleotides.

[0204] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) {e.g., by no more than 3 {e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 20 contiguous nucleotides.

[0205] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) {e.g., by no more than 3 {e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 21 contiguous nucleotides.

[0206] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) {e.g., by no more than 3 {e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 22 contiguousnucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 22 contiguous nucleotides.

[0207] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense strand consists of 23 contiguous nucleotides.

[0208] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.1.2 Sense Strand(i) Antisense Strand Complementarity

[0209] 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).

[0210] 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.

[0211] 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 atleast 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.

[0212] In some embodiments, the nucleotide sequence of the region of complementarity comprises one or more 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 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.

[0213] 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.

[0214] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(ii) Overall Length

[0215] 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.

[0216] 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.

[0217] 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.

[0218] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(iii) Exemplary Sense Strands

[0219] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0220] 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 a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0221] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotidesequence of a portion of a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0222] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0223] 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 B TGI, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0224] 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 BTG1, CDKN1B, DUSP2, IGLL5,or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of aportion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0225] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 19 contiguous nucleotides.

[0226] 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 BTG1, CDKN IB, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 20 contiguous nucleotides.

[0227] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of aBTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 21 contiguous nucleotides.

[0228] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 22 contiguous nucleotides.

[0229] 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 aBTGl, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand comprises 23 contiguous nucleotides.

[0230] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 byno more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0231] 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 BTG1, CDKN IB, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0232] 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 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 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 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of SEQ ID NO: 10. 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: 13. 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: 16.

[0233] 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B,DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 19 contiguous nucleotides.

[0234] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 20 contiguous nucleotides.

[0235] 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 BTG1, CDKN IB, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 21 contiguous nucleotides.

[0236] 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 BTG1, CDKN IB, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 22 contiguous nucleotides.

[0237] 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 portionof a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the sense strand consists of 23 contiguous nucleotides.

[0238] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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.

[0239] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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.

[0240] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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.

[0241] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0242] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35 contiguous nucleotides.

[0243] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 {e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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.

[0244] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 19 contiguous nucleotides.

[0245] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 20 contiguous nucleotides.

[0246] 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 any one ofSEQ ID NOS: 1 , 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS:1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 21 contiguous nucleotides.

[0247] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS:1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 22 contiguous nucleotides.

[0248] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS:1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand comprises 23 contiguous nucleotides.

[0249] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 sequenceof any one of SEQ ID NOS: 1 , 4, 7, 10, 13, or 16. 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.

[0250] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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.

[0251] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 19 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 19 contiguous nucleotides.

[0252] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 20 contiguous nucleotides.

[0253] In some embodiments, the sense strand consists of 21 contiguous nucleotides differingby no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS:1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 21 contiguous nucleotides.

[0254] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS:1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 22 contiguous nucleotides.

[0255] 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 any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 23 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS:1, 4, 7, 10, 13, or 16. In some embodiments, the sense strand consists of 23 contiguous nucleotides.

[0256] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.1.3 dsRNA Agents

[0257] 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 § 4.2.1.1) and a sense strand (e.g., described herein, e.g., described in § 4.2.1.2) 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)).

[0258] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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

[0259] 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.

[0260] 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 strand and 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).

[0261] 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 allpurposes).(ii) Length of Double Stranded Region

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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

[0267] 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 §§ 4.3, 4.3.1).

[0268] 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 nucleotide overhang 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.

[0269] 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.

[0270] 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 anucleotide overhang at the 5'-end. Tn some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-cnd. 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.

[0271] 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.

[0272] 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

[0273] 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 contain different 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.

[0274] 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 someembodiments, the double stranded region comprises 21 nucleotides. Tn some embodiments, the antisense strand comprises a 2-nuclcotidc 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.

[0275] 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.

[0276] In some embodiments, the sense strand comprises 21 nucleotides. In some embodiments, the antisense strand comprises 21 nucleotides. In some embodiments, the sense strand 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.

[0277] 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 doublestranded 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.

[0278] 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.

[0279] 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 strand comprises 24 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 sense strand comprises a 3-nucleotide overhang at the 3' end.

[0280] 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

[0281] In some embodiments, the antisense strand and the sense strand are part of the samelarger 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.

[0282] 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.

[0283] In some embodiments, the sense strand consists of 19 nucleotides. In some embodiments, the antisense strand consists of 21 nucleotides. In some embodiments, the sense strand 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.

[0284] 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 strandedregion consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3' end; and the sense strand comprises a 2-nuclcotidc overhang at the 3' end.

[0285] 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.

[0286] 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 strand consists of 21 nucleotides; the antisense strand consists of 19 nucleotides; the double stranded region consists of 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.

[0287] 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.

[0288] In some embodiments, the sense strand consists of 19 nucleotides. In some embodiments, the antisense strand consists of 19 nucleotides. In some embodiments, the sensestrand 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

[0289] 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

[0290] In some embodiments, the antisense strand is an antisense strand described herein. In some embodiments, the sense strand is a sense strand described herein. In some embodiments, the antisense strand is an antisense strand described in § 4.2.1.1. In some embodiments, the sense strand is a sense strand described in § 4.2.1.2. In some embodiments, the antisense strand is an antisense strand described in § 4.2.1.1; and the sense strand is a sense strand described in § 4.2.1.2. It is to be understood that any sense strand described herein (e.g., in § 4.2.1.2); and be utilized in combination with any antisense strand in a dsRNA agent described herein (e.g., in § 4.2.1.1). For the sake of clarity, the entire contents of in §§ 4.2.1.1 and § 4.2.1.2, are incorporated by reference into the instant section.(vi) Exemplary dsRNA Agents

[0291] The nucleotide sequence of exemplary unmodified and / or modified dsRNAi agents comprising a sense and antisense strand (e.g., suitable for targeting BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6, suitable for inhibiting BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 expression)) are described in herein.

[0292] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of BTG1,CDKN1B, DUSP2, IGLL5, or KLHL6 (e.g., human BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6) 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 5 (e.g., 0, 1, 2, 3, 4, or 5) e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the region of any one of SEQ ID NOS: 1, 4, 7, 10, 13, or 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17.

[0293] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of BTG1 (e.g., (hBTGl) 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 BTG1 (e.g., (hBTGl), 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) (e.g., 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 5 (e.g., 0, 1,2, 3, 4, or 5) (e.g., 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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.

[0294] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of CDKN1B (e.g., (hCDKNIB) 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 CDKN1B (e.g., (hCDKNIB), 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) (e.g., 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 morethan 5 (e.g., 0, 1 , 2, 3, 4, or 5) (e.g., 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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.

[0295] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of DUSP2 (e.g., (hDUSP2) 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 DUSP2 (e.g., (hDUSP2), 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) (e.g., 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 5 (e.g., 0, 1,2, 3, 4, or 5) (e.g., 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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.

[0296] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5), 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of SEQ ID NO: 11. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of SEQ ID NO: 10. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the region of SEQ ID NO: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

[0297] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5), 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of SEQ ID NO: 14. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of SEQ ID NO: 13. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the region of SEQ ID NO: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

[0298] In some embodiments, the dsRNA agent (e.g., for inhibiting expression of KLHL6 (e.g., (hKLHL6) 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 KLHL6 (e.g., (hKLHL6), 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of SEQ ID NO: 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of SEQ ID NO: 16. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the region of SEQ ID NO: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.

[0299] 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.4.2.2 Antisense Oligonucleotide RNA Agents

[0300] 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.

[0301] 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.4.2.2.1 Targeting Region

[0302] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA)).

[0303] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, 1GLL5, or KLHL6 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., aBTGl, CDKN1B, DUSP2, IGLL5,or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1,CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA)).

[0304] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 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 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 ofcomplementarity 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA), a portion of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA))).

[0305] 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 some embodiments, 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 ofcomplementarity 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.

[0306] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA) of sufficient length to allow it to be a substrate for cleavage directed by the antisense oligonucleotide.

[0307] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 gene).

[0308] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a BTG1 (e.g., hBTGl) 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 BTG1 (e.g., hBTGl) 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 BTG1 (e.g., hBTGl) 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).

[0309] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a CDKN1B (e.g., hCDKNIB) mRNA. In some embodiments, the target nucleic acidmolecule is at least a portion (e.g., a portion) of an mRNA formed in the expression of a CDKN 1 B (e.g., hCDKNIB) 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: 4 (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 CDKN1B (e.g., hCDKNIB) 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: 4 (or a variant or fragment thereof).

[0310] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a DUSP2 (e.g., hDUSP2) 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 DUSP2 (e.g., hDUSP2) 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: 7 (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 DUSP2 (e.g., hDUSP2) 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: 7 (or a variant or fragment thereof).

[0311] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a IGLL5 (e.g., hIGLL5) 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 IGLL5 (e.g., hIGLL5) 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: 10 (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 IGLL5 (e.g., hIGLL5) 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: 10 (or a variant or fragment thereof).

[0312] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a IGLL5 (e.g., hIGLL5) 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 IGLL5 (e.g., hIGLL5) 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: 13 (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 IGLL5 (e.g., hIGLL5) 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: 13 (or a variant or fragment thereof).

[0313] In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a KLHL6 (e.g., hKLHL6) 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 KLHL6 (e.g., hKLHL6) 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: 16 (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 KLHL6 (e.g., hKLHL6) 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: 16 (or a variant or fragment thereof).

[0314] 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 targetnucleic 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.

[0315] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.2.2 Overall Length

[0316] 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).

[0317] 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).

[0318] 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).

[0319] 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.

[0320] 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.

[0321] 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 antisenseoligonucleotide 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.

[0322] 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 some embodiments, 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 someembodiments, 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.

[0323] 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 some embodiments, 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 someembodiments, 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.

[0324] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.2.3 Exemplary Antisense Oligonucleotides

[0325] 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 the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0326] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0327] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 1 nucleotides from the nucleotide sequence of the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0328] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisenseoligonucleotide 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0329] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0330] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 reversecomplement of a portion of a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0331] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide comprises 19 contiguous nucleotides.

[0332] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides.

[0333] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 aBTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide comprises 21 contiguous nucleotides.

[0334] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CD KN IB, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides.

[0335] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CD KN IB, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide comprises 23 contiguous nucleotides.

[0336] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In someembodiments, 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0337] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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.

[0338] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide consists of 19 contiguous nucleotides differing by no more than 1 nucleotides fromthe nucleotide sequence of the reverse complement of a portion of a BTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide consists of 19 contiguous nucleotides.

[0339] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides.

[0340] 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 nucleotide sequence of the reverse complement of a portion of a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides.

[0341] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 aBTG1 , CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides.

[0342] 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA. 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) (e.g., 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 BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 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 BTG1, CD KN IB, DUSP2, IGLL5, or KLHL6 mRNA. In some embodiments, the antisense oligonucleotide consists of 23 contiguous nucleotides.

[0343] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0344] 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 nomore than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0,I, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0345] 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 any one of SEQ ID NOS: 2, 5, 8,I I, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0346] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises at least 30 (e.g., at least 31, 32, 33, 34, or 35) contiguous nucleotides.

[0347] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0348] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0349] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 20 contiguous nucleotides.

[0350] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 21 contiguous nucleotides.

[0351] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 22 contiguous nucleotides.

[0352] In some embodiments, the antisense oligonucleotide comprises 30 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 30 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 30 contiguous nucleotides differing by no more than I nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide comprises 30 contiguous nucleotides.

[0353] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0354] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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.

[0355] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 20 contiguous nucleotides.

[0356] 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 nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisenseoligonucleotide consists of 21 contiguous nucleotides differing by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 21 contiguous nucleotides.

[0357] 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 any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. 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) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 22 contiguous nucleotides.

[0358] In some embodiments, the antisense oligonucleotide consists of 30 contiguous nucleotides differing by no more than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 30 contiguous nucleotides differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) (e.g., by no more than 3 (e.g., 0, 1, 2, or 3)) nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 30 contiguous nucleotides differing by no more than 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOS: 2, 5, 8, 11, 14, or 17. In some embodiments, the antisense oligonucleotide consists of 30 contiguous nucleotides.

[0359] Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.3 Modified RNA Agents

[0360] In some embodiments, the RNA agent (e.g., RNAi agent (e.g., siRNA)) (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, antisense oligonucleotide, etc.)comprises one or more modified nucleotide(s) (as defined herein). The modified agent may have one or more different (e.g., improved) properties relative to a corresponding unmodified RNA agent. For example, the modified RNA agent may exhibit decreased immunostimulatory activity (e.g., when administered to a subject), increased stability (e.g., in vivo, in a cell, when administered to a subject), and / or increased inhibition of expression of a target nucleic acid molecule (e.g., a target mRNA (e.g., a BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6 mRNA)), or any combination thereof.4.3.1 Nature of Nucleotide Modifications

[0361] Nucleotide modifications can include modification to any one of more of the nucleoside and / or the internucleoside linkage. Nucleoside modifications include modification to the sugar (e.g., ribose) moiety and / or the nucleobase. In some embodiments, the modified agent (or component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more nucleotides comprising a modified sugar moiety. In some embodiments, the modified agent (or component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more nucleotides comprising a modified nucleobase. In some embodiments, the modified agent (or component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more nucleotides comprising a modified intemucleoside linkage. In some embodiments, the modified agent (or component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more nucleotides comprising one, two, or three of a modified sugar moiety, a modified nucleobase, and / or a modified intemucleoside linkage.

[0362] Exemplary nucleotide modifications are described below and also known in the art, see, e.g., WO2021257782, W02013075035, WO2022246251, and WO2022271573, the entire contents of each of which are incorporated by reference herein for all purposes.4.3.1.1 Modified Nucleosides

[0363] In some embodiments, the modified RNA agent (or any component thereof) (e.g., antisense strand, sense strand, dsRNA agent, antisense oligonucleotide, etc.) comprises one or more nucleotide comprising a modified nucleoside. As discussed above, nucleoside modifications can include modification of the sugar (e.g., ribose) moiety and / or modification of the nucleobase.(i) Sugar Modifications

[0364] In some embodiments, the modified RNA agent (or any component thereof) (e.g.,antisense strand, sense strand, dsRNA agent, antisense oligonucleotide, etc.) comprises one or more nucleotides comprising a modified sugar (e.g., ribose) moiety.

[0365] The modified sugar (e.g., ribose) moiety can comprise, for example, a substituent at any one or more position of the sugar (e.g., ribose), including e.g., positions 2', 4', and / or 5'. In some embodiments, the modified sugar (e.g., ribose) comprises a substituent at 2' position of the sugar (e.g., ribose). In some embodiments, the modified sugar (e.g., ribose) comprises a substituent at 5' position of the sugar (e.g., ribose). In some embodiments, the modified sugar (e.g., ribose) comprises a substituent at 5' position of the sugar (e.g., ribose).

[0366] In some embodiments, the RNA agent (or any component thereof) comprises any one or more of the following substituents (e.g., at any position of the sugar (e.g., ribose) (e.g., at position 2')): a group for improving the stability of the RNA agent, a group for improving the pharmacokinetic properties of the RNA agent, or a group for improving the pharmacodynamic properties of the RNA agent, an RNA cleaving group, a reporter group, an intercalator, and / or other substituents having similar properties.

[0367] Exemplary substituents include, for example, but are not limited to, substitution (e.g., at any position of the sugar (e.g., ribose) (e.g., at position 2')) with any one of the following: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted Ci to Cio alkyl or C2 to Cio alkenyl and alkynyl. Additional exemplary substitutions (e.g., at any position of the sugar (e.g., ribose) (e.g., at position 2')) include, for example, but are not limited to, substitution with any one of the following: 0[(CH2)n0]m, CH3, O(CH2)UOCH3, O(CH2)nNH2, O(CH2)nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10.

[0368] In some embodiments, the modified sugar (e.g., ribose) comprises any one of the following modifications: 2'-O-methyl (2'-0Me), 2'O-methoxyethyl (2'-0-M0E), 2'deoxy-2'- fluoro (2'-F), 2'-arabino-fluoro (2'-Ara-F), 2'-O-benzyl, 2'-O-methyl-4-pyridine (2-O-methyl-4- pyridine (2'-O-CH2Py(4)).

[0369] In some embodiments, the RNA agent (or any component thereof) comprises any of the following substituents at the 2'-position of the sugar (e.g., ribose): Ci to Cio lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, or a substituted silyl. In some embodiments, the RNA agent(or any component thereof) comprises a 2'-methoxyethoxy (2'-0 — CH2CH2OCH3, also known as 2'-O-(2-mcthoxycthyl) or 2'-M0E) (see, e.g., Martin ct al., Hclv. Chim. Acta, 1995, 78:486-504, the entire contents of which is incorporated by reference herein for all purposes) (i.e., an alkoxyalkoxy group). In some embodiments, the RNA agent (or any component thereof) comprises a 2'- dimethylaminooxy ethoxy, i.e., a O(CH2)2ON(CH3)2 group, also known as 2'-DMAOE; a 2'- dimethylaminoethoxyethoxy (also known in the art as 2'-O-dimethylaminoethoxyethyl or 2'- DMAEOE), i.e., 2'-O— CH2— O— CH2— N(CH3)2; a 5'-Me-2'-F nucleotide, a 5'-Me-2'-OMe nucleotide, a 5'-Me-2'-deoxynucleotide, (both R and S isomers in these three families); a 2'- alkoxyalkyl; and 2'-NMA (N-methylacetamide).

[0370] Exemplary US patents that describe the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920; the entire contents of each of the foregoing are hereby incorporated herein by reference for all purposes.(a) Non-Bicyclic Sugar' Modifications

[0371] In some embodiments, the modified sugar (e.g., ribose) moiety comprises a non- bicyclic modified sugar (e.g., ribose) moiety. In some embodiments, the modified sugar (e.g., ribose) moiety comprises a furanosyl ring comprising one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. In some embodiments one or more non-bridging substituent of a non-bicyclic modified sugar moiety is branched. Such non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2', 4', and / or 5' positions.

[0372] In some embodiments, non-bicyclic modified sugar moiety comprises a substituent group at the 2'-position of the sugar (e.g., ribose). Examples of 2'- substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2'-O-methyl (2'-0Me), 2'0- methoxyethyl (2'-0-M0E), 2 'deoxy-2 '-fluoro (2'-F), 2'-arabino-fluoro (2'-Ara-F), 2'-O-benzyl, 2'- O-methyl-4-pyridine (2-O-methyl-4-pyridine (2'-O-CH2Py(4)), and 2’-O-N-alkyl acetamide (e.g., 2'-O-N-methyl acetamide (“NMA”), 2'-O-N-dimethyl acetamide, 2'-O-N-ethyl acetamide, and 2'- O-N-propyl acetamide). For example, see, e.g., U.S. 6,147,200, Prakash et al., 2003, Org. Lett., 5, 403-6, the entire contents of which is incorporated by reference herein for all purposes.

[0373] In some embodiments, the 2'-substituent group is a halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, O-C1-C10 alkoxy, O-C1-C10 substituted alkoxy, O-C1-C10 alkyl, O-C1-C10 substituted alkyl, S-alkyl, N(Rm)-alkyl, O-alkenyl, S-alkenyl, N(Rm)-alkenyl, O-alkynyl, S- alkynyl, N(Rm)-alkynyl, O-alkylenyl-O- alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH2)2SCH3,0(CH2)2ON(Rm)(Rn) or OCH2C(=O)- N(Rm)(Rn), where each Rmand Rnis, independently, H, an amino protecting group, or substituted or unsubstituted C1-C10 alkyl, or a 2'- substituent group described in any one of the following: Cook et al., U.S. 6,531,584; Cook et al., U.S. 5,859,221; and Cook et al., U.S. 6,005,087, the entire contents of which are incorporated herein by reference for all purposes. In some embodiments, these 2'-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl.

[0374] In some embodiments, a 2'-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2'-substituent group selected from: F, NH2, N3, OCF3, 0CH3, O(CH2)3NH2, CH2CH=CH2, OCH2CH=CH2, OCH2CH2OCH3, O(CH2)2SCH3, O(CH2)2ON(Rm)(Rn), O(CH2)2O(CH2)2N(CH3)2, and N-substituted acetamide (OCH2C(=O)- N(Rm)(Rn)), where each Rmand Rnis, independently, H, an amino protecting group, or substituted or unsubstituted C1-C10 alkyl. In some embodiments, a 2 '-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2'-substituent group selected from: F, OCF, OCH3, OCH2CH2OCH3, O(CH2)2SCH3, O(CH2) ON(CH3)2, O(CH2)2O(CH2)2N(CH3)2, and OCH2C(=O)-N(H)CH3(“N...

Claims

CLAIMSWhat is claimed is:

1. A method of treating, ameliorating, or preventing a CDKN1B, BTG1, DUSP2, IGLL5, or KLHL6 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 CDKN1B, BTG1, DUSP2, IGLL5, or KLHL6 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 CDKN1B, BTG1, DUSP2, IGLL5, or KLHL6 mutation set forth in Table 2 is detected in the DNA, RNA, or protein.

2. The method of claim 1, wherein the gene is CDKN IB and the one or more somatic mutation and the one or more somatic mutation comprises one or more of chrl2:12717949:A- >T; chrl2:12718008:C->T; chrl2:12717909:CC->TG; chrl2:12717940:GC->G; or chrl2:12718016:G->C.

3. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of BTG1 (e.g., human BTG1 (hBTGl)) 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 BTG1 (e.g., (hBTGl) 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 BTG1 (e.g., (hBTGl).

7. The dsRNA agent of claim 6, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding BTG1 (e.g., (hBTGl).

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 BTG1 (e.g., (hBTGl) 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 BTG1 (e.g., (hBTGl), 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 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.

15. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of CDKN1B (e.g., human CDKN1B (hCDKNIB)) comprisinga 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: 5.

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: 4.

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: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

18. A dsRNA agent for inhibiting expression of CDKN1B (e.g., (hCDKNIB) 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 CDKN1B (e.g., (hCDKNIB).

19. The dsRNA agent of claim 18, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding CDKN1B (e.g., (hCDKNIB).

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: 5.

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: 4.

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: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

24. A dsRNA agent for inhibiting expression of CDKN1B (e.g., (hCDKNIB) 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 CDKN1B (e.g., (hCDKNIB), 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: 5.

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: 4.

26. The dsRNA agent of claim 24 or 25, 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: 4 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 5.

27. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of DUSP2 (e.g., human DUSP2 (hDUSP2)) 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: 8.

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: 7.

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: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

30. A dsRNA agent for inhibiting expression of DUSP2 (e.g., (hDUSP2) 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 DUSP2 (e.g., (hDUSP2).

31. The dsRNA agent of claim 30, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding DUSP2 (e.g., (hDUSP2).

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: 8.

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: 7.

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: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

36. A dsRNA agent for inhibiting expression of DUSP2 (e.g., (hDUSP2) 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 DUSP2 (e.g., (hDUSP2), 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: 8.

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: 7.

38. The dsRNA agent of claim 36 or 37, 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: 7 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 8.

39. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of IGLL5 (e.g., human IGLL5 (hIGLLS)) 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: 11.

40. The dsRNA agent of claim 39, 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: 10.

41. The dsRNA agent of claim 39 or 40, 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: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

42. A dsRNA agent for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5).

43. The dsRNA agent of claim 42, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding IGLL5 (e.g., (hIGLL5).

44. The dsRNA agent of claim 42 or 43, wherein the region of complementarity comprises at least 15 contiguous nucleotides.

45. The dsRNA agent of any one of claims 42-44, 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: 11.

46. The dsRNA agent of any one of claims 42-45, 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: 10.

47. The dsRNA agent of any one of claims 42-46, 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: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

48. A dsRNA agent for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5), 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: 11.

49. The dsRNA agent of claim 48, 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: 10.

50. The dsRNA agent of claim 48 or 49, 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: 10 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 11.

51. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of IGLL5 (e.g., human IGLL5 (hIGLL5)) 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: 14.

52. The dsRNA agent of claim 51, 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: 13.

53. The dsRNA agent of claim 51 or 52, 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: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

54. A dsRNA agent for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5).

55. The dsRNA agent of claim 54, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding IGLL5 (e.g., (hIGLL5).

56. The dsRNA agent of claim 54 or 55, wherein the region of complementarity comprises at least 15 contiguous nucleotides.

57. The dsRNA agent of any one of claims 54-56, 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: 14.

58. The dsRNA agent of any one of claims 54-57, 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: 13.

59. The dsRNA agent of any one of claims 54-58, 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: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

60. A dsRNA agent for inhibiting expression of IGLL5 (e.g., (hIGLL5) 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 IGLL5 (e.g., (hIGLL5), 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: 14.

61. The dsRNA agent of claim 60, 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: 13.

62. The dsRNA agent of claim 60 or 61, 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: 13 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 14.

63. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of KLHL6 (e.g., human KLHL6 (hKLHL6)) 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: 17.

64. The dsRNA agent of claim 63, 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: 16.

65. The dsRNA agent of claim 63 or 64, 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 theregion of SEQ ID NO: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.

66. A dsRNA agent for inhibiting expression of KLHL6 (e.g., (hKLHL6) 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 KLHL6 (e.g., (hKLHL6).

67. The dsRNA agent of claim 66, wherein the region of complementarity is fully complementary to the portion of the mRNA sequence encoding KLHL6 (e.g., (hKLHL6).

68. The dsRNA agent of claim 66 or 67, wherein the region of complementarity comprises at least 15 contiguous nucleotides.

69. The dsRNA agent of any one of claims 66-68, 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: 17.

70. The dsRNA agent of any one of claims 66-69, 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: 16.

71. The dsRNA agent of any one of claims 66-70, 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: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.

72. A dsRNA agent for inhibiting expression of KLHL6 (e.g., (hKLHL6) 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 KLHL6 (e.g., (hKLHL6), 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: 17.

73. The dsRNA agent of claim 72, 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: 16.

74. The dsRNA agent of claim 72 or 73, 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 theregion of SEQ ID NO: 16 that is complementary to the sequence of the antisense strand from the nucleotide sequence of SEQ ID NO: 17.

75. The dsRNA agent of any one of claims 3-74, wherein the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.

76. The dsRNA agent of any one of claims 3-75, 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.

77. The dsRNA agent of any one of claims 3-76, wherein substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.

78. The dsRNA agent of any one of claims 3-77, wherein at least one of the modified nucleotides comprises a modified sugar- (e.g., ribose moiety).

79. The dsRNA agent of any one of claims 3-78, wherein at least one of the modified nucleotides comprises a modified nucleobase.

80. The dsRNA agent of any one of claims 3-79, wherein the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

81. The dsRNA agent of any one of claims 3-80, 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.

82. The dsRNA agent of any one of claims 3-81, 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.

83. The dsRNA agent of any one of claims 3-82, 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.

84. The dsRNA agent of any one of claims 3-83, wherein antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides.

85. The dsRNA agent of any one of claims 3-84, wherein antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

86. The dsRNA agent of any one of claims 3-85, wherein the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides.

87. The dsRNA agent of any one of claims 3-86, wherein the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides2 nucleotides).

88. The dsRNA agent of any one of claims 3-87, 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.

89. The dsRNA agent of any one of claims 3-88, wherein the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length.

90. The dsRNA agent of any one of claims 3-89, wherein the double stranded region is about 21 nucleotide pairs in length.

91. The dsRNA agent of any one of claims 3-90, 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).

92. The dsRNA agent of any one of claims 3-91, wherein the sense strand and the antisense strand are separate nucleic acid molecules (z.e., connected only through the double stranded region).

93. A conjugate comprising the dsRNA agent of any one of claims 3-92 and a heterologous moiety.

94. The conjugate of claim 93, wherein the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

95. The conjugate of any one of claims 93-94, wherein the heterologous moiety is attached to the dsRNA agent via a linker.

96. The conjugate of any one of claims 93-95, 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.

97. 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 3-92, the dsRNA agent of any one of claims 3-92, of the conjugate of any one of claims 93-96.

98. A carrier comprising the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, or the vector of claim 97.

99. The carrier of claim 98, wherein the carrier comprises a nanoparticle, a polymer, a lipid- based delivery system, as dendrimer, a cationic delivery system, or a hydrogel.

100. The carrier of claim 99, wherein the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

101. A cell comprising the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, or the carrier of any one of claims 98-100.

102. A pharmaceutical composition comprising the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, or the cell of claim 101, and a pharmaceutically acceptable excipient.

103. A kit comprising the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102.

104. A diagnostic kit comprising one or more reagent for use in a method of detecting the presence or absence of one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation described herein, e.g., a somatic mutation set forth in Table 2 herein) in a sample from a subject.

105. A method of treating, ameliorating, or preventing a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

106. The method of claim 105, wherein the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

107. The method of claim 105 or 106, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

108. The method of any one of claims 105-107, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

109. The method of any one of claims 105-108, wherein the gene associated disease is a BTG1 associated disease, a CDKN1B associated disease, DUSP2 associated disease, a IGLL5 associated disease, or a KLHL6 associated disease.

110. The method of any one of claims 105-109, wherein(i) the gene associated disease is a BTG1 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic BTG1 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells),(ii) the gene associated disease is a CDKN1B associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic CDKN1B mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells),(iii) the gene associated disease is a DUSP2 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic DUSP2 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells),(iv) the gene associated disease is a IGLL5 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic IGLL5 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells), or(v) the gene associated disease is a KLHL6 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic KLHL6 mutation(e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells).

111. The method of any one of claims 105-110, wherein the therapeutic agent comprises an anti-inflammatory agent e.g., an anti-inflammatory agent described herein).

112. The method of any one of claims 105-111, wherein the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

113. The method of any one of claims 105-112, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

114. The method of claim 113, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102.

115. 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

116. The method of claim 115, wherein the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

117. The method of claim 115 or 116, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

118. The method of any one of claims 115-117, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

119. The method of any one of claims 115-118, wherein the therapeutic agent is an antiinflammatory agent (e.g., described herein).

120. The method of any one of claims 1 15- 119, wherein the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

121. The method of any one of claims 115-120, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

122. The method of claim 121, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102.

123. A method of diagnosing a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease.

124. The method of claim 123, wherein the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

125. The method of claim 123 or 124, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

126. The method of any one of claims 123-125, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

127. The method of any one of claims 123-126, wherein the gene is associated disease is a BTG1 associated disease, a CDKN1B associated disease, DUSP2 associated disease, a IGLL5 associated disease, or a KLHL6 associated disease.

128. The method of any one of claims 123-127, wherein(i) the gene associated disease is a BTG1 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic BTG1 mutation (e.g., asomatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells),(ii) the gene associated disease is a CDKN1B associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic CDKN1B mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells),(iii) the gene associated disease is a DUSP2 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic DUSP2 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells),(iv) the gene associated disease is a IGLL5 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic IGLL5 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells), or(v) the gene associated disease is a KLHL6 associated disease and (b) comprises detecting, or having detected, the presence or absence of one or more somatic KLHL6 mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein (e.g., from a cell or population of cells).

129. The method of any one of claims 123-128, wherein the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease is a proinflammatory (e.g., autoimmune) disease.

130. The method of any one of claims 123-129, wherein the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease is an autoimmune disease.

131. The method of any one of claims 123-130, 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

132. The method of any one of claims 123-131, further comprising administering to the subject a therapeutic agent if a somatic mutation (e.g., a somatic mutation set forth in Table 2) is detected in the DNA, RNA, or protein.

133. The method of any one of claims 123- 132, wherein the therapeutic agent is an antiinflammatory agent (e.g., described herein).

134. The method of any one of claims 123-133, wherein the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

135. The method of any one of claims 123-134, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

136. The method of claim 135, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102.

137. 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) 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.

138. The method of claim 137, 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

139. The method of claim 137 or 138, wherein the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

140. The method of any one of claims 137-139, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

141. The method of any one of claims 137-140, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

142. The method of any one of claims 137- 141 , further comprising administering to the subject the therapeutic agent if the subject is selected.

143. The method of any one of claims 137-142, wherein the therapeutic agent is an antiinflammatory agent (e.g., described herein).

144. The method of any one of claims 137-143, wherein the therapeutic agent inhibits expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

145. The method of any one of claims 137-144, wherein the therapeutic agent is an inhibitory nucleic acid molecule that targets the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

146. The method of claim 145, wherein the inhibitory nucleic acid molecule comprises the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102.

147. An in vitro method of screening a sample from a subject for one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2), the method comprising(a) isolating and purifying DNA, RNA, or protein (e.g., from a cell or population of cells) from a sample obtained from the subject; and(b) detecting the presence or absence of one or more somatic gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA, RNA, or protein.

148. The method of any one of claims 105-147, 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 gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) mutation (e.g., a somatic mutation set forth in Table 2) in the DNA.

149. The method of any one of claims 105-148, wherein the sample is a blood, tissue, or cell sample.

150. The method of any one of claims 105-149, wherein the sample is biopsy.

151. The method of any one of claims 105-150, wherein the sample comprises a cell (e.g., a T- cell) or a population of cells (e.g., a population of T-cells).

152. The method of any one of claims 105- 1 1 , wherein at least one of the one or more somatic mutation is a loss of function mutation, a gain of function mutation, a misscnsc mutation, synonymous, and / or non-synonymous.

153. The method of any one of claims 105-152, wherein the one or more somatic mutation is a loss of function mutation.

154. The method of any one of claims 105-153, wherein the one or more somatic mutation truncates the protein encoded by the gene.

155. The method of any one of claims 105-154, wherein the one or more somatic mutation is one or more somatic mutation set forth herein.

156. The method of any one of claims 105-155, wherein the one or more somatic mutation is one or more somatic mutation set forth in Table 2 herein.

157. A method of reducing or inhibiting expression of a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in a cell, the method comprising delivering into the cell the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102, to thereby reduce or inhibit expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in the cell.

158. A method of reducing or inhibiting expression of a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in a cell in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102, to thereby reduce or inhibit expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) in the cell in the subject.

159. The method of any one of claims 157-158, wherein the gene is BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6.

160. A method of treating, ameliorating, or preventing a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102, to thereby treat, ameliorate, or prevent the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease in the subject.

161. The method of claim 160, wherein the gene associated disease is a BTG1 associated disease, a CDKN1B associated disease, a DUSP2 associated disease, an IGLL5 associated disease, or a KLHL6 associated disease.

162. The method of any one of claims 160-161, wherein the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease associated disease is a proinflammatory disease (e.g., an autoimmune disease).

163. The method of any one of claims 160-162, wherein the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease associated disease is an autoimmune disease.

164. The method of any one of claims 160-163, wherein the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6) associated disease is treated, ameliorated, or prevented through the reduction or inhibition expression of the gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

165. 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 3-92, the conjugate of any one of claims 93-96, the vector of claim 97, the carrier of any one of claims 98-100, the cell of claim 101, or the pharmaceutical composition of claim 102, to thereby treat, ameliorate, or prevent the proinflammatory (e.g., autoimmune) disease in the subject.

166. The method of any claim 165, wherein the proinflammatory (e.g., autoimmune) disease is treated, ameliorated, or prevented through a reduction or inhibition of expression of a gene (e.g., BTG1, CDKN1B, DUSP2, IGLL5, or KLHL6).

167. The method of any one of claims 105-166, wherein the subject is a human.