RNA agents targeting ZBTB7a 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 ZBTB7A (e.g., hZBTB7A); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing ZBTB7A expression (e.g., mRNA expression), methods of treating ZBTB7A associated diseases.

Description

Attorney Docket No. 66504.26WO01RNA AGENTS TARGETING ZBTB7A AND RELATED METHODSRELATED APPLICATIONS

[0001] This application claims priority to U.S. Serial No.: 63 / 703,681, filed October 4, 2024, the entire contents of each of which is incorporated herein by reference.1. FIELD

[0002] This disclosure relates to RNAi agents (e.g., double stranded RNA (dsRNA) agents comprising a sense strand and an antisense strand) targeting zinc finger and BTB domain containing 7A (ZBTB7A). The disclosure further relates to pharmaceutical compositions comprising the same; and methods of utilizing the same, including, e.g., methods of treating ZBTB7A associated diseases.2. BACKGROUND

[0003] Transcription factors comprising zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domains (ZBTBs) arc a highly conserved protein family that comprises a multifunctional and heterogeneous group of transcription factors, mainly modulating cell developmental events and cell fate. Transcription factor zinc finger and BTB domain containing 7A (ZBTB7A) represses the transcription of a range of genes involved in e.g., cell proliferation and differentiation and is involved in several processes, including, e.g., erythrocyte maturation; negative regulation of signal transduction; and regulation of nucleobase-containing compound metabolic process. ZBTB7A is also known to enables several functions, including, e.g., SMAD binding activity; androgen receptor binding activity; and transcription corepressor binding activity.3. SUMMARY

[0004] Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting ZBTB7A (e.g., hZBTB7A); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing ZBTB7A expression (e.g., mRNA expression), methods of treating ZBTB7A associated diseases.Attorney Docket No. 66504.26WO01

[0005] Accordingly, in one aspect, provided herein are dsRNA agents for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 or set forth in any one of SEQ ID NOS: 725-1264.

[0006] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Tables 2-5 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

[0007] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 or set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

[0008] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 or set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

[0009] In one aspect, provided herein are dsRNA agents for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in Tables 2-5; and the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Tables 2-5.

[0010] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisenseAttorney Docket No. 66504.26WO01 strands of any one of dsRNA agents 1 -485 set forth in Tables 2-5; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Tables 2-5.

[0011] In one aspect, provided herein are dsRNA agents for inhibiting expression of zinc finger and BTB domain containing 7A (ZBTB7A) (e.g., human ZBTB7A (hZBTB7A)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 725-1264.

[0012] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from any sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 4-759.

[0013] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the corresponding sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

[0014] In one aspect, provided herein are dsRNA agent for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0015] In some embodiments, the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.Attorney Docket No. 66504.26WO01

[0016] In one aspect, provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of zinc finger and BTB Domain Containing 7A (ZBTB7A) (e.g., human ZBTB7A (hZBTB7A)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 725-1264.

[0017] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from any sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 4-759.

[0018] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

[0019] In one aspect, provided herein are dsRNA agents for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5; and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in any one of Tables 2-5.

[0020] It should be understood that each of the following embodiments is applicable to each and any of the foregoing aspects as if recited directed after each aspect.

[0021] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from any sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 4-759.

[0022] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20,Attorney Docket No. 66504.26WO0121 ) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the corresponding sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

[0023] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.

[0024] In some embodiments, the sense strand comprises at least one modified nucleotide and the antisense strand comprises at least one modified nucleotide.

[0025] 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.

[0026] 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, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety) and a modified nucleobase. In some embodiments, the sense strand comprises at least one modified intemucleoside linkage and / or the antisense strand comprises at least one modified internucleoside linkage. In some embodiments, the sense strand comprises at least one modified intemucleoside linkage and the antisense strand comprises at least one modified intemucleoside linkage.

[0027] 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, antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. In some embodiments, antisense strand consists of 23 nucleotides; and the sense strand consists of 21 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.

[0028] In some embodiments, the sense strand and / or the antisense strand comprises a 3'Attorney Docket No. 66504.26WO01 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).

[0029] 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.

[0030] In some embodiments, the sense strand and the antisense strand are pail of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule. In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

[0031] In one aspect, provided herein are conjugates comprising a dsRNA agent described herein and a heterologous moiety.

[0032] In some embodiments, the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

[0033] In some embodiments, the heterologous moiety is a protein.

[0034] In some embodiments, the protein specifically binds to a moiety expressed by a hematopoietic cell e.g., on the surface of a hematopoietic cell). In some embodiments, the protein specifically binds to a moiety expressed by an erythroid precursor cell (e.g., on the surface of an erythroid precursor cell). In some embodiments, the protein specifically binds the transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)).

[0035] In some embodiments, the protein is an antibody. In some embodiments, the antibody comprises or consists of a full-length antibody, a Fab, a Fab', a F(ab')2, a Fab-Fc, a scFv, a scFv- Fc, a (scFvrf-Fc, an Fv, a single domain antibody (sdAb) (e.g., a VHH), a sdAb-Fc (e.g., a VHH- Fc), a (sdAb)2 (e.g., a (VHH)2), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc). In some embodiments, the antibody comprises or consists of a full-length antibody, a Fab-Fc, a scFv-Fc, a (scFv)2-Fc, a sdAb- Fc (e.g., a VHH-Fc), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc).

[0036] In some embodiments, the antibody is an IgG (e.g., a human IgG (hlgG)) antibody. In some embodiments, the antibody is a hlgGl, hIgG2, hIgG3, or hIgG4 antibody (e.g., a hlgGl or hIgG4 antibody). In some embodiments, the antibody comprises an immunoglobulin (Ig) (e.g., aAttorney Docket No. 66504.26WO01 human Ig (hlg)) Fc region. In some embodiments, the Ig (e.g., hlg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig is a hlg. In some embodiments, the hlg is a human IgG (hlgG). In some embodiments, the hlgG is hlgGl or hIgG4. In some embodiments, the Ig (e.g., hlg) Fc region comprises one or more amino acid substitutions relative to a reference Ig (e.g., hlg) Fc region that reduces or abolishes one or more of the following effector functions relative to the reference hlg Fc region: antibody dependent cell mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and / or affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla))).

[0037] In some embodiments, the antibody does not (or does not substantially) block binding of TF (e.g., hTF) to the TFR (e.g., hTFRl).

[0038] In some embodiments, the protein is a TFR ligand (or a functional fragment or functional variant thereof).

[0039] In some embodiments, the TFR ligand comprises transferrin (TF) (e.g., human transferrin (hTF)) (or a functional fragment or functional variant thereof).

[0040] In some embodiments, the heterologous moiety is a targeting moiety.

[0041] In some embodiments, the targeting moiety specifically binds to a moiety expressed by a hematopoietic cell (e.g., on the surface of a hematopoietic cell). In some embodiments, the targeting moiety specifically binds to a moiety expressed by an erythroid precursor cell (e.g., on the surface of an erythroid precursor cell). In some embodiments, the targeting moiety specifically binds TFR (e.g., hTFR (e.g., hTFRl)).

[0042] In some embodiments, the targeting moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

[0043] In some embodiments, the targeting moiety is a protein.

[0044] In some embodiments, the targeting moiety is an antibody. In some embodiments, the antibody comprises or consists of a full-length antibody, a Fab, a Fab', a F(ab')2, a Fab-Fc, a scFv, a scFv-Fc, a (scFv)2-Fc, an Fv, a single domain antibody (sdAb) (e.g., a VHH), a sdAb-Fc (e.g., a VHH-Fc), a (sdAb)2 (e.g., a (VHH)2), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc). In some embodiments, the antibody comprises or consists of a full-length antibody, a Fab-Fc, a scFv-Fc, a (scFv)2-Fc, a sdAb-Fc (e.g., a VHH-Fc), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc).Attorney Docket No. 66504.26WO01

[0045] In some embodiments, the antibody is an IgG (e.g., a human IgG (hlgG)) antibody. In some embodiments, the antibody is a hlgGl, hIgG2, hIgG3, or hIgG4 antibody (e.g., a hlgGl or hIgG4 antibody). In some embodiments, the antibody comprises an immunoglobulin (Ig) (e.g., a human Ig (hlg)) Fc region. In some embodiments, the Ig (e.g., hlg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig (e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig is a hlg. In some embodiments, the hlg is a human IgG (hlgG). In some embodiments, the hlgG is hlgGl or hIgG4. In some embodiments, the Ig (e.g., hlg) Fc region comprises one or more amino acid substitutions relative to a reference Ig (e.g., hlg) Fc region that reduces or abolishes one or more of the following effector functions relative to the reference hlg Fc region: antibody dependent cell mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and / or affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla))).

[0046] In some embodiments, the antibody does not (or does not substantially) block binding of TF (e.g., hTF) to the TFR (e.g., hTFRl).

[0047] In some embodiments, the targeting moiety is a TFR ligand (or a functional fragment or functional variant thereof).

[0048] In some embodiments, the TFR ligand comprises transferrin (TF) (e.g., human transferrin (hTF)) (or a functional fragment or functional variant thereof).

[0049] In some embodiments, the conjugate exhibits one or more of the following properties: (a) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce death of the target cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the hematopoietic cell remains viable; (c) upon internalization into a hematopoietic cell, the conjugate does not induce death of the hematopoietic cell; and / or (d) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)).

[0050] In some embodiments, the conjugate exhibits one or more of the following properties: (a) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate is internalized into the hematopoietic cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce deathAttorney Docket No. 66504.26WO01 of the target cell; (c) upon binding to TFR (e.g., hTFR (e.g., TFR1 )) expressed on the surface of a hematopoietic cell, the hematopoietic cell remains viable; (d) upon internalization into a hematopoietic cell, the conjugate does not induce death of the hematopoietic cell; and / or (e) upon binding to TFR (e.g., hTFR e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)).

[0051] In some embodiments, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) exhibits one or more of the following properties: (a) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate is internalized into the hematopoietic cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate does not induce death of the target cell; (c) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the hematopoietic cell remains viable; (d) upon internalization into a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate does not induce death of the hematopoietic cell; and / or (e) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)).

[0052] In some embodiments, the heterologous moiety is attached to the dsRNA agent via a linker. In some embodiments, the linker is cleavable.

[0053] 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.

[0054] 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 described herein.

[0055] In one aspect, provided herein are carriers comprising a dsRNA agent described herein, a conjugate described herein, or a vector described herein.

[0056] 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,Attorney Docket No. 66504.26WO01 an exosome, or a micelle.

[0057] In one aspect, provided herein arc cells comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, or a carrier described herein.

[0058] 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.

[0059] 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.

[0060] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.

[0061] In some embodiments, the cell is in vitro, ex vivo, or in vivo. In some embodiments, the cell is a subject (e.g., a human subject).

[0062] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to 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 deliver the dsRNA, conjugate, vector, earner, cell, or pharmaceutical composition to the subject.

[0063] In one aspect, provided herein are methods of reducing or inhibiting expression of ZBTB7A (e.g., hZBTB7A) in a cell, the method comprising delivering into the cell a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of ZBTB7A (e.g., hZBTB7A) in the cell.

[0064] In one aspect, provided herein are methods of reducing or inhibiting expression of ZBTB7A (e.g., hZBTB7A) 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 describedAttorney Docket No. 66504.26WO01 herein, to thereby reduce or inhibit expression of ZBTB7A (e.g., hZBTB7A) in the cell in the subject.

[0065] In one aspect, provided herein are methods of treating, ameliorating, or preventing a ZBTB7A (e.g., hZBTB7A) 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 ZBTB7A (e.g., hZBTB7A) associated disease in the subject.

[0066] In some embodiments, the ZBTB7A associated disease is an inherited blood disorder.

[0067] In some embodiments, the inherited blood disorder is a hemoglobinopathy. In some embodiments, the hemoglobinopathy is sickle cell disease, sickle cell trait, hemoglobin C disease, hemoglobin C trait, hemoglobin S / C disease, hemoglobin D disease, hemoglobin E disease, a thalassemia (e.g., a-thalassemia, P-thalassemia, 6-thalassemia, or y-thalassemia), a condition associated with hemoglobin with increased oxygen affinity, a condition associated with hemoglobin with decreased oxygen affinity, unstable hemoglobin disease, or methemoglobinemia.

[0068] In some embodiments, the inherited blood disorder is an inherited bone marrow failure syndrome. In some embodiments, the inherited bone marrow failure syndrome is amegakaryocytic thrombocytopenia (Amega), diamond blackfan anemia (DBA), dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, severe congenital neutropenia (SCN), Schwachman diamond syndrome (SDS), GATA2 deficiency, cyclic neutropenia, Dubowitz syndrome, Kostmann syndrome, refractory cytopenia, thrombocytopenia absent radii (TAR), a SAMD9 / SAMD9E disorder, or a MECOM-associated syndrome.

[0069] In one aspect, provided herein are methods of treating, ameliorating, or preventing an inherited blood disorder 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 inherited blood disorder in the subject.

[0070] In some embodiments, the inherited blood disorder is a hemoglobinopathy. In some embodiments, the hemoglobinopathy is sickle cell disease, sickle cell trait, hemoglobin C disease, hemoglobin C trait, hemoglobin S / C disease, hemoglobin D disease, hemoglobin E disease, a thalassemia (e.g., a-thalassemia, P-thalassemia, 8-thalassemia, or y-thalassemia), a conditionAttorney Docket No. 66504.26WO01 associated with hemoglobin with increased oxygen affinity, a condition associated with hemoglobin with decreased oxygen affinity, unstable hemoglobin disease, or methemoglobinemia.

[0071] In one aspect, provided herein are methods of treating, ameliorating, or preventing a hemoglobinopathy 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 hemoglobinopathy in the subject.

[0072] In some embodiments, the hemoglobinopathy is sickle cell disease, sickle cell trait, hemoglobin C disease, hemoglobin C trait, hemoglobin S / C disease, hemoglobin D disease, hemoglobin E disease, a thalassemia (e.g., a-thalassemia, P-thalassemia, 8-thalassemia, or y- thalassemia), a condition associated with hemoglobin with increased oxygen affinity, a condition associated with hemoglobin with decreased oxygen affinity, unstable hemoglobin disease, or methemoglobinemia.

[0073] In one aspect, provided herein are methods of treating, ameliorating, or preventing an inherited bone marrow failure syndrome 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 inherited bone marrow failure syndrome in the subject.

[0074] In some embodiments, the inherited bone marrow failure syndrome is amegakaryocytic thrombocytopenia (Amega), diamond blackfan anemia (DBA), dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, severe congenital neutropenia (SCN), Schwachman diamond syndrome (SDS), GATA2 deficiency, cyclic neutropenia, Dubowitz syndrome, Kostmann syndrome, refractory cytopenia, thrombocytopenia absent radii (TAR), a SAMD9 / SAMD9L disorder, or a MECOM-associated syndrome.

[0075] In one aspect, provided herein are methods of inducing expression of fetal hemoglobin 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 induce expression of fetal hemoglobin the subject.

[0076] In one aspect, provided herein are methods of increasing the level of fetal hemoglobinAttorney Docket No. 66504.26WO01 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 increase the level of fetal hemoglobin the subject.

[0077] In one aspect, provided herein are methods of increasing the ratio of fetal hemoglobin to adult hemoglobin 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 increase the ratio of fetal hemoglobin to adult hemoglobin in the subject.

[0078] In some embodiments, the subject is a human.4. DETAILED DESCRIPTION

[0079] The inventors have further discovered, inter alia, RNAi agents that inhibit expression of ZBTB7A (e.g., hZBTB7A). As such, the RNAi agents described herein arc useful for the treatment of ZBTB7A mediated diseases. As such, the current disclosure provides RNAi agents (e.g., dsRNAi agents comprising a sense strand and an antisense strand) capable of inhibiting ZBTB7A expression (e.g., in a cell, in a cell in a subject); and their use in, inter alia, pharmaceutical compositions, and methods of treating diseases (e.g., ZBTB7A mediated diseases).TABLE OF CONTENTS4.2 RNAi Agents4.2.1 Antisense Strand4.2.1.1 Targeting Region4.2.1.2 Overall Length4.2.1.3 Exemplary Antisense Strands4.2.2 Sense Strand4.2.2.1 Antisense Strand Complementarity4.2.2.2 Overall Length4.2.2.3 Exemplary Sense Strands4.2.3 dsRNA Agents4.2.3.1 Single & Multiple Nucleic Acid Molecules4.2.3.2 Length of Double Stranded RegionAttorney Docket No. 66504.26WO01 Antisense Strands de Linkages cleoside Linkages Thereof ieties)Attorney Docket No. 66504.26WO014.11 Pharmaceutical Compositions4.12 Methods of Use4.12.1 Methods of Delivery4.12.2 Methods of Reducing or Inhibiting ZBTB7A Expression4.12.3 Methods of Inducing Expression of Fetal Hemoglobin4.12.4 Methods of Treating, Ameliorating, or Preventing a ZBTB7A Associated Disease4.12.5 Methods of Treating, Ameliorating, or Preventing an Inherited Blood Disorder4.12.6 Methods of Treating, Ameliorating, or Preventing an Hemoglobinopathy4.12.7 Methods of Treating, Ameliorating, or Preventing an Inherited Bone Marrow Failure Syndrome4.13 Kits4.1 Definitions

[0080] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The term “and / or” where used herein is to be taken as specific disclosure of each of theAttorney Docket No. 66504.26WO01 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).

[0085] 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.

[0086] The terms “about” or “comprising essentially of’ refer 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” or “comprising essentially of’ should be assumed to be within an acceptable error range for that particular value or composition.

[0087] As used herein, the term “administering” refers to the physical introduction of an agent, 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. Administering includes both self-administration by the subject and administration to the subject by a third party.

[0088] As used herein, the terms “agent” and “moiety” are used interchangeable herein and are used generically to describe any macro or micro molecule. Exemplary moieties include, but are not limited polypeptides, proteins, peptides, polynucleotides (e.g., DNA, RNA), small molecules, carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG) (or any combinations thereof). In some embodiments, the term “moiety” is used to describe any macro or micro molecule that can be operably connected to a dsRNA agent described herein. For example, proteins (e.g., antibodies (e.g., anti-TFR antibodies)), targeting moieties, etc., that can be operable connected to a dsRNA agent described herein.Attorney Docket No. 66504.26WO01

[0089] As used herein, the term “affinity” refers to the strength of the binding of one protein (e.g., an Antibody) to another protein (e.g., an Antigen). The affinity of a protein is measured by the dissociation constant Kd, defined as [Antibody] x [Antigen] / [Antibody-Antigen] where [Antibody-Antigen] is the molar concentration of the Antibody- Antigen complex, [Antibody] is the molar concentration of the unbound Antibody and [Ligand] is the molar concentration of the unbound Antigen. The affinity constant Ka is defined by 1 / Kd. Standard methods of measuring affinity are known to the person of ordinary skill in the art. Exemplary methods of measuring affinity include, surface plasmon resonance (SPR) (e.g., BIAcore®-based assay), a common method known in the art (see, e.g., Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 55:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, the full contents of each of which are incorporated by reference herein for all purposes).

[0090] As used herein, the term “antibody” or “antibodies” is used in the broadest sense and encompasses various immunoglobulin (Ig) (e.g., human Ig (hlg), murine Ig (mlg)) structures, including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific (e.g., bispecific, trispecific) antibodies, and antibody fragments so long as they exhibit the desired antigen-binding activity (i.e., antigen binding fragments or variants). The term antibody thus includes, for example, full-length antibodies; antigen-binding fragments of full-length antibodies; molecules comprising antibody CDRs, VH regions, and / or VL regions; and antibody-like scaffolds (e.g., fibronectins). Examples of antibodies include, without limitation, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, camelized antibodies, intrabodies, a variable domain of a new antigen receptor beta-lactamase (VNAR fragments), affybodies, diabodies, tribodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (e.g.,VHH, (VHH)2), single chain antibodies, single-chain Fvs (scFv; (scFv) ), Fab fragments (e.g., Fab, single chain Fab (scFab), F(ab’)2 fragments, disulfide-linked Fvs (sdFv), Fc fusions (e.g., Fab-Fc, scFv- Fc, VHH-Fc, (SCFV) -FC, (VHH) -FC), and antigen-binding fragments of any of the above, and conjugates or fusion proteins comprising any of the above. Antibodies can be of Ig isotype (e.g., IgG, IgE, IgM, IgD, or IgA), any class (e.g., IgGi, IgG2, IgGa, IgGr, IgAi or IgA2), or any subclass (e.g., IgG2a or IgG b) of Ig). In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgGi or IgG4) or subclass thereof. In certain embodiments, antibodies described herein are mlgG antibodies, or a class (e.g., mlgGl or mIgG2a) or subclassAttorney Docket No. 66504.26WO01 thereof. In some embodiments, the antibody is a human, humanized, or chimeric IgGi or IgG4 monoclonal antibody. In some embodiments, the term antibodies refers to a monoclonal or polyclonal antibody population. Antibodies described herein can be produced by any standard methods known in the art, e.g., recombinant production in host cells, see, e.g., § 4.7; or synthetic production.

[0091] As used herein, the term “antibody-like scaffold” refers to non-Ig based antigen binding domain. Various antibody-like scaffolds are known in the art. For example, 10th type III domain of fibronectin (e.g., AdNectins®) and designed ankyrin repeat proteins (e.g., DARPins®) have been used as alternative scaffolds for antigen-binding domains, see, e.g., Gebauer and Skerra, Engineered protein scaffolds as next-generation antibody therapeutics. Curr Opin Chem Biol 13:245-255 (2009) and Stumpp et al., Darpins: A new generation of protein therapeutics. Drug Discovery Today 13: 695-701 (2008), the full contents of each of which is incorporated by reference herein for all purposes. Exemplary antibody-like scaffolds include, but are not limited to, lipocalins (see, e.g., US7250297) (e.g., Anticalin®), protein A-derived molecules such as z- domains of protein a (see, e.g., US5831012) (e.g., Affibody®), A domains of membrane receptors stabilized by disulfide bonds and Ca2+ (see, e.g., US7803907) (e.g., Avimer / Maxibody®), a serum transferrin (see, e.g., US2004023334) (e.g., Transbody®); a designed ankyrin repeat protein (see, e.g., US7417130) (e.g., DARPin®), a fibronectin (see, e.g., US6818418) (e.g., AdNectin®), a C- type lectin domain (see, e.g., US2004132094) (e.g., Tetranectin®); a human gamma-crystallin or ubiquitin (see, e.g., US7838629) (e.g., Affilin®); a kunitz type domain of human protease inhibitors (see, e.g., US2004209243), C-Type Lectins (see, e.g., US2004132094) (e.g., Tetranectins®), cysteine knots or knottins (see, e.g., US7186524) (e.g., Microbodies®), nucleic acid aptamers (see, e.g., US5475096), thioredoxin A scaffold (see, e.g., US6004746) (peptide aptamers), and 10th type III domain of fibronectin (see, e.g., US6818418) (e.g., AdNectins®), and cystine-dense peptides (see, e.g., W02023023031). Additional exemplary antibody-like scaffolds are known in the art and for example described in Storz U. Intellectual property protection: strategies for antibody inventions. MAbs. 2011;3(3):310-317. doi:10.4161 / mabs.3.3.15530. The entire contents of each of the foregoing references is incorporated herein by reference for all purposes. Antibody like scaffolds include e.g., naturally occurring antigen binders, variant (e.g., functional valiants) of naturally occurring antigen binders, fragments (e.g., functional fragments) of naturally occurring antigen binders, and synthetic antigen binders (i.e., not naturally occurringAttorney Docket No. 66504.26WO01 antigen binders).

[0092] As used herein, the term “antibody dependent cell mediated cytotoxicity” or “ADCC” refers to an immune mechanism leading to the lysis of antibody (or an Fc region containing protein) (e.g., an Ig Fc containing fusion protein described herein) -coated target cells by immune effector cells (e.g., NK cells). As used herein, the term “reduced ADCC” and the like refers to either a reduction in the number of target cells that are lysed in a given time, at a given concentration of antibody (or an Ig Fc region containing protein) (e.g., an Fc region containing fusion protein described herein) in the medium surrounding the target cells, by the mechanism of ADCC defined above, and / or an increase in the concentration of antibody (or an Fc region containing protein) (e.g., an Fc containing fusion protein described herein) in the medium surrounding the target cells, required to achieve the lysis of a given number of target cells in a given time, by the mechanism of ADCC defined above. The reduction in ADCC is relative to the ADCC mediated by the same antibody (or an Fc region containing protein) (e.g., an Fc containing fusion protein described herein) produced by the same type of host cells, using the same standard production, purification, formulation and storage methods (which are known to those skilled in the art), but that has not been engineered (e.g., does not comprise one or more amino acid variation, e.g., amino acid substitution, that mediates a decrease in ADCC). For example the reduction in ADCC mediated by an antibody (or an Fc region containing protein) (e.g., an Fc containing fusion protein described herein) comprising in its Fc region an amino acid substitution that reduces ADCC, is relative to the ADCC mediated by the same antibody (or an Fc region containing protein) (e.g., an Fc containing fusion protein described herein) without said amino acid substitution in the Fc region.

[0093] As used herein, the term “antisense 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 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A mRNA)).

[0094] 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.Attorney Docket No. 66504.26WO01

[0095] As used herein, the term “bicyclic nucleoside” (“BNA”) is a nucleoside comprising a bicyclic sugar.

[0096] As used herein, the term “blunt end” refers to a dsRNA molecule that does not contain any unpaired nucleotides at the end (e.g., 31terminus, 5' terminus) of the dsRNA molecule (i.e., no nucleotide overhang(s)). The dsRNA molecule can have, for example, a blunt end at the 3' end, 5' end, or both the 3' and 5' end of the molecule.

[0097] As used herein, the term “CDR” or “complementarity determining region” refers to the noncontiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), the entire contents of each of which is incorporated herein by reference for all purposes. Unless otherwise specified, the term “CDR” is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). A person of ordinary skill in the ail would be able to determine the CDRs as defined by another scheme, e.g., Chothia, IMGT, using ordinary methods known in the art.

[0098] The terms “CHI” and “CHI region” are used interchangeably herein and refer to the first constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CHI region is set forth in SEQ ID NO: 1785.

[0099] The terms “CH2” and “CH2 region” are used interchangeably herein and refer to the second constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CH2 region is set forth in SEQ ID NO: 1787.

[0100] The terms “CH3” and “CH3 region” are used interchangeably herein and refer to the third constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CH3 region is set forth in SEQ ID NO: 1788.

[0101] 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 mostAttorney Docket No. 66504.26WO01 appropriate for a hybridization test. Complementary sequences include, e.g., Watson-Crick base pairs. For example, complementary nuclcobasc 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).

[0102] As used herein, the term “conjugation” refers to chemical conjugation of an agent (e.g., a nucleic acid molecule) with a moiety (e.g., carbohydrate, small molecule, polypeptide (e.g., antibody), polynucleotide, lipid, synthetic polymer (e.g., polymers of polyethylene glycol (PEG)), etc.). The moiety can be directly connected to the 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 detailed instructions for their use readily available from the commercial suppliers.

[0103] The terms “constant region” and “constant domain” are used interchangeably herein and refer to a carboxyl terminal portion of a light and / or heavy chain of a full-length antibody which is not directly involved in binding of an antibody to antigen, but which can exhibit various effector functions, such as interaction with an Ig Fc receptor (e.g., Fc gamma receptor). The constant region of an Ig molecule generally has a more conserved amino acid sequence relative to an Ig variable domain.

[0104] As used herein, the term “differing by no 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.

[0105] 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,Attorney Docket No. 66504.26WO01 bacterial, fungal, protozoal infection).

[0106] 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.

[0107] 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.

[0108] The term “effector function” when used in reference to an Ig Fc region or a protein comprising an Ig Fc region e.g., a full-length antibody) refers to those biological activities attributable to the Ig Fc region of a typical full-length antibody, which therefore vary with the antibody isotype. Antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), Fc receptor binding (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla)), and Clq binding.

[0109] As used herein, the term “erythroid precursor cell” refers to any precursor of a mature erythrocyte (i.e., a mature enucleated red blood cell). As such, erythroid precursor cells include, but are not limited to, megakaryocyte erythroid progenitor cells, proerythroblast cells, early erythroblast cells, intermediate erythroblast cells, late erythroblast cells, and reticulocytes. In some embodiments, erythroid precursor cells include megakaryocyte erythroid progenitor cells, proerythroblast cells, early erythroblast cells, intermediate erythroblast cells, and late erythroblast cells. In some embodiments, erythroid precursor cells include proerythroblast cells, early erythroblast cells, intermediate erythroblast cells, and late erythroblast cells.

[0110] As used herein, the term “erythroid precursor cell targeting agent” refers to an agent that specifically binds to an antigen expressed on an erythroid precursor cell (or a subset thereof). For example, the antigen expressed in or on the erythroid precursor cell may be a membrane protein, for example an integral membrane protein or a peripheral membrane protein. Typically, an erythroid precursor cell targeting agent specifically binds to an antigen on the erythroid precursor cell that facilitates internalization of the erythroid precursor cell targeting agent (and any associated molecular payload) into the erythroid precursor cell. In some embodiments, an erythroidAttorney Docket No. 66504.26WO01 precursor cell targeting agent specifically binds to an internalizing, cell surface receptor on the erythroid precursor cell and is capable of being internalized into the erythroid precursor cell through receptor mediated internalization. In some embodiments, the erythroid precursor cell targeting agent is a protein (e.g., antibody), a peptide, a nucleic acid (e.g., an aptamer), or small molecule. In some embodiments, the erythroid precursor cell targeting agent is linked to a molecular payload.

[0111] As used herein, the term “EU numbering system” refers to the EU numbering convention for the constant regions of an antibody, as described in Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al, Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991, the entire contents of each of which is incorporated herein by reference for all purposes.

[0112] As used herein, the term “Fab” refers to an antigen binding domain that comprises a Fab heavy chain that comprises from N- to C-terminus a VH region and a CHI region; and a light chain comprising from N- to C-terminus a VL region and a CL region; and wherein the Fab heavy chain and the light chain associate to form an antigen binding domain.

[0113] The term “Fab-Fc” as used herein refers to an antibody that comprises a Fab operably linked to an Fc region.

[0114] As used herein, the term “Fc region” refers to the C-terminal region of a Ig (e.g., a human Ig) heavy chain that comprises from N- to C-terminus at least a CH2 region operably connected to a CH3 region. In some embodiments, the Fc region comprises an Ig hinge region or at least a portion of an Ig hinge region operably connected to the N-terminus of the CH2 region. In some embodiments, the Fc region is engineered relative to a reference Fc region (e.g., comprises one or more amino acid modification), e.g., described herein. Additional examples of proteins with engineered Fc regions can be found in Saunders 2019 (K. O. Saunders, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” 2019, Frontiers in Immunology, V. 10, Art. 1296, pp. 1-20, the entire contents of which is incorporated herein by reference for all purposes).

[0115] As used herein, the terms “first” and “second” with respect to Fc regions etc., are used for convenience of distinguishing when there is more than one of each type of moiety. Use of these terms is not intended to confer a specific order or orientation in the protein unless explicitly so stated. For example, an antibody described herein (e.g., in the case of a full-length antibody) mayAttorney Docket No. 66504.26WO01 contain two Fc regions that associate e.g., via one or more covalent (e.g., disulfide) bond.

[0116] As used herein, the term “framework region” or “FR region” refers to the amino acid residues that are part of the variable region of an antibody, but are not part of the CDRs (e.g., using the Kabat definition of CDRs).

[0117] As used herein, the term “full-length antibody” refers to an antibody having a structure substantially similar to a native antibody structure (i) a first Ig light chain comprising from N- to C-terminus a light chain variable region (VL) region and a light chain constant region (CL) region; (ii) a first Ig heavy chain comprising from N- to C-terminus a heavy chain variable region (VH) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a second Ig heavy chain comprising from N- to C-terminus a VH region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iv) a second Ig light chain comprising from N- to C-terminus a VL region and a VH region; wherein said first light chain and said first heavy chain associate to form a first antigen binding domain; wherein said second light chain and said second heavy chain associate to form a second antigen binding domain; and wherein said first heavy chain and said second heavy chain associate to form a dimer. In some embodiments, the two heavy chains comprise a substantially identical amino acid sequence; and the two light chains comprise a substantially identical amino acid sequence. In some embodiments, the two heavy chains comprise a substantially identical amino acid sequence except for one or more amino acid modifications that promote heterodimerization of the correct heavy chains (e.g., as described herein); and the two light chains comprise a substantially identical amino acid sequence. Antibody chains may be substantially identical but not entirely identical if they differ due to post-translational modifications, such as C-terminal cleavage of lysine residues, alternative glycosylation patterns, etc.

[0118] 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.

[0119] 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 ofAttorney Docket No. 66504.26WO01 bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a pail of the first and / or second nucleic acid molecule.

[0120] The term “functional variant” as used herein in reference to a protein refers to a protein that comprises at least one but no more than 20%, not more than 15%, not more than 12%, no more than 10%, no more than 8% amino acid variation (e.g., substitution, deletion, addition) compared to the amino acid sequence of a reference protein, wherein the protein retains at least one particular function of the reference protein. Not all functions of the reference protein e.g., wild type) need be retained by the functional variant of the protein. In some instances, one or more functions are selectively reduced or eliminated. In some embodiments, the reference protein is a wild type protein.

[0121] The term “functional fragment” as used herein in reference to a protein refers to a fragment of a reference protein that retains at least one particular function. Not all functions of the reference polypeptide or protein need be retained by a functional fragment of the protein. In some instances, one or more functions are selectively reduced or eliminated. In some embodiments, the reference protein is a wild type protein.

[0122] As used herein, the term “fuse” and grammatical equivalents thereof refer to the operable connection of at least a one polypeptide derived from a first polypeptide to another polypeptide derived from a second polypeptide, wherein the first and second polypeptides are different. The term fuse encompasses both a direct connection of the at least two polypeptides through a peptide bond, and the indirect connection through a linker (e.g., a peptide linker).

[0123] As used herein, the term “fusion protein” and grammatical equivalents thereof refers to a protein that comprises at least one polypeptide derived from a first polypeptide operably connected to another polypeptide derived from a second polypeptide, wherein the first and second polypeptides are wherein the first and second polypeptides are not naturally found operably connected together. The at least two polypeptides of the fusion protein can be directly operably connected through a peptide bond; or can be indirectly operably connected through a linker (e.g., a peptide linker). Therefore, for example, the term fusion protein encompasses embodiments, wherein Polypeptide A is directly operably connected to Polypeptide B through a peptide bond (Polypeptide A - Polypeptide B), and embodiments, wherein Polypeptide A is operably connected to Polypeptide B through a peptide linker (Polypeptide A - peptide linker - Polypeptide B). In some embodiments, the first polypeptide and the second polypeptide are different.Attorney Docket No. 66504.26WO01

[0124] As used herein, the term “half-life extension moiety” refers to a moiety (e.g., small molecule, polypeptide, polynucleotide, carbohydrate, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that when conjugated or otherwise operably connected (e.g., fused) to a polypeptide or protein (the subject polypeptide or protein), increases the half-life of the subject polypeptide or protein in vitro when administered to a subject (e.g., a human subject). The pharmacokinetic properties of the polypeptide or protein can be evaluated utilizing in vitro models known in the art.

[0125] As used herein, the term “half-life extension polypeptide” refers to a polypeptide that when operably connected to another polypeptide (the subject polypeptide), increases the half-life of the subject polypeptide in vitro when administered to a subject (e.g., a human subject). The pharmacokinetic properties of the polypeptide or protein can be evaluated utilizing in vitro models known in the ail.

[0126] As used herein, the term “heavy chain” refers to the portion of an immunoglobulin (e.g., a human Ig) that typically comprises from N- to C-terminus a heavy chain variable region (VH), a CHI region, a hinge region, a CH2 region, and a CH3 region. The constant regions of the heavy chain (i.e., the CHI region, the hinge region, the CH2 region, and the CH3 region) can be any distinct isotype, for example, human alpha (a), delta (8), epsilon (s), gamma (y), and mu (p), based on the amino acid sequence of the constant domain, which give rise to the hlgA, hlgD, IgE, hlgG, and hlgM classes of human antibodies, respectively, including subclasses of hlgG, e.g., hlgGi, h!gG2, hlgG?, and h!gG4. As used herein, the term “heavy chain” when used in reference to a human antibody can refer to any distinct type, e.g., alpha (a), delta (8), epsilon (s), gamma (y), and mu (p), based on the amino acid sequence of the constant domain, which give rise to human IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of human IgG, e.g., IgGi, IgG2, IgG?, and IgG4.

[0127] As used herein, the term “hematopoietic cell” refers to any blood cell. As such, the term hematopoietic cell, includes, but is not limited to, hematopoietic pluripotent stem cells (HSPCs), common myeloid progenitor cells, megakaryocyte erythroid progenitor cells, erythroid progenitor cells, proerythroblast cells, early erythroblast cells, intermediate erythroblast cells, late erythroblast cells, reticulocytes, megakaryocytes, platelets, granulocyte monocyte progenitor cells, monoblasts, promonocytes, monocytes, macrophages, myeloblasts, promyelocytes, myelocytes, eosinophils, basophils, neutrophils, common lymphoid progenitor cells, pro-NK lymphoblasts, NK cells, pro-B lymphoblasts, B lymphocytes, pro-T lymphoblasts, T lymphoblasts, and plasma cells.Attorney Docket No. 66504.26WO01

[0128] As used herein, the term “hematopoietic cell targeting agent” refers to an agent that specifically binds to an antigen expressed on a hematopoietic cell (or a subset thereof). For example, the antigen expressed in or on the hematopoietic cell may be a membrane protein, for example an integral membrane protein or a peripheral membrane protein. Typically, a hematopoietic cell targeting agent specifically binds to an antigen on the hematopoietic cell that facilitates internalization of the hematopoietic cell targeting agent (and any associated molecular payload) into the hematopoietic cell. In some embodiments, a hematopoietic cell targeting agent specifically binds to an internalizing, cell surface receptor on the hematopoietic cell and is capable of being internalized into the hematopoietic cell through receptor mediated internalization. In some embodiments, the hematopoietic cell targeting agent is a protein (e.g., antibody), a peptide, a nucleic acid (e.g., an aptamer), or small molecule. In some embodiments, the hematopoietic cell targeting agent is linked to a molecular payload.

[0129] 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.

[0130] The terms “hinge” or “hinge region” are used interchangeably herein and refer to the hinge region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl hinge region is set forth in SEQ ID NO: 1786.

[0131] 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.

[0132] 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, deletion, or inversion of one or more nucleotide compared to a reference nucleic acid molecule. As used herein, the term “variant” or “variation” with reference to a peptide or protein refers to a peptide or protein that comprises at least one substitution, addition, deletion, or inversion of an amino acid residue compared to a reference peptide or protein.Attorney Docket No. 66504.26WO01

[0133] As used herein, the term “modified agent” when used in reference to a nucleic acid molecule-based 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.), refers to a nucleic acid molecule based 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.) that comprises one or more modified nucleotide (as defined herein).

[0134] 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 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.

[0135] 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.

[0136] 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.

[0137] As used herein, the term “operably connected” refers to the linkage of two moieties in a functional relationship. For example, a polypeptide is operably connected to another polypeptide when they are linked (either directly or indirectly via a peptide linker) in frame such that both polypeptides are functional (e.g., a fusion protein described herein). Or for example, a transcription regulatory polynucleotide e.g., a promoter, enhancer, or other expression control element is operably linked to a polynucleotide that encodes a protein if it affects the transcription of the polynucleotide that encodes the protein. The term “operably connected” can also refer to the conjugation of a moiety to e.g., a polynucleotide or polypeptide (e.g., the conjugation of a PEGAttorney Docket No. 66504.26WO01 polymer to a protein).

[0138] 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.

[0139] 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 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, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, which is herein incorporated 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 acidAttorney Docket No. 66504.26WO01 sequences, a PAM 120 weight residue table, a gap length penalty of 1 , 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.

[0140] 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. A “pharmaceutically acceptable earner 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.

[0141] The terms “nucleic acid molecule” and “polynucleotide” 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 altered nucleotides; and contain a natural, nonnatural, or altered internucleoside 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).

[0142] 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).

[0143] 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 shorterAttorney Docket No. 66504.26WO01 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.

[0144] 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.

[0145] 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 altered intemucleoside linkages, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule.

[0146] As used herein, the term “RNAi agent” refers to an 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., ZBTB7A) 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, wherein optionally the sense strand and the antisense strand each independently comprise or consist of from about 19-23 nucleotides.

[0147] The term “scFv” or “single chain variable fragment” refers to an antibody that comprises a VH region operably connected via a peptide linker to a VL region, wherein the VH and VL regions associate to specifically bind an antigen (e.g., form an antigen binding domain). In some embodiments, the scFv comprises from N- to C-terminus an VH region, a peptide linker, and an VL region. In some embodiments, the scFv comprises from N- to C-terminus an VL region, a peptide linker, and an VH region.

[0148] The term “(scFv ” as used herein refers to an antibody that comprises a first and a second scFv operably connected (e.g., via a peptide linker). The first and second scFv canAttorney Docket No. 66504.26WO01 specifically bind the same or different antigens. In some embodiments, the first and second scFv arc operably connected by a peptide linker.

[0149] The term “scFv-Fc” as used herein refers to an antibody that comprises a scFv operably linked (e.g., via a peptide linker) to an Fc domain or subunit of an Fc domain. In some embodiments, a scFv is operably connected to only a first Fc domain of a first and a second Fc domain pair. In some embodiments, a first scFv is operably connected to a first Fc domain and a second scFv is operably connected to a second Fc domain of a first and second Fc domain pair.

[0150] The term “(scFv)2-Fc” as used herein refers to a (scFv)2 operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, a (scFv is operably connected to only a first Fc domain of a first and a second Fc domain pair. In some embodiments, a first (scFv)2 is operably connected to a first Fc domain and a second (scFv)2 is operably connected to a second Fc domain of a first and second Fc domain pair.

[0151] 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).

[0152] As used herein, the term “single domain antibody” or “sdAb” refers to an antibody having a single monomeric variable antibody domain. A sdAb is able to specifically bind to a specific antigen. A VHH (as defined herein) is an example of a sdAb.

[0153] As used herein, the term “specifically binds” refers to preferential interaction, i.e., significantly higher binding affinity, between a first protein (e.g., an antibody) and a second protein (e.g., an antigen) relative to other amino acid sequences. Herein, when a first protein is said to “specifically bind” to a second protein, it is understood that the first protein specifically binds to an epitope of the second protein. The term “epitope” refers to the portion of the second protein that the first protein specifically recognizes. The term specifically binds includes molecules that are cross reactive with the same epitope of a different species. For example, an antibody that specifically binds human TFR may be cross reactive with TFR of another species (e.g., cynomolgus, murine, etc.), and still be considered herein to specifically bind human TFR. A protein can specifically bind more than one different protein. Specific binding can be measured,Attorney Docket No. 66504.26WO01 e.g., through measuring binding affinity (e.g., using standard methods known in the art and described herein (e.g., surface plasmon resonance (SPR) (e.g., BIAcorc®-bascd assay), a common method known in the ait (see, e.g., Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 55:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, the full contents of each of which are incorporated by reference herein for all purposes).

[0154] 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).

[0155] As used herein, “substantially complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, at least 85%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0156] In some embodiments, the term “substantially all” means at least 95%, 96%, 97%, 98% or 99%, e.g., of the subject of said sentence. The term “substantially all” preferably excludes 100%. For example, in some embodiments, the term “substantially all of the nucleotides in the sense strand and / or antisense strand are modified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are modified. For example, in some embodiments, the term “substantially all of the nucleotides of the agent are modified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are modified. For example, in some embodiments, the term “substantially all of the nucleotides of the agent are unmodified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are unmodified. For example, in some embodiments the term “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 phosphorothioate groups presentAttorney Docket No. 66504.26WO01 in the dsRNA agent” means that wherein the dsRNA agent is in the sodium salt form, sodium ions arc present in the composition comprising the dsRNA agent as counterions for at least 95%, 96%, 97%, 98% or 99% of the phosphodiester or phosphorothioate groups present in the dsRNA agent.

[0157] 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., ZBTB7A)). In some embodiments, the target nucleic acid sequence is an mRNA molecule formed during the transcription of a target gene (e.g., ZBTB7A)). In some embodiments, the target nucleic acid molecule comprises an mRNA that is a product of RNA processing of a primary transcription product. 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 ZBTB7A gene. In one embodiment, the target sequence is within the protein coding region of ZBTB7A.

[0158] As used herein, the term “therapeutic agent” refers to an agent (e.g., a conjugate described herein) capable of achieving a desired therapeutic result in a subject or ex vivo (e.g., capable of treating a disease as defined herein) when administered at a therapeutically effective amount.

[0159] 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 (or infection); improves a symptom of disease or infection, e.g., decreases severity of disease or infection symptoms, decreases frequency or duration of disease or infection symptoms, increases disease or infection symptom-free periods; prevents or reduces impairment or disability due to the disease or infection; 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 agent in in vitro assays.

[0160] As used herein, the term “transferrin” or “TF” refers to the plasma glycoprotein transferrin that functions, inter alia, in iron metabolism and the transport of iron through the blood to various tissues, such as the liver, spleen, and bone marrow. The amino acid sequence of a reference human TF (hTF) protein is set forth in SEQ ID NO: 1726 (UniProt Accession P02787).Attorney Docket No. 66504.26WO01

[0161] As used herein, the term “transferrin receptor” or “TFR” refers to the transmembrane homodimcric glycoprotein that functions, inter alia, in the cellular’ uptake of iron from the plasma glycoprotein transferrin. The term TFR includes, where applicable, multiple isoforms and homologs. For example, human TFR (hTFR) includes homologs hTFRl and hTFR2. The amino acid sequence of a reference hTFRl protein is set forth in SEQ ID NO: 1724 (UniProt Accession P02786|). TFR1 is also commonly known in the art as CD71. The terms TFR1 and CD71 are used interchangeably herein. The amino acid sequence of a reference hTFR2 protein is set forth in SEQ ID NO: 1725 (UniProt Accession Q9UP52).

[0162] 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.

[0163] As used herein, the term “variation” or “variant” or use the like in reference to a nucleotide or nucleic acid sequence refers to a nucleic acid molecule that comprises at least one substitution, addition, deletion, or inversion of one or more nucleotide compared to a reference nucleic acid molecule. Likewise, as used herein, the term “variation” or “variant” or use the like with reference to a peptide or protein refers to a peptide or protein that comprises at least one substitution, addition, deletion, or inversion of an amino acid residue compared to a reference peptide or protein.

[0164] A “variation that promotes heterodimerization of a first Fc region and a second Fc region” (or similar phrasing) is a manipulation of the peptide backbone or the post-translational modifications of an Fc region that reduces or prevents the association of a polypeptide comprising the Fc region with an identical polypeptide to form a homodimer. A modification promoting association as used herein particularly includes separate modifications made to each of the two Fc regions desired to associate i.e., a first Fc region and a second Fc region), wherein theAttorney Docket No. 66504.26WO01 modifications are complementary to each other so as to promote association of the two Fc regions. For example, a modification promoting association may alter the structure or charge of one or both of the Fc regions so as to make their association sterically or electrostatically favorable, respectively. Thus, heterodimerization occurs between a polypeptide comprising the first Fc region and a polypeptide comprising the second Fc region, which might be non-identical in the sense that further components fused to each of the Fc regions (e.g., antigen binding domains) are not the same. In some embodiments the modification promoting association comprises an amino acid mutation in the Fc region, specifically an amino acid substitution. In a particular embodiment, the modification promoting association comprises a separate amino acid mutation, specifically one or more amino acid substitution, in each of the first Fc region and the second Fc region e.g., described herein).

[0165] As used herein, the term “variable region” refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular' antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In particular embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0166] The terms “VL” and “VL region” are used interchangeably to refer to an immunoglobulin light chain variable region. A VL region can be incorporated into an antibody, e.g., a scFv, a Fab, a full-length antibody. For example, a scFv comprises a VL region operably connected via a peptide linker to a VH region.

[0167] The terms “VH” and “VH region” are used interchangeably to refer to an immunoglobulin heavy chain variable region. A VH region can be incorporated into an antibody,Attorney Docket No. 66504.26WO01 e.g., a scFv, a Fab, a full-length antibody. For example, a scFv comprises a VH region operably connected via a peptide linker to a VL region.

[0168] The term “VHH” as used herein refers to a type of single domain antibody (sdAb) that has a single monomeric heavy chain variable antibody domain (VH). Such antibodies can be found in or produced from camelid mammals (e.g., camels, llamas) which are naturally devoid of light chains or synthetically produced.

[0169] The term “(VHH)2” as used herein refers to an antibody that comprises a first and a second VHH operably connected (e.g., via a peptide linker). The first and the second VHH can specifically bind the same or different antigens. In some embodiments, the first and second VHH are operably connected by a peptide linker.

[0170] The term “VHH-Fc” as used herein refers to an antibody that comprises a VHH operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, a VHH is operably connected to only a first Fc domain of a first and a second Fc domain pair. In some embodiments, a first VHH is operably connected to a first Fc domain and a second VHH is operably connected to a second Fc domain of a first Fc and a second Fc pair.

[0171] The term “(VHH)2-Fc” as used herein refers to (VHH)2 operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, a (VHH) is operably connected to only a first Fc domain of a first and a second Fc domain pair. In some embodiments, a first (VHH)2 is operably connected to a first Fc domain and a second (VHH)2 is operably connected to a second Fc domain of a first Fc and a second Fc pair.

[0172] As used herein, the term “ZBTB7A” or “zinc finger and BTB domain containing 7” refers to the transcription factor four C-terminal Kriippel-type zinc fingers with a sequencespecific DNA-binding capacity and the N-terminal (broad-complex, tram-track, and bric-a-brac) BTB domain, capable for the formation of homo- or hetero -dimers. The mRNA sequence of a reference hZBTB7A gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_015898.4). The amino acid sequence of a reference hZBTB7A protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_056982.1). The term ZBTB7A includes naturally occurring variants of ZBTB7A. ZBTB7A 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.4.2 RNAi AgentsAttorney Docket No. 66504.26WO01

[0173] Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents), useful in, inter alia, inhibiting expression of zinc finger and BTB domain-containing protein 7A (ZBTB7A) (e.g., human ZBTB7A (hZBTB7A)) (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 ZBTB7A (e.g., hZBTB7A) mRNA).

[0174] ZBTB7A is a transcription factor that e.g., represses transcription of a range of genes involved in e.g., cell proliferation and differentiation. The mRNA sequence of a reference hZBTB7A gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_015898.4). The reverse complement sequence of the hZBTB7A mRNA is set forth in SEQ ID NO: 2. The amino acid sequence of a reference hZBTB7A protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_056982.1). See Table 1, herein.Table 1. The mRNA and Amino Acid Sequence of a Reference hZBTB7A Protein.Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01

[0175] In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises one or more RNA molecule. In some embodiments, the agent e.g., RNAi agent, dsRNA agent) comprises an antisense strand. In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises a sense strand. In some embodiments, the agent comprises one or more single stranded RNA (ssRNA) molecules. In some embodiments, the agent (e.g., RNAi agent, dsRNA agent) comprises a dsRNA agent.

[0176] In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand. In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, the agent (e.g., RNAi 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.4.2.1 Antisense Strand4.2.1.1 T argeting Region

[0177] 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A mRNA)).

[0178] 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A mRNA)). For example,Attorney Docket No. 66504.26WO01 the nucleotide sequence of the region of complementarity may he at least 70% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A mRNA)).

[0179] 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A mRNA)). In some embodiments, theAttorney Docket No. 66504.26WO01 nucleotide sequence of the region of complementarity comprises or consists of no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complcmcntary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 e.g., 2, 1, or 0) non- complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1 (e.g., 0) non-complementary nucleotide mismatch relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complcmcntary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises 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 ail and described herein can be utilized to evaluate the effect of any non-complementary mismatches between an antisense strandAttorney Docket No. 66504.26WO01 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A mRNA))).

[0180] In some embodiments, the region of complementarity comprises or consists of 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 or 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 comprises or consists of about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 20 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 21 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 22 nucleotides. In some embodiments, the region of complementarity comprises or 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.

[0181] 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 ZBTB7A mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a ZBTB7A 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).

[0182] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., aAttorney Docket No. 66504.26WO01ZBTB7A 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 ZBTB7A mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA (e.g., a ZBTB7A 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 ZBTB7A gene). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a ZBTB7A (e.g., hZBTB7A) 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 ZBTB7A (e.g., hZBTB7A) 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 ZBTB7A (e.g., hZBTB7A) 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).

[0183] In some embodiments, the target nucleic acid molecule comprises or consists of 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 or consists of from about 19-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 21-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 21-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises or 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 comprises or consists of about 19 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 20 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 21 nucleotides. In some embodiments, the target nucleic acid molecule comprises orAttorney Docket No. 66504.26WO01 consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths arc also contemplated to be pail of the disclosure.4.2.1.2 Overall Length

[0184] In some embodiments, the antisense strand comprises or consists of 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 or consists of 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 or consists of 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 or consists of 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.

[0185] In some embodiments, the antisense strand comprises or 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 comprises or 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 comprises or consists of about 21 nucleotides. In some embodiments, the antisense strand comprises or consists of about 23 nucleotides. In preferred embodiments, the antisense strand comprises or consists of about 23 nucleotides. In preferred embodiments, the antisense strand comprises 23 nucleotides. In preferred embodiments, the antisense strand consists of 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.1.3 Exemplary Antisense Strands

[0186] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, theAttorney Docket No. 66504.26WO01 nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2- 5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0187] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0188] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequenceAttorney Docket No. 66504.26WO01 of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0189] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0190] Tables 2-5 (e.g., Table 3 or 5) further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5’ end) of the ZBTB7A mRNA transcript targeted by the select antisense strand.

[0191] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g.,Attorney Docket No. 66504.26WO010, 1 , 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5.

[0192] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19- 22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5.

[0193] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of Tables 2-5. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5.

[0194] Tables 2-5 further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of anyAttorney Docket No. 66504.26WO01 one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript targeted by the select antisense strand.

[0195] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0196] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 725- 1264.

[0197] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%,Attorney Docket No. 66504.26WO0197%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ TD NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0198] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0199] Tables 2-5 further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1- 7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript targeted by the select antisense strand.

[0200] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23Attorney Docket No. 66504.26WO01(e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in SEQ ID NOS: 725-1264. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0201] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0202] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0203] As described above, Tables 2-5 further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. The disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2Attorney Docket No. 66504.26WO01 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript targeted by the select antisense strand.

[0204] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5.

[0205] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22,20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5.Attorney Docket No. 66504.26WO01

[0206] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of Tables 2-5. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5.

[0207] As described above, Tables 2-5 further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. The disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5 (e.g., Table 3 or 5) and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript targeted by the select antisense strand.

[0208] It is to be understood, that although the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) are not described as being modified (e.g., comprising chemically modified nucleotides), conjugated, etc., the disclosure includes any antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) that is unmodified, unconjugated, modified (e.g., as described herein), or conjugated (e.g., as described herein).4.2.2 Sense Strand4.2.2.1 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 antisenseAttorney Docket No. 66504.26WO01 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 at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0212] 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 at least a portion of an antisense strand. 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 at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. 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-complementaryAttorney Docket No. 66504.26WO01 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 or consists of 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 or 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 comprises or consists of about 19, 20, or 21 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 20 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 21 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengthsAttorney Docket No. 66504.26WO01 are also contemplated to be part of the disclosure.4.2.2.2 Overall Length

[0214] In some embodiments, the sense strand comprises or consists of 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 or consists of from about18-25 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 or consists of 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 or consists of 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.

[0215] In some embodiments, the sense strand comprises or 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 comprises or 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 comprises or consists of about 19, 20, 21, 22, 23 nucleotides. In some embodiments, the sense strand comprises or consists of about 19, 20, 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 20 nucleotides. In some embodiments, the sense strand comprises or consists of about 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 21 nucleotides. In preferred embodiments, the sense strand comprises or consists of about 21 nucleotides. In preferred embodiments, the sense strand comprises 21 nucleotides. In preferred embodiments, the sense strand consists of 21 nucleotides. In some embodiments, the sense strand comprises or 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.4.2.2.3 Exemplary Sense Strands

[0216] In some embodiments, the nucleotide sequence of the sense strand differs by no moreAttorney Docket No. 66504.26WO01 than 5 (e.g., 0, 1 , 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Tabic 3 or 5). In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand differs by no more than2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0217] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table3 or 5) differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0218] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any oneAttorney Docket No. 66504.26WO01 of Tables 2-5 (e.g., Table 3 or 5). Tn some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0219] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0220] Tables 2-5 further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript targeted by the select sense strand.

[0221] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g.,Attorney Docket No. 66504.26WO0123))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0222] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22,20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises from about21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0223] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of Tables 2-5. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0224] Tables 2-5 further identify the target nucleic acid molecule within the reference ZBTB7A mRNA transcript at least partially identical to each of the sense strands. As such, the disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of anyAttorney Docket No. 66504.26WO01 one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1- 3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript identical to the select sense strand.

[0225] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0226] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than I (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0227] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-Attorney Docket No. 66504.26WO01759. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4- 759. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0228] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0229] Tables 2-5 further identify the target nucleic acid molecule within the cited reference ZBTB7A mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript targeted by the select sense strand.

[0230] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in SEQ ID NOS: 4-759. In some embodiments,Attorney Docket No. 66504.26WO01 the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21 , 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0231] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0232] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0233] As described above, Tables 2-5 further identify the target nucleic acid molecule within the reference ZBTB7A mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5’ end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript identical to the select sense strand.Attorney Docket No. 66504.26WO01

[0234] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5.

[0235] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5.

[0236] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3)Attorney Docket No. 66504.26WO01 nucleotides from the sense strand set forth in any one of Tables 2-5. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5.

[0237] As described above, Tables 2-5 further identify the target nucleic acid molecule within the reference ZBTB7A mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5 (e.g., Table 3 or 5) and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the ZBTB7A mRNA transcript identical to the select sense strand.

[0238] It is to be understood, that although the sense strands set forth in any one of Tables 2- 5 (e.g., Table 3 or 5) are not described as being modified (e.g., comprising chemically modified nucleotides), conjugated, etc., the disclosure includes any sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) that is unmodified, unconjugated, modified (e.g., as described herein), or conjugated (e.g., as described herein).4.2.3 dsRNA Agents

[0239] In some embodiments, the agent (e.g., RNAi agent) comprises a dsRNA agent comprising an antisense strand (e.g., described herein, e.g., described in § 4.2.1) and a sense strand (e.g., described herein, e.g., described in § 4.2.2) 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)).

[0240] 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 ZBTB7A mRNA), a portion of a target mRNA (e.g., a ZBTB7A 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 aAttorney Docket No. 66504.26WO01 portion of an antisense strand.4.2.3.1 Single & Multiple Nucleic Acid Molecules

[0241] As described herein, and known in the art, the sense strand and the antisense strand can be pail 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 part of a single larger nucleic acid molecule.

[0242] 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).

[0243] 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 by herein by reference for all purposes).4.2.3.2 Length of Double Stranded Region

[0244] 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 inAttorney Docket No. 66504.26WO01 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.

[0245] 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. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.4.2.3.3 Nucleotide Overhangs & Blunt Ends

[0246] In some embodiments, the dsRNA agent comprises one or more (e.g., 1 or 2) 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).

[0247] 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 or consists of about 1, 2, 3, 4, or 5 nucleotides. In some embodiments, the nucleotide overhang comprises or consists of about 1 nucleotide. In some embodiments, the nucleotide overhang comprises or consists of about 2 nucleotides.

[0248] 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 nucleotideAttorney Docket No. 66504.26WO01 overhang.

[0249] Furthermore, the nuclcotidc(s) of an overhang can be present on the 5'-cnd, 3'- end, or both the 5'-end, 3'- end of an antisense or sense strand. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end and the 3 '-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5 '-end and the 3 '-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end; and the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end; and the sense strand comprises a nucleotide overhang at the 5'-end.

[0250] 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 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 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.4.2.3.4 Exemplary Structural Combinations of Sense & Antisense Strands

[0251] 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.Attorney Docket No. 66504.26WO01

[0252] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 23 nucleotides. In some preferred embodiments, the sense strand comprises 21 nucleotides; and the antisense strand comprises 23 nucleotides. In some preferred embodiments, the sense strand consists of 21 nucleotides; and the antisense strand consists of 23 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 23 nucleotides; the double stranded region comprises or 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.

[0253] In some embodiments, the sense strand comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the sense strand comprises or consists of 19 nucleotides; and the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 19 nucleotides; the antisense strand comprises or consists of 21 nucleotides; the double stranded region comprises or 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.

[0254] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 21 nucleotides; the double stranded region comprises orAttorney Docket No. 66504.26WO01 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.

[0255] In some embodiments, the sense strand comprises or consists of 20 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 20 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 20 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or 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.

[0256] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or 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.

[0257] In some embodiments, the sense strand comprises or consists of 24 nucleotides. In some embodiments, the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the sense strand comprises or consists of 24 nucleotides; and the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 24 nucleotides; the antisense strand comprises or consists of 23 nucleotides; the double stranded region comprises or consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'end;Attorney Docket No. 66504.26WO01 and the sense strand comprises a 3-nucleotide overhang at the 3' end.

[0258] In some embodiments, the sense strand comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 19 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or 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 comprises or consists of 19 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or 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

[0259] In some embodiments, the antisense strand and the sense strand are pail of the same larger nucleic acid molecule, wherein the nucleic acid molecule comprises or consists of 44 nucleotides, the antisense portion comprises or consists of 21 nucleotides, the sense strand portion of the nucleic acid molecule comprises 19 nucleotides, the double stranded region comprises or 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 comprises or consists of 4 unpaired nucleotides that create a hairpin loop.4.2.3.5 Exemplary Antisense Strands & Sense Strands

[0260] 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. In some embodiments, the sense strand is a sense strand described in § 4.2.2. In some embodiments, the antisense strand is an antisense strand described in § 4.2.1; and the sense strand is a sense strand described in § 4.2.2. It is to be understood that any sense strand described herein (e.g., in § 4.2.2); and be utilized in combination with any antisense strand in a dsRNA agent described herein (e.g., in § 4.2.1). For the sake of clarity, the entire contents of in §§ 4.2.1 and § 4.2.2, are incorporated by reference into the instant section in § 4.2.3.5.

[0261] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the senseAttorney Docket No. 66504.26WO01 strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0262] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of Tables 2- 5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth inAttorney Docket No. 66504.26WO01 any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0263] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at leastAttorney Docket No. 66504.26WO0196%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0264] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5). In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

[0265] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotideAttorney Docket No. 66504.26WO01 sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 19 e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0266] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22,Attorney Docket No. 66504.26WO0115-21 , 15-20, 15-19, 15-18, 15- 17, 15-16, 16-22, 16-20, 16-19, 16-18, 16- 17, 17-23, 17-22, 17-21 ,17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18,18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23,20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19- 20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19- 20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0267] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strandAttorney Docket No. 66504.26WO01 comprises or consists of about 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2- 5; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisenseAttorney Docket No. 66504.26WO01 strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0268] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of Tables 2-5; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of Tables 2-5.

[0269] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in any one of Tables 2-5; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of Tables 2-5.

[0270] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19,20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 19 (e.g.,Attorney Docket No. 66504.26WO0120, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21 , 22, 23 (e.g., 21 ))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5.

[0271] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21,17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18,18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 66504.26WO01 nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23,20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19- 20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19- 20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises from about21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5.

[0272] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g.,19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguousAttorney Docket No. 66504.26WO01 nucleotides differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand setAttorney Docket No. 66504.26WO01 forth in any one of Tables 2-5.

[0273] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of Tables 2-5; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding sense strand set forth in any one of Tables 2-5.

[0274] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in any one of Tables 2-5; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5.

[0275] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725- 1264. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725- 1264 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forthAttorney Docket No. 66504.26WO01 in any one of SEQ ID NOS: 725-1264.

[0276] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725- 1264. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0277] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, theAttorney Docket No. 66504.26WO01 nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0278] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 725- 1264. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759; and the nucleotide sequence of the antisense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 725-1264.

[0279] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any oneAttorney Docket No. 66504.26WO01 of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 4-759.

[0280] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0,Attorney Docket No. 66504.26WO011 , 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises at least 23 (e.g.,24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 21 (e.g., 22, 23, 24,25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759.

[0281] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22,20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21,21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22,22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725- 1264; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one ofAttorney Docket No. 66504.26WO01SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759.

[0282] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725- 1264; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4- 759. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of at aboutAttorney Docket No. 66504.26WO0121, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21 , 22, 23 (e.g., 21 )) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759.

[0283] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 4-759 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of SEQ ID NOS: 4-759.

[0284] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of SEQ IDAttorney Docket No. 66504.26WO01NOS: 4-759.

[0285] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of theAttorney Docket No. 66504.26WO01 antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759).

[0286] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22,20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21,21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20- 23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises from about 21-23 (e.g., 21-Attorney Docket No. 66504.26WO01 l, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1 , 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759).

[0287] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g.,19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS:Attorney Docket No. 66504.26WO014-759). In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759). In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759).

[0288] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of SEQ ID NOS: 4-759.

[0289] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 4-759).

[0290] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18,Attorney Docket No. 66504.26WO0119, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21 , 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises at least 19 e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises at least 21 e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.Attorney Docket No. 66504.26WO01

[0291] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21,17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1- 485; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23,18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22- 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23,20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about from about21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1- 485; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21- 22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0292] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotideAttorney Docket No. 66504.26WO01 sequence of the antisense strand of any one of dsRNA agents 1 -485; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 66504.26WO01 nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0293] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-485 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of the dsRNA agents 1-485; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in the corresponding (the same) dsRNA agent.

[0294] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence the antisense strand of any one of dsRNA agents 1-485; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.4.2.3.6 Exemplary dsRNA Agents

[0295] The nucleotide sequence of exemplary unmodified dsRNA agents comprising a sense and antisense strand (e.g., suitable for targeting hZBTB7A, suitable for inhibiting hZBTB7A expression)) are set forth in Table 2. More specifically, Table 2 sets forth the nucleotide sequence of exemplary sense strands, antisense strands, and dsRNA agent pairs of sense and antisense strands. It is to be understood that while the sense and antisense strands are set forth in pairs in Table 2, the disclosure encompasses dsRNA agents comprising any sense strand and any antisense set forth in Table 2 (e.g., that are at least partially complementary (e.g., as could be determined by a person of ordinary skill in the art)). It is to be understood that while the nucleotide sequence of the sense strands and antisense strands in Table 2 are set forth as unmodified (not containing any modified nucleotides), the disclosure encompasses the sense and antisense sense strands set forthAttorney Docket No. 66504.26WO01 in Table 2 comprising one or more modified nucleotide (e.g., as described herein). An exemplary mRNA target sequence in ZBTB7A mRNA target sequence NM_015898.4 (SEQ ID NO: 2) is provided but is not intended to be limiting.Table 2. Unmodified Sense and Antisense Strand Sequences of ZBTB7A dsRNA Agents.Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01

[0296] The nucleotide sequence of exemplary preferred unmodified versions of the dsRNA agents set forth in Table 2 are set forth in Table 3. More specifically, Table 3 sets forth the nucleotide sequence of exemplary sense strands, antisense strands, and dsRNA agent pairs of sense and antisense strands that may be preferred in some embodiments.Table 3. Unmodified Sense and Antisense Strand Sequences of Exemplary PreferredAttorney Docket No. 66504.26WO01ZBTB7A dsRNA Agents.Attorney Docket No. 66504.26WO01

[0297] The nucleotide sequence of exemplary modified versions of the dsRNA agents set forth in Tabic 2 arc set forth in Table 4. More specifically, Table 4 sets forth the nucleotide sequence of exemplary sense strands, antisense strands, and dsRNA agent pairs of sense and antisense strands. It is to be understood that while the sense and antisense strands are set forth in pairs in Table 4, the disclosure encompasses dsRNA agents comprising any sense strand and any antisense set forth in Table 4 (e.g., that are at least partially complementary (e.g., as could be determined by a person of ordinary skill in the art)). It is to be understood that while the nucleotide sequence of the sense strands and antisense strands in Table 4 are set forth as modified (i.e., contain at least one modified nucleotide), the disclosure encompasses the sense and antisense sense strands set forth in Table 4 comprising other nucleotide modifications (e.g., as described herein) or that are unmodified. An exemplary mRNA target sequence in ZBTB7A mRNA target sequence NM_015898.4 (SEQ ID NO: 2) is provided but is not intended to be limiting.Table 4. Modified Sense and Antisense Strand Sequences of ZBTB7A dsRNA Agents.Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01

[0298] The nucleotide sequence of exemplary preferred modified versions of the dsRNA agents set forth in Table 4 are set forth in Table 5. More specifically, Table 5 sets forth the nucleotide sequence of exemplary sense strands, antisense strands, and dsRNA agent pairs of sense and antisense strands that may be preferred in some embodiments.Attorney Docket No. 66504.26WO01Table 5. Modified Sense and Antisense Strand Sequences of Exemplary Preferred ZBTB7A dsRNA Agents.Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01Attorney Docket No. 66504.26WO01

[0299] The nucleotide sequence presented in Table 4 and Table 5, utilize the following abbreviations set forth in Table 6.Table 6. Abbreviations of Nucleotide Modifications Utilized in Table 4 and Table 5.Attorney Docket No. 66504.26WO01

[0300] 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 agent as counterions for all of the phosphodiester or phosphorothioate groups present in the dsRNA agent.4.3 Modified RNAi Agents

[0301] In some embodiments, the 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.) 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 agent. For example, the modified 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 ZBTB7A mRNA)), or any combination thereof.4.3.1 Nature of Nucleotide Modifications

[0302] 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 moreAttorney Docket No. 66504.26WO01 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.

[0303] 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 is incorporated by reference herein for all purposes. Exemplary modifications are further provided in Hu, B., Zhong, L., Weng, Y. et al. Therapeutic siRNA: state of the art. Sig Transduct Target Ther S, 101 (2020). https: / / doi.org / 10.1038 / s41392-020-0207-x (e.g., Table 2), the entire contents of each of which is incorporated by reference herein for all purposes.4.3.1.1 Modified Nucleosides

[0304] In some embodiments, the modified agent (or any component thereof) (e.g., antisense strand, sense strand, dsRNA agent, 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

[0305] In some embodiments, the modified agent (or any component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more nucleotides comprising a modified sugar (e.g., ribose) moiety.

[0306] 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).

[0307] In some embodiments, the 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 agent, a group for improving the pharmacokinetic properties of the agent, or a group for improving the pharmacodynamic properties of the agent, an RNA cleaving group, a reporter group, an intercalator, or other substituents having similarAttorney Docket No. 66504.26WO01 properties.

[0308] Exemplary substituents include, for example, but arc 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)nOCH3, 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.

[0309] 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)).

[0310] In some embodiments, the 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 agent (or any component thereof) comprises a 2 '-methoxy ethoxy (2’-0 — CH2CH2OCH3, also known as 2'-O-(2-methoxyethyl) or 2'- MOE) (see, e.g., Martin et al., Helv. Chim. Acta, 1995, 78:486-504, the entire contents of which is incorporated by reference herein for all purposes) (i.e., an alkoxy-alkoxy group). In some embodiments, the agent (or any component thereof) comprises a 2'-dimethylaminooxyethoxy, i.e., a O(CH2)2ON(CH3)2group, also known as 2'-DMAOE; a 2 '-dimethylaminoethoxy ethoxy (also known in the art as 2'-O-dimethylaminoethoxyethyl or 2'-DMAEOE), i.e., 2'-0 — 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- methy lacetamide) .

[0311] Exemplary sugar (e.g., ribose) modifications include, but are not limited to, 2'-O- methyl (2'-0Me), 2'-O-methoxyethyl (2'-0-M0E), 2 'deoxy-2 '-fluoro (2'-F), 2'-arabine-fluro (2'- Ara-F), 2'-O-benzyl, 2'-O-methyl-4-pyridine (2'-O-CH2Py(4)), Locked Nucleic Acid (LNA), (S)- cEt-BNA, Tricyclo-DNA (tcDNA), PMO, Unlocked Nucleic Acid (UNA), Glycol Nucleic AcidAttorney Docket No. 66504.26WO01(also referred to as glycerol nucleic acid).

[0312] 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. Exemplary sugar modifications are further provided in Hu, B., Zhong, L., Weng, Y. et al. Therapeutic siRNA: state of the art. Sig Transduct Target Ther S, 101 (2020). https: / / doi.org / 10.1038 / s41392-020-0207-x {e.g., Table 2), the entire contents of each of which is incorporated by reference herein for all purposes.(a) Non-Bicyclic Sugar Modifications

[0313] 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.

[0314] 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.

[0315] 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,Attorney Docket No. 66504.26WO01 independently, H, an amino protecting group, or substituted or unsubstituted C1-C10 alkyl, or a 2'- substitucnt group described in any one of the following: Cook ct al., U.S. 6,531,584; Cook ct 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.

[0316] 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, OCH3, 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)2ON(CH3)2, O(CH2)2O(CH2)2N(CH3)2, and OCH2C(=O)-N(H)CH3(“NMA”). In some embodiments, a 2'- substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2'-substituent group selected from: F, OCH3, OCH2CH2OCH3, and OCH2C(=O)-N(H)CH3.

[0317] In some embodiments, non-bicyclic modified sugar moiety comprises a substituent group at the 3'-position of the sugar (e.g., ribose). Examples of substituent groups suitable for the 3 '-position of modified sugar moieties include but are not limited to alkoxy e.g., methoxy), alkyl (e.g., methyl, ethyl).

[0318] In some embodiments, non-bicyclic modified sugar moiety comprises a substituent group at the 4'-position of the sugar (e.g., ribose). Examples of 4'-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128.

[0319] In some embodiments, non-bicyclic modified sugar moiety comprises a substituent group at the 5 '-position of the sugar (e.g., ribose). Examples of substituent groups suitable for the 5 '-position of modified sugar moieties include, but are not limited to, vinyl (e.g., 5'-vinyl), alkoxy (e.g., methoxy (e.g., 5'-methoxy)), and alkyl (e.g., methyl (R or S) (e.g., 5'-methyl (R or S)), ethyl).

[0320] In some embodiments, non-bicyclic modified sugar moieties comprise more than oneAttorney Docket No. 66504.26WO01 non-bridging sugar substituent, for example, 2'-F-5'-methyl sugar moieties and the modified sugar moictics and modified nucleosides described in Migawa ct al., WO 2008 / 101157 and Rajccv ct al., US2013 / 0203836, the entire contents of each of which is incorporated herein by reference for all purposes.

[0321] In some embodiments, modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by isomeric configuration. For example, a 2'- deoxyfuranosyl sugar moiety may be in seven isomeric configurations other than the naturally occurring -D- deoxyribosyl configuration. Such modified sugar moieties are described in, e.g., WO 2019 / 157531, the entire contents of which are incorporated by reference herein for all purposes.

[0322] In some embodiments, the sugar (e.g., ribose) modification comprises an unlocked nucleotide (UNA). UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked sugar' (e.g., ribose) residue. For example, in some embodiments, the bonds between Cl'-C4' have been removed (i.e., the covalent carbon-oxygen- carbon bond between the Cl' and C4' carbons). In some embodiments, the C2'-C3' bond (i.e., the covalent carbon-carbon bond between the C2' and C3' carbons) of the sugar (e.g., ribose) have been removed. See, e.g., Nuc. Acids Symp. Series, 52, 133-134 (2008) and Fluiter et al., Mol. Biosyst., 2009, 10, 1039, the entire contents of which are incorporated herein by reference. UNAs and methods of making are known in the art. See, e.g., U.S. Pat. No. 8,314,227; and US2013 / 0096289; US2013 / 0011922; and US2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference.(b) Bicyclic Sugar Modifications

[0323] In some embodiments, the modified sugar (e.g., ribose) moiety comprises a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar (e.g., ribose) moiety (e.g., that locks the nucleic acid in one conformation) (locked nucleic acids (LNAs)). In some embodiments, the bicyclic sugar- (e.g., ribose) moiety comprises a bridge between the 4' and the 2' furanose ring atoms. Examples of such 4' to 2' bridging sugar substituents include but are not limited to: 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' (“LNA”), 4'-CH2- S-2', 4'-(CH2)2-O-2' (“ENA”), 4'-CH(CHri-O-2' (referred to as “constrained ethyl” or “cEf ’), 4'- CH2- O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CH2OCH3)-O-2' (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. 7,399,845, Bhat et al., U.S. 7,569,686, Swayze et al.,Attorney Docket No. 66504.26WO01U.S. 7,741 ,457, and Swayze et al., U.S. 8,022,193), 4'-C(CH3)(CH3)-O-2' and analogs thereof (see, e.g., Seth ct al., U.S. 8,278,283), 4'- CH2-N(OCH3)-2' and analogs thereof see, e.g., Prakash ct al., U.S. 8,278,425), 4'-CH2-O-N(CH3)-2' (see, e.g., Allerson et al., U.S. 7,696,345 and Allerson et al., U.S. 8,124,745), 4'-CH2-C(H)(CH3)-2' (see, e.g., Zhou, et al., J. Org. Chem.,2QQ9, 74, 118-134), 4'-CH2-C(=CH2)-2' and analogs thereof (see, e.g., Seth et al., U.S. 8,278,426), 4'-C(RaRb)-N(R)- 0-2', 4'-C(RaRb)-O-N(R)-2', 4'-CH2-O-N(R)-2', and 4'-CH2-N(R)-O-2', wherein each R, Ra, and Rb is, independently, H, a protecting group, or C1-C12 alkyl (see, e.g. Imanishi et al., U.S. 7,427,672). The entire contents of all of the foregoing references is incorporated by reference herein for all purposes.

[0324] In some embodiments, such 4' to 2' bridges independently comprise from 1 to 4 linked groups independently selected from: -[C(Ra)(Rb)]n-, -[C(Ra)(Rb)]n-O-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -C(=NRa)-, -C(=O)-, -C(=S)-, -O-, -Si(Ra)2-, -S(=O)X-, and -N(Ra)-; wherein: x is 0, 1, or 2; n is 1, 2, 3, or 4; each Raand Rb is, independently, H, a protecting group, hydroxyl, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)- H), substituted acyl, CN, sulfonyl (S(=0)2-Jl), or sulfoxyl (S(=O)-J1); and each JI and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, acyl (C(=O)- H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl, or a protecting group.

[0325] Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731- 7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastavaet al., J. Am. Chem. Soc., 2007, 129, 8362-8379;Wengel et a., U.S. 7,053,207; Imanishi et al., U.S. 6,268,490; Imanishi et al. U.S. 6,770,748; Imanishi et al., U.S. RE44,779; Wengel et al., U.S. 6,794,499; Wengel et al., U.S. 6,670,461; Wengel et al., U.S. 7,034,133; Wengel et al., U.S. 8,080,644; Wengel et al., U.S. 8,034,909; Wengel et al., U.S. 8,153,365; Wengel et al., U.S. 7,572,582; Ramasamy et al., U.S. 6,525,191; Torsten et al., WOAttorney Docket No. 66504.26WO012004 / 106356; Wengel et al., WO 1999 / 014226; Seth et al., WO 2007 / 134181 ; Seth et al., U.S. 7,547,684; Seth ct al., U.S. 7,666,854; Seth ct. al., U.S. 8,088,746; Seth et al., U.S. 7,750,131; Seth et al., U.S. 8,030,467; Seth et al., U.S. 8,268,980; Seth et al., U.S. 8,546,556; Seth et al., U.S. 8,530,640; Migawa et al., U.S. 9,012,421; Seth et al., U.S. 8,501,805; and U.S. Patent Publication Nos. Allerson et al., US2008 / 0039618 and Migawa et al., US2015 / 0191727. The entire contents of all of the foregoing references is incorporated by reference herein for all purposes.

[0326] In some embodiments, the modified sugar (e.g., ribose) comprises a constrained ethyl nucleotide comprising a 4'-CH(CH3) — O-2' bridge. In some embodiments, the constrained ethyl nucleotide is in the S conformation (S-cEt). In some embodiments, the modified sugar (e.g., ribose) comprises a conformationally restricted nucleotide (CRN). CRNs are nucleotide analogs with a linker connecting the C2' and C4' carbons of ribose or the C3 and — C5' carbons of ribose. Representative publications that teach the preparation of certain of the above include, but are not limited to, US2013 / 0190383; and WO2013 / 036868, the entire contents of each of which are hereby incorporated herein by reference.

[0327] In some embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the a-L configuration or in the -D configuration. Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example ot-L-ribofuranose and -D-ribofuranose (see, e.g., WO 99 / 14226, the entire contents of which are incorporated herein by reference for all purposes).

[0328] Additional representative U.S. Patents and U.S. Patent Publications that teach the preparation of bicyclic nucleosides e.g., locked nucleic acid) include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, the entire contents of each of which arc hereby incorporated herein by reference.(ii) Nucleobase Modifications

[0329] In some embodiments, the modified agent (or any component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more nucleotides comprising a modified nucleobase.Attorney Docket No. 66504.26WO01

[0330] As used herein, “unmodified” nucleobases refer to the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U). Modified nucleobases include other synthetic and natural nucleobases.

[0331] Exemplary nucleobase modifications, include, e.g., pseudouridine, 2'-thiouridine, N6'- methyladenosine, 5 '-methylcytidine, 5'-fluoro-2'-deoxyuridine, N-ethylpiperidine 7'-EAA triazole modified adenine, N-ethylpiperidine 6'-EAA triazole modified adenine, 6'-phenylpyrrolo- cytosine, 2',4'-difluorotoluyl ribonucleoside, and 5 '-nitroindole.

[0332] Further modified nucleobases include, but are not limited to, 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N- 6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 5- methylcytosine, 2-aminopropyladenine, 5-hydroxy methyl cytosine, xanthine, hypoxanthine, deoxythimidine (dT), 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2- propyladenine , 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (-C=C-CH3) uracil, 5- propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4- thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7- methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N- benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-Nbenzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine- 2-one, l,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-l,3-diazaphenoxazine-2-one (G- clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza- adenine, 7-deazaguanosine, 2- aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. 3,687,808; The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch el al., Angewandle Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, Crooke, S.T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S.T., Ed., CRC Press, 2008, 163-166 and 442-443; the entire contents of each of which is incorporated herein by reference for all purposes.Attorney Docket No. 66504.26WO01

[0333] In some embodiments, the modified nucleobase comprises a pseudouridine, 2'thiouridinc (s2U), N6'-mcthyladcnosinc, 5 'mcthylcy tidinc (m5C), 5 'fluoro-2 'deoxy uridine, N- ethylpiperidine 7-EAA triazole modified adenine, N-ethylpiperidine 6'triazole modified adenine, 6-phenylpyrrolo-cytosine (PhpC), 2',4'-difluorotoluyl ribonucleoside (rF), or 5 'nitroindole. In some embodiments, the modified nucleobase comprises a 5-substituted pyrimidine; 6- azapyrimidine; or N-2, N-6 and 0-6 substituted purines (including 2-aminopropyladenine, 5- propynyluracil and 5-propynylcytosine). 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2'-O-methoxyethyl sugar modifications.

[0334] Representative U.S. Patents an published applications that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, U.S. Pat. Nos. 3,687,808, 4,845,205; 5,130,30; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540;5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,681,941; 5,750,692; 6,015,886; 6,147,200;6,166,197; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610;7,427,672; 7,495,088; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257;5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; U.S. 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470;5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,166,199; and 6,005,096, the entire contents of each of which is hereby incorporated herein by reference for all purposes. Exemplary nucleobase modifications are further provided in Hu, B., Zhong, L., Weng, Y. et al. Therapeutic siRNA: state of the art. Sig Transduct Target Ther S, 101 (2020). https: / / doi.org / 10.1038 / s41392-020-0207-x (e.g., Table 2), the entire contents of each of which is incorporated by reference herein for all purposes.4.3.1.2 Internucleoside Linkage Modifications

[0335] In some embodiments, the modified agent (or any component thereof) (e.g., antisense strand, sense strand, dsRNA agent, etc.) comprises one or more modified internucleoside linkage. Modified internucleoside linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of an agent (e.g., described herein).Attorney Docket No. 66504.26WO01

[0336] The naturally occurring internucleoside linkage of RNA and DNA is a 3' to 5' phosphodicstcr linkage. In some embodiments, the modified intcrnuclcosidc linkage contains a normal 3'-5' linkage. In some embodiments, the modified intemucleoside linkage contains a 2'-5' linkage. In some embodiments, the modified intemucleoside linkage has an inverted polarity wherein the adjacent pairs of nucleoside units are linked e.g., 3'-5' to 5'-3' or 2'-5' to 5'-2'.

[0337] The two main classes of modified intemucleoside linking can be defined by the presence or absence of a phosphorous atom.

[0338] Exemplary intemucleoside linkage modifications are further provided in Hu, B., Zhong, L., Weng, Y. et al. Therapeutic siRNA: state of the art. Sig Transduct Target Ther 5, 101 (2020). https: / / doi.org / 10.1038 / s41392-020-0207-x (e.g., Table 2), the entire contents of each of which is incorporated by reference herein for all purposes.(i) Modified Phosphorous Containing Internucleoside Linkages

[0339] In some embodiments, the modified intemucleoside linkage comprises a phosphorous atom. Representative modified phosphorus-containing intemucleoside linkages include but are not limited to phosphorothioates (PS (Rp isomer or Sp isomer)) (e.g., 5'phosphorothioate), phosphotriesters, phosphoramidates (e.g., 3'-amino phosphoramidate and aminoalky Iphosphoramidates), chiral phosphorothioates, phosphorodithioates (PS2), aminoalkylphosphotriesters, methyl and other alkyl phosphonates (e.g., methylphosphonate (MP), 3'-alkylene phosphonates), methpxypropyl-phosphonates (MOP), 5'-(E)-vinylphosphonates, 5'methyl phosphonates, (S)-5'C-methyl with phosphates, phosphinates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, boranophosphates, and peptide nucleic acids (PNAs).

[0340] In some embodiments, the modified internucleoside linkage comprises phosphorothioates (PS (Rp isomer or Sp isomer)) (e.g., 5'phosphorothioate), phosphorodithioates, methylphosphonate, methpxypropyl-phosphonate, 5'-(E)-vinylphosphonate, 5'methyl phosphonate, (S)-5'C-methyl with phosphate, phosphinate, or a peptide nucleic acid.

[0341] Methods of preparing polynucleotides containing one or more modified phosphorus- containing intemucleoside linkage are known in the ail. See, e.g., U.S. Pat. Nos. 3,687,808;4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302;5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925;5,519,126; 5,536,821; 5,541,316; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050;Attorney Docket No. 66504.26WO016,028,188; 6,124,445; 6,160,109; 6, 169,170; 6,172,209; 6, 239,265; 6,277,603; 6,326,199; 6,346,614; 6,444,423; 6,531,590; 6,534,639; 6,608,035; 6,683,167; 6,858,715; 6,867,294; 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and U.S. Pat. RE39464, the entire contents of each of which are hereby incorporated herein by reference for all purposes. Exemplary modifications are further provided in Hu, B., Zhong, L., Weng, Y. et al. Therapeutic siRNA: state of the art. Sig Transduct Target Ther S, 101 (2020). https: / / doi.org / 10.1038 / s41392-020-0207-x e.g., Table 2), the entire contents of each of which is incorporated by reference herein for all purposes.(ii) Modified Non-Phosphorous Containing Internucleoside Linkages

[0342] In some embodiments, the modified intemucleoside linkage does not contain a phosphorous atom. Modified internucleoside linkages that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl intemucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar- portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S, and CHi component parts.

[0343] Representative non-phosphorous containing intemucleoside linking groups include but are not limited to methylenemethylimino (-CH2-N(CH3)-O-CH2-), thiodiester, thionocarbamate (- O-C(=O)(NH)-S-); siloxane ( O-SiH -O ); and N,N'-dimethylhydrazine (-CH2-N(CH3)-N(CH3)-).

[0344] Methods of preparing polynucleotides comprising modified intemucleoside linkages do not contain a phosphorous atom are known in the art. See, e.g., U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439, the entire contents of each of which are hereby incorporated herein by reference.4.3.1.3 Additional Exemplary Nucleotide Modifications

[0345] In some embodiments, the modified agent comprises one or more RNA mimetic in which both the sugar and the intemucleoside linkage of the nucleotide units are replaced with novelAttorney Docket No. 66504.26WO01 groups. The nucleobase units are maintained for hybridization with an appropriate nucleic acid target (e.g., a target mRNA). In some embodiments, the RNA mimetic is a peptide nucleic acid (PNA). In PNAs, the ribose moiety of the RNA nucleotide is replaced with an amide containing moiety (e.g., an aminoethylglycine). The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide. Representative US patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, the entire contents of each of which are hereby incorporated herein by reference. Additional PNA compounds suitable for use in the agents described herein are described in, for example, in Nielsen et al., Science, 1991, 254, 1497-1500, the entire contents of which is incorporated by reference herein for all purposes.

[0346] Potentially stabilizing modifications to the terminal ends of the agents (e.g., described herein) can also be incorporated to agents described herein. For example, N-(acetylaminocaproyl)- 4-hydroxyprolinol (Hyp-C6-NHAc), N-(caproyl-4-hydroxyprolinol (Hyp-C6), N-(acetyl-4- hydroxyprolinol (Hyp-NHAc), thy midine-2'-O-deoxy thymidine (ether), N-(aminocaproyl)-4- hydroxyprolinol (Hyp-C6-amino), 2-docosanoyl-uridine-3''-phosphate, inverted base dT(idT) and others. Such modifications are known in the art. See, e.g., WO2011 / 005861, the entire contents of which is incorporated herein by reference.4.3.2 Extent of Modified Nucleotides

[0347] In some embodiments, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the agent (or any component (e.g., nucleic acid molecule) thereof) (e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent) are modified. In some embodiments, about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the agent (or any component (e.g., nucleic acid molecule) thereof) (e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) are modified. In some embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 of the nucleotides of the agent (or any component (e.g., nucleic acid molecule) thereof) (e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) are modified. In some embodiments, substantially all of the nucleotides of the agent (or any component (e.g., nucleic acid molecule) thereof) (e.g.,Attorney Docket No. 66504.26WO01 described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) are modified. In some embodiments, all of the nucleotides of the agent (or any component e.g., nucleic acid molecule) thereof) (e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) are modified.

[0348] 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 and / or antisense strand are modified. For example, at least 50% of the nucleotides of ...

Claims

Attorney Docket No. 66504.26WO01CLAIMSWhat is claimed is:

1. A double stranded RNA (dsRNA) agent for inhibiting expression of zinc finger and BTB domain containing 7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein(a) the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 1245; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 368.

2. A dsRNA agent for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 or set forth in any one of SEQ ID NOS: 725-1264.

3. The dsRNA agent of claim 2, wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Tables 2-5 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

4. The dsRNA agent of claim 2 or 3, wherein the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 or set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in any one of Tables 2-5 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

5. The dsRNA agent of any one of claims 2-4, wherein the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 or set forth in any one of SEQ ID NOS: 725-1264; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding senseAttorney Docket No. 66504.26WO01 strand set forth in any one of Tables 2-5 or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

6. A dsRNA agent for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in Tables 2-5; and the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Tables 2-5.

7. The dsRNA agent of claim 6, wherein the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-485 set forth in Tables 2-5; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Tables 2-5.

8. A dsRNA agent for inhibiting expression of ZBTB7A (e.g., human ZBTB7A (hZBTB7A)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2- 5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 725-1264.

9. The dsRNA agent of claim 8, wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from any sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 4-759.

10. The dsRNA agent of claim 8 or 9, wherein the sense strand comprises at least 15 (e.g.,16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3,Attorney Docket No. 66504.26WO014, or 5) nucleotides from the corresponding sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

11. A dsRNA agent for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5 (e.g., Table 3 or 5); and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in any one of Tables 2-5 (e.g., Table 3 or 5).

12. The dsRNA agent of claim 11, wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

13. A dsRNA agent for inhibiting expression of ZBTB7A (e.g., human ZBTB7A (hZBTB7A)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 725-1264.

14. The dsRNA agent of claim 13, wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from any sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or set forth in any one of SEQ ID NOS: 4-759.

15. The dsRNA agent of claim 13 or 14, wherein the sense strand comprises at least 15 (e.g.,16. 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, orAttorney Docket No. 66504.26WO013) nucleotides from the corresponding sense strand set forth in any one of Tables 2-5 (e.g., Table 3 or 5) or the corresponding sense strand set forth in one of SEQ ID NOS: 4-759.

16. A dsRNA agent for inhibiting expression of ZBTB7A (e.g., hZBTB7A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strands of any one of dsRNA agents 1-485 set forth in any one of Tables 2-5; and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in any one of Tables 2-5.

17. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.

18. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified nucleotide and the antisense strand comprises at least one modified nucleotide.

19. The dsRNA agent of any one of the preceding claims, 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.

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

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

22. The dsRNA agent of any one of the preceding claims, wherein at least one of the modified nucleotides comprises a modified nucleobase.

23. The dsRNA agent of any one of the preceding claims, wherein at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety) and a modified nucleobase.Attorney Docket No. 66504.26WO0124. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified intcrnuclcosidc linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

25. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified internucleoside linkage and the antisense strand comprises at least one modified intemucleoside linkage.

26. The dsRNA agent of any one of the preceding claims, 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.

27. The dsRNA agent of any one of the preceding claims, 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, 19-3020-30, 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.

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

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

30. The dsRNA agent of any one of the preceding claims, wherein antisense strand consists of 23 nucleotides; and the sense strand consists of 21 nucleotides.

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

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

33. The dsRNA agent of any one of the preceding claims, 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.Attorney Docket No. 66504.26WO0134. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length.

35. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is about 21 nucleotide pairs in length.

36. The dsRNA agent of any one of the preceding claims, 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.

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

38. A conjugate comprising the dsRNA agent of any one of claims 1-37 and a heterologous moiety.

39. The conjugate of claim 38, wherein the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

40. The conjugate of claim 39, wherein the heterologous moiety is a protein.

41. The conjugate of claim 40, wherein the protein specifically binds to a moiety expressed by a hematopoietic cell (e.g., on the surface of a hematopoietic cell).

42. The conjugate of claim 40 or 41, wherein the protein specifically binds to a moiety expressed by an erythroid precursor cell (e.g., on the surface of an erythroid precursor cell).

43. The conjugate of any one of claims 40-42, wherein the protein specifically binds the transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)).

44. The conjugate of any one of claims 40-43, wherein the protein is an antibody.

45. The conjugate of claim 44, wherein the antibody comprises or consists of a full-length antibody, a Fab, a Fab', a F(ab')2, a Fab-Fc, a scFv, a scFv-Fc, a (scFv)2-Fc, an Fv, a single domain antibody (sdAb) (e.g., a VHH), a sdAb-Fc (e.g., a VHH-Fc), a (sdAbh (e.g., a (VHHh), or a (sdAb) -Fc (e.g., a (VHH)2-Fc).

46. The conjugate of any one of claims 44-45, wherein the antibody comprises or consists of a full-length antibody, a Fab-Fc, a scFv-Fc, a (scFv)2-Fc, a sdAb-Fc (e.g., a VHH-Fc), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc).

47. The conjugate of any one of claims 44-46, wherein the antibody is an IgG (e.g., a human IgG (hlgG)) antibody.Attorney Docket No. 66504.26WO0148. The conjugate of any one of claims 44-47, wherein the antibody is a hlgGl , h!gG2, h!gG3, or h!gG4 antibody (e.g., a hlgGl or h!gG4 antibody).

49. The conjugate of any one of claims 44-48, wherein the antibody comprises an immunoglobulin (Ig) (e.g., a human Ig (hlg)) Fc region.

50. The conjugate of any one of claims 44-49, wherein the Ig (e.g., hlg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region.

51. The conjugate of any one of claims 44-50, wherein the Ig (e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region.

52. The conjugate of any one of claims 44-51 , wherein the Ig is a hlg.

53. The conjugate of claim 52, wherein the hlg is a human IgG (hlgG).

54. The conjugate of claim 53, wherein the hlgG is hlgGl or hIgG4.

55. The conjugate of any one of claims 44-54, wherein the Ig (e.g., hlg) Fc region comprises one or more amino acid substitutions relative to a reference Ig (e.g., hlg) Fc region that reduces or abolishes one or more of the following effector functions relative to the reference hlg Fc region: antibody dependent cell mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and / or affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla))).

56. The conjugate of any one of claims 44-55, wherein the antibody does not (or does not substantially) block binding of TF (e.g., hTF) to the TFR (e.g., hTFRl).

57. The conjugate of claim 40, wherein the protein is a TFR ligand (or a functional fragment or functional variant thereof).

58. The conjugate of claim 57, wherein the TFR ligand comprises transferrin (TF) (e.g., human transferrin (hTF)) (or a functional fragment or functional variant thereof).

59. The conjugate of any one of claims 38-58, wherein the heterologous moiety is a targeting moiety.

60. The conjugate of claim 59, wherein the targeting moiety specifically binds to a moiety expressed by a hematopoietic cell (e.g., on the surface of a hematopoietic cell).

61. The conjugate of claim 59 or 60, wherein the targeting moiety specifically binds to a moiety expressed by an erythroid precursor cell (e.g., on the surface of an erythroid precursor cell).Attorney Docket No. 66504.26WO0162. The conjugate of any one of claims 59-61 , wherein the targeting moiety specifically binds TFR (e.g., hTFR (e.g., hTFRl)).

63. The conjugate of any one of claims 59-62, wherein the targeting moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

64. The conjugate of claim 63, wherein the targeting moiety is a protein.

65. The conjugate of claim 64, wherein the targeting moiety is an antibody.

66. The conjugate of claim 65, wherein the antibody comprises or consists of a full-length antibody, a Fab, a Fab', a F(ab')2, a Fab-Fc, a scFv, a scFv-Fc, a (scFv) -Fc, an Fv, a single domain antibody (sdAb) (e.g., a VHH), a sdAb-Fc (e.g., a VHH-Fc), a (sdAb (e.g., a (VHH ), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc).

67. The conjugate of any one of claims 65-66, wherein the antibody comprises or consists of a full-length antibody, a Fab-Fc, a scFv-Fc, a (scFv)2-Fc, a sdAb-Fc (e.g., a VHH-Fc), or a (sdAb)2-Fc (e.g., a (VHH)2-Fc).

68. The conjugate of any one of claims 65-67, wherein the antibody is an IgG (e.g., a human IgG (hlgG)) antibody.

69. The conjugate of any one of claims 65-68, wherein the antibody is a hlgGl, h!gG2, h!gG3, or h!gG4 antibody (e.g., a hlgGl or h!gG4 antibody).

70. The conjugate of any one of claims 65-69, wherein the antibody comprises an immunoglobulin (Ig) (e.g., a human Ig (hlg)) Fc region.

71. The conjugate of any one of claims 65-70, wherein the Ig (e.g., hlg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region.

72. The conjugate of any one of claims 65-71, wherein the Ig (e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region.

73. The conjugate of any one of claims 65-72, wherein the Ig is a hlg.

74. The conjugate of claim 73, wherein the hlg is a human IgG (hlgG).

75. The conjugate of claim 74, wherein the hlgG is hlgGl or hIgG4.

76. The conjugate of any one of claims 65-75, wherein the Ig (e.g., hlg) Fc region comprises one or more amino acid substitutions relative to a reference Ig (e.g., hlg) Fc region that reduces or abolishes one or more of the following effector functions relative to the reference hlg Fc region: antibody dependent cell mediated cytotoxicity (ADCC), complement dependentAttorney Docket No. 66504.26WO01 cytotoxicity (CDC), and / or affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, Fey R lie, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla))).

77. The conjugate of any one of claims 65-76, wherein the antibody does not (or does not substantially) block binding of TF (e.g., hTF) to the TFR (e.g., hTFRl).

78. The conjugate of claim 64, wherein the targeting moiety is a TFR ligand (or a functional fragment or functional variant thereof).

79. The conjugate of claim 78, wherein the TFR ligand comprises transferrin (TF) (e.g., human transferrin (hTF)) (or a functional fragment or functional variant thereof).

80. The conjugate of any one of claims 38-79, wherein the conjugate exhibits one or more of the following properties: (a) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce death of the target cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the hematopoietic cell remains viable; (c) upon internalization into a hematopoietic cell, the conjugate does not induce death of the hematopoietic cell; and / or (d) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)).

81. The conjugate of any one of claims 38-80, wherein the conjugate exhibits one or more of the following properties: (a) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate is internalized into the hematopoietic cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce death of the target cell; (c) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the hematopoietic cell remains viable; (d) upon internalization into a hematopoietic cell, the conjugate does not induce death of the hematopoietic cell; and / or (e) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)).

82. The conjugate of any one of claims 38-81, wherein the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) exhibits one or more of the following properties: (a) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate is internalized into the hematopoietic cell; (b) upon binding to TFRAttorney Docket No. 66504.26WO01(e.g., hTFR (e.g., TFR1 )) expressed on the surface of a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate docs not induce death of the target cell; (c) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the hematopoietic cell remains viable; (d) upon internalization into a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate does not induce death of the hematopoietic cell; and / or (e) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a hematopoietic cell, the protein (e.g., an antibody) that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) or conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)).

83. The conjugate of any one of claims 38-82, wherein the heterologous moiety is attached to the dsRNA agent via a linker.

84. The conjugate of claim 83, wherein the linker is cleavable.

85. The conjugate of any one of claims 38-84, 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.

86. 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 1-37.

87. A carrier comprising the dsRNA agent of any one of claims 1-37, the conjugate of any one of claims 38-85, or the vector of claim 86.

88. The carrier of claim 87, wherein the carrier comprises a nanoparticle, a polymer, a lipid- based delivery system, as dendrimer, a cationic delivery system, or a hydrogel.

89. The carrier of claim 88, wherein the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

90. A cell comprising the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, or the carrier of any one of claims 87-89.

91. A pharmaceutical composition comprising the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87- 89, or the cell of claim 90, and a pharmaceutically acceptable excipient.

92. A kit comprising the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, the cell of claim 90, or the pharmaceutical composition of claim 91.Attorney Docket No. 66504.26WO0193. A method of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.

94. The method of claim 93, wherein the cell is in vitro, ex vivo, or in vivo.

95. The method of claim 93 or 94, wherein the cell is a subject (e.g., a human subject).

96. A method of delivering a dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, the cell of claim 90, or the pharmaceutical composition of claim 91, to thereby deliver the dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to the subject.

97. A method of reducing or inhibiting expression of ZBTB7A (e.g., hZBTB7A) in a cell, the method comprising delivering into the cell the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby reduce or inhibit expression of ZBTB7A (e.g., hZBTB7A) in the cell.

98. A method of reducing or inhibiting expression of ZBTB7A (e.g., hZBTB7A) in a cell in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1- 37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby reduce or inhibit expression of ZBTB7A (e.g., hZBTB7A) in the cell in the subject.

99. A method of treating, ameliorating, or preventing a ZBTB7A (e.g., hZBTB7A) associated disease in a subject, the method comprising administering to the dsRNA of any one of claims 1- 37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby treat, ameliorate, or prevent the ZBTB7A (e.g., hZBTB7A) associated disease in the subject.

100. The method of claim 99, wherein ZBTB7A associated disease is an inherited blood disorder.

101. The method of claim 100, wherein the inherited blood disorder is a hemoglobinopathy.Attorney Docket No. 66504.26WO01102. The method of claim 101 , wherein the hemoglobinopathy is sickle cell disease, sickle cell trait, hemoglobin C disease, hemoglobin C trait, hemoglobin S / C disease, hemoglobin D disease, hemoglobin E disease, a thalassemia (e.g., a-thalassemia, P-thalassemia, 8-thalassemia, or y- thalassemia), a condition associated with hemoglobin with increased oxygen affinity, a condition associated with hemoglobin with decreased oxygen affinity, unstable hemoglobin disease, or methemoglobinemia.

103. The method of claim 100, wherein the inherited blood disorder is an inherited bone marrow failure syndrome.

104. The method of claim 103, wherein the inherited bone marrow failure syndrome is amegakaryocytic thrombocytopenia (Amega), diamond blackfan anemia (DBA), dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, severe congenital neutropenia (SCN), Schwachman diamond syndrome (SDS), GATA2 deficiency, cyclic neutropenia, Dubowitz syndrome, Kostmann syndrome, refractory cytopenia, thrombocytopenia absent radii (TAR), a SAMD9 / SAMD9E disorder, or a MECOM-associated syndrome.

105. A method of treating, ameliorating, or preventing an inherited blood disorder in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the earner of any one of claims 87- 89, or the pharmaceutical composition of claim 91, to thereby treat, ameliorate, or prevent the inherited blood disorder in the subject.

106. The method of claim 105, wherein the inherited blood disorder is a hemoglobinopathy.

107. The method of claim 106, wherein the hemoglobinopathy is sickle cell disease, sickle cell trait, hemoglobin C disease, hemoglobin C trait, hemoglobin S / C disease, hemoglobin D disease, hemoglobin E disease, a thalassemia (e.g., a-thalassemia, P-thalassemia, 8-thalassemia, or y- thalassemia), a condition associated with hemoglobin with increased oxygen affinity, a condition associated with hemoglobin with decreased oxygen affinity, unstable hemoglobin disease, or methemoglobinemia.

108. A method of treating, ameliorating, or preventing a hemoglobinopathy in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87- 89, or the pharmaceutical composition of claim 91, to thereby treat, ameliorate, or prevent the hemoglobinopathy in the subject.Attorney Docket No. 66504.26WO01109. The method of claim 108, wherein the hemoglobinopathy is sickle cell disease, sickle cell trait, hemoglobin C disease, hemoglobin C trait, hemoglobin S / C disease, hemoglobin D disease, hemoglobin E disease, a thalassemia (e.g., ot-thalassemia, P-thalassemia, 8-thalassemia, or y- thalassemia), a condition associated with hemoglobin with increased oxygen affinity, a condition associated with hemoglobin with decreased oxygen affinity, unstable hemoglobin disease, or methemoglobinemia.

110. A method of treating, ameliorating, or preventing an inherited bone marrow failure syndrome in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby treat, ameliorate, or prevent the inherited bone marrow failure syndrome in the subject.

111. The method of claim 110, wherein the inherited bone marrow failure syndrome is amegakaryocytic thrombocytopenia (Amega), diamond blackfan anemia (DBA), dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, severe congenital neutropenia (SCN), Schwachman diamond syndrome (SDS), GATA2 deficiency, cyclic neutropenia, Dubowitz syndrome, Kostmann syndrome, refractory cytopenia, thrombocytopenia absent radii (TAR), a SAMD9 / SAMD9E disorder, or a MECOM-associated syndrome.

112. A method of inducing expression of fetal hemoglobin in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby induce expression of fetal hemoglobin the subject.

113. A method of increasing the level of fetal hemoglobin in a subject, the method comprising administering to the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87-89, or the pharmaceutical composition of claim 91, to thereby increase the level of fetal hemoglobin the subject.

114. A method of increasing the ratio of fetal hemoglobin to adult hemoglobin in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-37, the conjugate of any one of claims 38-85, the vector of claim 86, the carrier of any one of claims 87- 89, or the pharmaceutical composition of claim 91, to thereby increase the ratio of fetal hemoglobin to adult hemoglobin in the subject.Attorney Docket No. 66504.26WO01115. The method of any one of claims 93-1 14, wherein the subject is a human.