RNAI agents targeting JAK2 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 JAK2 (including, e.g., JAK2 gain of function variants (e.g., JAK2-V617F)) and conjugates comprising the same (e.g., TFR targeting conjugates). The disclosure further relates to pharmaceutical compositions comprising the same; and methods of utilizing the same, including, e.g., methods of treating JAK2 mediated diseases (e.g., JAK2 gain of function mediated diseases (JAK2-V617F mediated diseases)).

Description

Attorney Docket No. 66504.13WO01RNAI AGENTS TARGETING JAK2 AND RELATED METHODS RELATED APPLICATIONS

[0001] This application claims priority to U.S. Serial No.: 63 / 746.932, filed January 18, 2025, the entire contents of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 12, 2026, is named 66504_13WO0l_SL.xml and is 1,187,167 bytes in size.1. FIELD

[0003] This disclosure relates to RNAi agents (e.g., double stranded RNA (dsRNA) agents comprising a sense strand and an antisense strand) targeting Janus kinase 2 (JAK2) (including, e.g., JAK2 gain of function variants (e.g., JAK2-V617F)) and conjugates comprising the same (e.g., TFR targeting conjugates). The disclosure further relates to pharmaceutical compositions comprising the same; and methods of utilizing the same, including, e.g., methods of treating JAK2 mediated diseases (e.g., JAK2 gain of function mediated diseases (JAK2-V617F mediated diseases)).2. BACKGROUND

[0004] JAK2 is a is a member of the Janus kinase family, which comprises four main members, JAK1, JAK2, JAK3, and TYK2. JAK2 is a non-receptor tyrosine kinase that, inter alia, mediates signaling through the JAK / STAT signaling pathway. JAK2 functions in various cellular processes, including, but not limited to, cell growth, differentiation, proliferation, and survival. JAK2 further mediates signaling events in both innate and adaptive immunity, including roles in both cytokine and growth factor signalling. Unlike other tyrosine kinases, JAK2 has only a catalytic domain without an Src homology 2 (SH2) domain, which enables it to phosphorylate not only receptors e.g., cytokine receptors) that bind to it but also multiple signaling molecules containing SH2 domains.Attorney Docket No. 66504.13WO013. SUMMARY

[0005] Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting JAK2 (e.g., a JAK2 gain of function variant (e.g., JAK2-V617F)); conjugates (e.g., TFR targeting conjugates) comprising the same; and methods of manufacturing and pharmaceutical compositions comprising any of the foregoing. Further provided herein are methods of utilizing the agents e.g., RNAi agents, dsRNA agents, conjugates, etc.) including, e.g., methods of inhibiting or reducing JAK2 (e.g., a JAK2 gain of function variant (e.g., JAK2-V617F)) expression (e.g., mRNA expression, protein expression), methods of treating JAK2 (e.g., JAK2 gain of function variant (e.g., JAK2-V617F)) mediated diseases (including, e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis).

[0006] Accordingly, in one aspect provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of JAK2-V617F, 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 Table 2 or Table 14 or set forth in any one of SEQ ID NOS: 311-348 or 391-411.

[0007] 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 Table 2 or Table 14 or set forth in any one of SEQ ID NOS: 273-310 or 349-390. 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 Table 2 or Table 14 or the corresponding sense strand set forth in one of SEQ ID NOS: 273-310 or 349-390.

[0008] In one aspect, provided herein are dsRNA agents for inhibiting expression of JAK2-V617F. 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 1-84 set forth in Table 2 or Table 14; 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,Attorney Docket No. 66504.13WO012, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2 or Table 14.

[0009] In one aspect, provided herein are dsRNA agents for inhibiting expression of JAK2-V617F, 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 set forth in SEQ ID NO: 311; 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 set forth in SEQ ID NO: 273: 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 SEQ ID NO: 312; 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 set forth in SEQ ID NO: 274; 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 SEQ ID NO: 313; 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 set forth in SEQ ID NO: 275; 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 SEQ ID NO: 314; 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 set forth in SEQ ID NO: 276; or 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 SEQ ID NO: 315; 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 set forth in SEQ ID NO: 277.

[0010] In one aspect, provided herein are dsRNA agents for inhibiting expression of JAK2-V617F, 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 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 311; 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 set forth in SEQ ID NO: 273; 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 SEQ ID NO: 312; 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 set forth in SEQ IDAttorney Docket No. 66504.13WO01NO: 274; 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 SEQ ID NO: 313; 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 set forth in SEQ ID NO: 275; 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 SEQ ID NO: 314; 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 set forth in SEQ ID NO: 276; or 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 SEQ ID NO: 315; 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 set forth in SEQ ID NO: 277.

[0011] In one aspect, provided herein are dsRNA agents for inhibiting expression of JAK2-V617F, 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 comprises the nucleotide sequence set forth in SEQ ID NO: 311; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 273; the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 312; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 274; the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 313; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 275; the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 314; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 276; or the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 315; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 277.

[0012] In one aspect, provided herein are dsRNA agents for inhibiting expression of Janus kinase 2 V617F (JAK2-V617F), 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 comprises the nucleotide sequence set forth in SEQ ID NO: 391; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ IDAttorney Docket No. 66504.13WO01NO: 349; the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 392; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 350; the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 393; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 351; the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 394; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 352; or the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 395; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 353.

[0013] In one aspect, provided herein are dsRNA agents for inhibiting expression of JAK2-V617F, 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 set forth in SEQ ID NO: 391; 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 set forth in SEQ ID NO: 349; 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 SEQ ID NO: 392; 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 set forth in SEQ ID NO: 350; 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 SEQ ID NO: 393; 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 set forth in SEQ ID NO: 351; 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 SEQ ID NO: 394; 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 set forth in SEQ ID NO: 352; or 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 SEQ ID NO: 395; 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 set forth in SEQ ID NO: 353.

[0014] In one aspect, provided herein are dsRNA agents for inhibiting expression of JAK2-Attorney Docket No. 66504.13WO01V617F, 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 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 391; 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 set forth in SEQ ID NO: 349; 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 SEQ ID NO: 392; 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 set forth in SEQ ID NO: 350; 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 SEQ ID NO: 393; 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 set forth in SEQ ID NO: 351; 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 SEQ ID NO: 394; 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 set forth in SEQ ID NO: 352; or 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 SEQ ID NO: 395; 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 set forth in SEQ ID NO: 353.

[0015] It should be understood that each of the following embodiments can be applicable to each of the foregoing aspects as if recited directly after each if the foregoing aspects.

[0016] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide. In some embodiments, 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.

[0017] In some embodiments, wherein substantially all (or all) of the nucleotides in the sense strand and / or antisense strand are modified.

[0018] In some embodiments, wherein at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).

[0019] In some embodiments, wherein (a) the sense strand comprises at least one 2'-O-methyl and / or the antisense strand comprises at least one 2'-O-methyl and / or (b) the sense strandAttorney Docket No. 66504.13WO01comprises at least one 2'-deoxy-2'-fluoro and / or the antisense strand comprises at least one 2'-deoxy-2'-fluoro.

[0020] In some embodiments, wherein (a) the sense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro; and the antisense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro.

[0021] In some embodiments, wherein at least one of the modified nucleotides comprises a modified nucleobase.

[0022] In some embodiments, wherein the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified internucleoside linkage.

[0023] In some embodiments, wherein the antisense strand comprises at least one vinyl-phosphonate. In some embodiments, wherein the antisense strand comprises a 5' vinyl-phosphonate. In some embodiments, wherein the sense strand comprises at least one vinyl-phosphonate-2'-0-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine) and / or the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine) (e.g., wherein the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine). In some embodiments, wherein the antisense strand comprises a 5' vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine). In some embodiments, wherein the antisense strand comprises an (E)-vinylphosphonate 2'-O-methylated (2’-0me) uridine at the 5’ end.

[0024] In some embodiments, wherein the sense strand comprises at least one phosphorothioate and / or the antisense strand comprises at least one phosphorothioate. In some embodiments, wherein the sense strand comprises at least one phosphorothioate and the antisense strand comprises at least one phosphorothioate.

[0025] In some embodiments, 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. In some embodiments, 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, 26-30, 27-30, 28-3029-30, 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, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, wherein antisenseAttorney Docket No. 66504.13WO01strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. In some embodiments, wherein antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

[0026] In some embodiments, wherein the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides. In some embodiments, wherein the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides (e.g., 2 nucleotides). In some embodiments, 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. In some embodiments, wherein the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length. In some embodiments, wherein the double stranded region is about 21 nucleotide pairs in length.

[0027] In some embodiments, 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). In some embodiments, wherein the sense strand and the antisense strand are separate nucleic acid molecules (z.e., connected only through the double stranded region).

[0028] In some embodiments, wherein the dsRNA agent selectively inhibits the expression and / or activity of JAK2-V617F. In some embodiments, wherein the dsRNA agent selectively inhibits the expression and / or activity of IAK2-V617F relative to wild-type JAK.2. In some embodiments, wherein the dsRNA agent preferentially inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2. In some embodiments, wherein the dsRNA agent exhibits greater inhibition of the expression and / or activity of JAK2-V617F relative to wild-type JAK2. In some embodiments, the dsRNA agent does not (or does not substantially) inhibit the expression and / or activity of wild-type JAK2. In some embodiments, the dsRNA agent inhibits the expression and / or activity of JAK2-V617F through binding to an mRNA molecule encoding JAK2-V617F. In some embodiments, the dsRNA agent inhibits the expression and / or activity of JAK.2-V617F through selectively binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2. In some embodiments, the dsRNA agent inhibits the expression and / or activity of JAK2-V617F through preferentially binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.Attorney Docket No. 66504.13WO01

[0029] In some embodiments, the dsRNA agent mediates one or more of the following degradation of the mRNA molecule, modification of the mRNA molecule, alteration in the splicing of the mRNA molecule, alteration (e.g., a decrease) in the stability of the mRNA molecule, or a block in the translation of the target mRNA molecule, or any combination of the foregoing.

[0030] In one aspect, provided herein are conjugates comprising a dsRNA agent described herein operably connected to a heterologous moiety.

[0031] In some embodiments, the heterologous moiety is a protein, peptide, small molecule, carbohydrate, lipid, or polymer. In some embodiments, the heterologous moiety is a protein. In some embodiments, the protein is an antibody. In some embodiments, the heterologous moiety comprises a means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)).

[0032] In one aspect, provided herein are conjugates comprising a dsRNA agent described herein operably connected to a means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)). In some embodiments, the means for binding to TFR (e.g., human TFR (hTFR) (e.g., hTFRl)) is a protein. In some embodiments, the means for binding to TFR (e.g., human TFR (hTFR) (e.g., hTFRl)) is an antibody (e.g., an antibody described herein).

[0033] In one aspect, provided herein are conjugates comprising: a means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)); operably connected to at least one inhibitory oligonucleotide that inhibits (e.g., selectively inhibits) the expression and / or activity of a JAK.2 gain of function variant (e.g., JAK2-V617F). In some embodiments, the means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)) comprises a protein. In some embodiments, the protein is an antibody that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) (an anti-TFR antibody).

[0034] In one aspect, provided herein are conjugates comprising: an antibody that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) (an anti-TFR antibody); operably connected to at least one inhibitory oligonucleotide that inhibits (e.g., selectively inhibits) the expression and / or activity of a JAK2 gain of function variant (e.g., JAK2-V617F).

[0035] It should be understood that each of the following embodiments can be applicable to each of the foregoing aspects as if recited directly after each if the foregoing aspects.

[0036] In some embodiments, the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody does not (or does not significantly) block binding of TF (e.g., hTF) to TFR (e.g., hTFR (e.g., hTFRl)). In someAttorney Docket No. 66504.13WO01embodiments, the anti-TFR (e.g., hTFR (e.g., TFR1)) 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).

[0037] In some embodiments, the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is an IgG (e.g., a human IgG (hlgG)) antibody. In some embodiments, the anti-TFR (e.g., hTFR (e.g., TFR1)) 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 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). 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.

[0038] 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, Fc RIIIa. and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla))). In some embodiments, the Ig (e.g., hlg) Fc region does not substantially mediate ADCC, does not substantially mediate CDC, and / or does not bind 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))). In some embodiments, the conjugate does not substantially mediate ADCC, does not substantially mediate CDC. and / or does not bind 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))).

[0039] 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 target cell, the conjugate is internalized into the target cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target 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 target cell, the targetAttorney Docket No. 66504.13WO01cell remains viable; (d) upon internalization into a target cell, the conjugate does not induce death of the target cell; (e) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target cell, the conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFR1)); and / or (f) binding of the conjugate to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target cell, does not block (or does not significantly block) binding of transferrin (TF) (e.g., hTF) to TFR (e.g., hTFR (e.g., hTFRl)) expressed by the target cell.

[0040] In some embodiments, binding of the conjugate to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target cell, does not block (or does not significantly block) binding of transferrin (TF) (e.g., hTF) to TFR (e.g., hTFR (e.g., hTFRl)).

[0041] In some embodiments, the target cell is a hematopoietic cell (e.g., in the bone marrow). In some embodiments, the target cell is a hematopoietic pluripotent stem cell (e.g., in the bone marrow). In some embodiments, the target cell is a common myeloid progenitor cell (e.g., in the bone marrow). In some embodiments, the target cell is a megakaryocyte erythroid progenitor cell or an early megakaryocyte (e.g., in the bone marrow).

[0042] In some embodiments, the at least one inhibitory oligonucleotide inhibits (e.g., selectively inhibits) the expression and / or activity of JAK2-V617F. In some embodiments, the inhibitory oligonucleotide selectively inhibits the expression and / or activity of JAK2-V617F. In some embodiments, the inhibitory oligonucleotide selectively inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2. In some embodiments, the inhibitory oligonucleotide preferentially inhibits the expression and / or activity of JAK.2-V617F relative to wild-type JAK2. In some embodiments, the inhibitory oligonucleotide exhibits greater inhibition of the expression and / or activity of JAK2-V617F relative to wild-type JAK2. In some embodiments, the inhibitory oligonucleotide does not (or does not substantially) inhibit the expression and / or activity of wild-type JAK2. In some embodiments, the inhibitory oligonucleotide inhibits the expression and / or activity of JAK2-V617F through binding to an mRNA molecule encoding JAK2-V617F. In some embodiments, the inhibitory oligonucleotide inhibits the expression and / or activity of JAK2-V617F through selectively binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2. In some embodiments, the inhibitory oligonucleotide inhibits the expression and / or activity of JAK2-V617F through preferentially binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.Attorney Docket No. 66504.13WO01

[0043] In some embodiments, the inhibitory oligonucleotide mediates one or more of the following degradation of the mRNA molecule, modification of the mRNA molecule, alteration in the splicing of the mRNA molecule, alteration (e.g., a decrease) in the stability of the mRNA molecule, or a block in the translation of the target mRNA molecule, or any combination of the foregoing.

[0044] In some embodiments, the inhibitory oligonucleotide comprises or consists of an antisense oligonucleotide (ASO), small interfering RNA (siRNA), a short hairpin RNA (shRNA), or a microRNA (miRNA). In some embodiments, the inhibitory oligonucleotide comprises or consists of an siRNA. In some embodiments, the inhibitory oligonucleotide comprises a sense strand and an antisense strand.

[0045] In some embodiments, the inhibitory oligonucleotide comprises or consists of an antisense strand comprising a region of complementarity to an mRNA molecule encoding JAK2 gain of function variant. In some embodiments, the inhibitory oligonucleotide comprises or consists of an antisense strand comprising a region of complementarity to an mRNA molecule encoding JAK2-V617F.

[0046] In some embodiments, the inhibitory oligonucleotide is single stranded or double stranded. In some embodiments, the inhibitory oligonucleotide is a DNA, RNA, or RNA and RNA hybrid molecule. In some embodiments, the inhibitory oligonucleotide comprises a sense strand and an antisense strand forming a double stranded region. In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region). 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.

[0047] In some embodiments, the inhibitory oligonucleotide comprises a dsRNA agent described herein.

[0048] In some embodiments, the inhibitory oligonucleotide comprises at least one modified nucleotide. In some embodiments, at least 25%, 30%. 35%, 40%, 45%. 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the inhibitory oligonucleotide areAttorney Docket No. 66504.13WO01modified. In some embodiments, substantially all (or all) of the nucleotides in the inhibitory oligonucleotide are modified.

[0049] In some embodiments, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).

[0050] In some embodiments, (a) the sense strand comprises at least one 2'-O-methyl and / or the antisense strand comprises at least one 2'-O-methyl and / or (b) the sense strand comprises at least one 2'-deoxy-2'-fluoro and / or the antisense strand comprises at least one 2'-deoxy-2'-fluoro. In some embodiments, (a) the sense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro; and the antisense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro.

[0051] In some embodiments, at least one of the modified nucleotides comprises a modified nucleobase.

[0052] In some embodiments, the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

[0053] In some embodiments, the antisense strand comprises at least one vinyl-phosphonate. In some embodiments, the antisense strand comprises a 5' vinyl-phosphonate. In some embodiments, the sense strand comprises at least one vinyl-phosphonate-2'-0-methyl (e.g., vinyl-phosphonate-2’-O-methyluridine) and / or the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine) (e.g., wherein the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine). In some embodiments, the antisense strand comprises a 5' vinyl-phosphonate-2'-0-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine). In some embodiments, the antisense strand comprises an (E)-vinylphosphonate 2'-O-methylated (2’-0me) uridine at the 5’ end.

[0054] In some embodiments, the sense strand comprises at least one phosphorothioate and / or the antisense strand comprises at least one phosphorothioate. In some embodiments, the sense strand comprises at least one phosphorothioate and the antisense strand comprises at least one phosphorothioate.

[0055] In some embodiments, the at least one modified nucleotide is a 2’ modified nucleotide (e.g., a 2'-fluoro (2'-F), 2'-O-methyl (2'-0-Me), 2'-0-methoxyethyl (2'-M0E), 2'-O- aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-0-DMA0E), 2'-O-dimethylaminopropyl (2'-0-DMAP), 2'-Attorney Docket No. 66504.13WO01O-dimethylaminoethyloxyethyl (2'-0-DMAE0E), 2'-O-N-methylacetamido (2'-0-NMA), locked nucleic acid (LNA), ethylene-bridged nucleic acid (ENA), and (S)- constrained ethyl-bridged nucleic acid (cEt) (e.g., a 2' modified nucleotide is 2'- O-methyl or 2'-fluoro (2'-F))).

[0056] In some embodiments, upon internalization into a target cell the conjugate inhibits (e.g., selectively inhibits) the expression and / or activity of JAK2-V617F. In some embodiments, upon internalization into a target cell the conjugate selectively inhibits the expression and / or activity of JAK2-V617F. hr some embodiments, upon internalization into a target cell the conjugate selectively inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2. In some embodiments, upon internalization into a target cell the conjugate does not (or does not substantially) inhibit the expression and / or activity of wild-type JAK2. In some embodiments, upon internalization into a target cell the conjugate inhibits the expression and / or activity of JAK2-V617F through binding to an mRNA molecule encoding JAK2-V617F. In some embodiments, upon internalization into a target cell the conjugate inhibits the expression and / or activity of JAK2-V617F through selectively binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2. In some embodiments, upon internalization into a target cell the conjugate inhibits the expression and / or activity of JAK2-V617F through preferentially binding to an mRNA molecule encoding JAK.2-V617F relative to an mRNA encoding wild-type JAK2.

[0057] In some embodiments, upon internalization into a target cell the conjugate mediates one or more of the following degradation of the mRNA molecule, modification of the mRNA molecule, alteration in the splicing of the mRNA molecule, alteration (e.g., a decrease) in the stability of the mRNA molecule, or a block in the translation of the target mRNA molecule, or any combination of the foregoing.

[0058] In some embodiments, (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is non-covalently conjugated to (b) the at least one inhibitory oligonucleotide. In some embodiments, (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is covalently conjugated to (b) the at least one inhibitory oligonucleotide. In some embodiments, (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is directly conjugated to (b) the at least one inhibitory oligonucleotide. In some embodiments, (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is indirectly conjugated to (b) the at least one inhibitory oligonucleotide through (c) a linker. In some embodiments, the linker is cleavable or non-cleavable. In some embodiments, the wherein (b) comprises at least 2, 3, 4, 5, 6,Attorney Docket No. 66504.13WO01or more inhibitory oligonucleotides. Tn some embodiments, each of the at least 2, 3, 4, 5, 6, or more inhibitory oligonucleotides are individually conjugated to (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody.

[0059] In one aspect, provided herein are vectors (e.g., a viral vector, a non- viral vector) encoding the antisense strand, the sense strand, or both the antisense and sense strand of a dsRNA agent described herein.

[0060] In one aspect, provided herein are carriers comprising a dsRNA agent described herein, a conjugate described herein, or a vector described herein.

[0061] In one aspect, provided herein are carriers conjugated to a dsRNA agent described herein, a conjugate described herein, or a vector described herein.

[0062] In some embodiments, the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, as dendrimer, a cationic delivery system, or a hydrogel. In some embodiments, the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

[0063] In one aspect, provided herein are cells (or population of cells) comprising a dsRNA agent described herein, a conjugate described herein, or a carrier described herein. In some embodiments, the cell (or population of cells) is in vitro, ex vivo, or in vivo.

[0064] In one aspect, provided herein are pharmaceutical compositions comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, or a cell (or population of cells) described herein, and a pharmaceutically acceptable excipient.

[0065] In one aspect, provided herein are kits comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0066] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell (or a population of cells), the method comprising introducing into a cell (or the population of cells) a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, earner, or pharmaceutical composition into the cell (or the population of cells). In some embodiments, the cell is in vitro, ex vivo, or in vivo. In some embodiments, the cell is aAttorney Docket No. 66504.13WO01subject (e.g., a human subject).

[0067] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, earner, 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 (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to the subject.

[0068] In one aspect, provided herein are methods of reducing and / or inhibiting expression and / or activity of a JAK.2 gain of function variant (e.g., JAK2-V617F) in a cell (or population of cells), the method comprising introducing into the cell (or the population of cells) a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce and / or inhibit expression and / or activity of the JAK2 gain of function variant (e.g., JAK2-V617F) in the cell (or population of cells).

[0069] In some embodiments, the cell (or a population of cells) is in vitro, ex vivo, or in vivo. In some embodiments, the cell (or a population of cells) is a subject (e.g., a human subject).

[0070] In one aspect, provided herein are methods of reducing and / or inhibiting expression and / or activity of a JAK2 gain of function variant (e.g., JAK2-V617F) in a cell (or a population of cells) in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce and / or inhibit expression and / or activity of the JAK2 gain of function variant (e.g., JAK2-V617F) in the cell (or a population of cells) in the subject. In some embodiments, the JAK2 gain of function variant is JAK2-V617F.

[0071] In one aspect, provided herein are methods of reducing and / or inhibiting expression and / or activity of JAK2-V617F in a cell (or population of cells), the method comprising introducing into the cell (or the population of cells) a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce and / or inhibit expression and / or activity of JAK2-V617F in the cell (or population of cells). In some embodiments, the cell (or a population of cells) is in vitro, ex vivo, or in vivo. In someAttorney Docket No. 66504.13WO01embodiments, the cell (or a population of cells) is a subject (e.g., a human subject).

[0072] In one aspect, provided herein are methods of reducing and / or inhibiting expression and / or activity of JAK2-V617F in a cell (or a population of cells) in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce and / or inhibit expression and / or activity of the JAK2-V617F in the cell (or a population of cells) in the subject.

[0073] In some embodiments, the cell (or a population of cells) comprises a hematopoietic cell (or a population of hematopoietic cells). In some embodiments, the cell (or a population of cells) comprises a hematopoietic pluripotent stem cell (or a population of hematopoietic pluripotent stem cells). In some embodiments, the cell (or population of cells) comprises one or more myeloid cell (or a population of one or more myeloid cell) (e.g., myeloblasts, erythrocytes, megakaryocytes (e.g., early megakaryocytes), megakaryocyte erythroid progenitor cells, neutrophils, and / or monocytes).

[0074] In one aspect, provided herein are methods of reducing the level of a population of myeloid cells in a subject, the method comprising administering to the subject, a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce the level of a population of myeloid cells in the subject.

[0075] In some embodiments, the population of myeloid cells comprises myeloblasts, erythrocytes, megakaryocytes (e.g., early megakaryocytes), megakaryocyte erythroid progenitor cells, neutrophils, and / or monocytes.

[0076] In one aspect, provided herein are methods of reducing the level of a platelets in a subject, the method comprising administering to the subject, a dsRNA agent described herein, a conjugate described herein, a vector described herein, a earner described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce the level of platelets in the subject.

[0077] In one aspect, provided herein are methods of treating, ameliorating, or preventing a disease in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, toAttorney Docket No. 66504.13WO01thereby treat, ameliorate, or prevent the disease in the subject.

[0078] In some embodiments, the disease is a myeloproliferative neoplasm, a cancer, or a congestive hepatopathy. In some embodiments, the disease is polycythemia vera, essential thrombocythemia, primary myelofibrosis, acute myeloid leukemia, or Budd-Chiari syndrome.

[0079] In one aspect, provided herein are methods of treating, ameliorating, or preventing a JAK2-V617F mediated disease in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the JAK.2-V617F mediated disease in the subject.

[0080] In some embodiments, the JAK2-V617F mediated disease is a myeloproliferative neoplasm, a cancer, or a congestive hepatopathy. In some embodiments, the JAK2-V617F mediated disease is polycythemia vera, essential thrombocythemia, primary myelofibrosis, acute myeloid leukemia, or Budd-Chiari syndrome.

[0081] In one aspect, provided herein are methods of treating, ameliorating, or preventing a myeloproliferative neoplasm in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the myeloproliferative neoplasm in the subject.

[0082] In some embodiments, the myeloproliferative neoplasm is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm. In some embodiments, the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or primary myelofibrosis.

[0083] In one aspect, provided herein are methods of treating, ameliorating, or preventing a cancer in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the cancer in the subject.

[0084] In some embodiments, the cancer is a myeloid leukemia. In some embodiments, the cancer is acute myeloid leukemia.

[0085] In one aspect, provided herein are methods of treating, ameliorating, or preventing aAttorney Docket No. 66504.13WO01congestive hepatopathy in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the congestive hepatopathy in the subject.

[0086] In some embodiments, the congestive hepatopathy is Budd-Chiari Syndrome.

[0087] In some embodiments, the method further comprises detecting, or having detected, the presence or absence of a genomic (e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2 gain of function variant. In some embodiments, the method further comprises detecting, or having detected, the presence or absence of a genomic e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2-V617F variant. In some embodiments, the method further comprises detecting, or having detected in DNA, RNA, or protein isolated and purified from a sample obtained from the subject, the presence or absence of a genomic e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2-V617F variant.

[0088] In some embodiments, the subject has been determined to be homozygous or heterozygous for a genomic {e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2-V617F variant. In some embodiments, the genomic {e.g., germline or somatic) mutation in JAK2 comprises the C.1849G>T single nucleotide polymorphism. In some embodiments, the genomic mutation in JAK2 is a germline mutation. In some embodiments, the genomic mutation in JAK2 is a somatic mutation.

[0089] In some embodiments, the somatic mutation in JAK2 is determined to be present in a subpopulation of cells in the subject. In some embodiments, the subpopulation of cells comprises hematopoietic cells. In some embodiments, the subpopulation of cells comprises hematopoietic pluripotent stem cells. In some embodiments, the subpopulation of cells comprises common myeloid progenitor cells.

[0090] In some embodiments, the sample is a blood sample or a bone marrow sample.

[0091] In some embodiments, the subject is a human.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] FIG. 1A is a line graph showing the concentration of hemoglobin (g / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated testAttorney Docket No. 66504.13WO01agent (Vehicle, Ruxolitinib, Con-1 , or Con-2).

[0093] FIG. IB is a line graph showing the concentration of hematocrit (L / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0094] FIG. 1C is a line graph showing the level of RBCs (xlO12 / L) in blood samples taken from mice at 0. 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0095] FIG. ID is a line graph showing the level of reticulocytes (xlO9 / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0096] FIG.2A is a line graph showing the level of platelets (xlO12 / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0097] FIG. 2B is a line graph showing the level of platelets (xlO9 / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0098] FIG. 2C is a line graph showing the level of platelets (xlO9 / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0099] FIG. 2D is a line graph showing the level of platelets (xlO9 / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0100] FIG. 2E is a line graph showing the level of platelets (xlO9 / L) in blood samples taken from mice at 0, 4, and 8 weeks post the start of treatment with in the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0101] FIG. 3A is a bar graph showing the weight of spleens (mg) taken from mice after 8 weeks of treatment with the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0102] FIG. 3B is a photograph showing the spleens (mg) of mice after 8 weeks of treatment with the indicated test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).

[0103] FIG. 4 is a bar graph showing the spleen cell frequencies of HSPCs quantified as percentage of total live cells in the spleen of mice after 8 weeks of treatment with the indicatedAttorney Docket No. 66504.13WO01test agent (Vehicle, Ruxolitinib, Con-1, or Con-2).5. DETAILED DESCRIPTION

[0104] Activating variations along the JAK2 pathway can result in uncontrolled proliferation, growth, and survival of hematopoietic cell lineages, leading to myeloproliferative neoplasms and other bone marrow derived clonal expansion disorders. There are currently limited therapeutics targeting JAK2 variant allele specific knockdown, with the majority of approaches focusing on tyrosine kinase inhibitors with improved selectivity for variant domains. As such, there is an unmet need for JAK2 variant (e.g., gain of function variant (e.g., JAK2-V617F)) specific inhibitory oligonucleotides (e.g., siRNAs) that can also, e.g., target dysfunctional hematopoietic cell lineages in the bone marrow, e.g., by utilizing JAK2 variant (e.g., gain of function variant (e.g., JAK2-V617F)) specific inhibitory oligonucleotides (e.g., siRNAs) conjugated to a TFR (e.g., TFR1) targeting moiety (e.g., an anti-TFRl antibody).

[0105] The inventors have, inter alia, discovered that inhibitory oligonucleotides capable of inhibiting expression and / or activity of JAK2 (e.g., a JAK2 gain of function variant (e.g., JAK2-V617F)) can be specifically targeted to therapeutically relevant subsets of hematopoietic cells through conjugation to a TFR targeting agent (e.g., an anti-TFR antibody). As such, the conjugates described herein are useful, inter alia, for the treatment of JAK2 (e.g., a JAK2 gain of function variant (e.g., JAK2-V617F)) mediated diseases (including e.g., myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia, primary myelofibrosis), cancers (e.g., acute myeloid leukemia), and congestive hepatopathy (e.g., Budd-Chiari syndrome)). The inventors have further discovered inter alia, RNAi agents that specifically inhibit expression of JAK2-V617F (e.g., relative to wild-type JAK2). As such, the current disclosure provides inhibitory oligonucleotides and conjugates; and their use in, inter alia, pharmaceutical compositions, and methods of treating diseases (e.g., JAK2 (e.g., a JAK2 gain of function variant (e.g., JAK2-V617F)) mediated diseases).TABLE OF CONTENTS5.1 Definitions5.2 JAK2-V617F Targeting Inhibitory Oligonucleotides5.2.1 RNAi Agents5.2.1.1 Antisense StrandAttorney Docket No. 66504.13WO01Overall LengthTargeting RegionExemplary Antisense StrandsSense StrandAntisense Strand ComplementarityOverall LengthExemplary Sense StrandsdsRNA AgentsSingle & Multiple Nucleic Acid MoleculesLength of Double Stranded RegionNucleotide Overhangs & Blunt EndsExemplary Structural Combinations of Sense & Antisense Strands Exemplary Antisense Strands & Sense StrandsExemplary Modifications of JAK2-V617F Targeting Inhibitory OligonucleotidesNature of Nucleotide ModificationsModified NucleosidesSugar ModificationsNucleobase ModificationsInternucleoside Linkage ModificationsAdditional Exemplary Nucleotide ModificationsExtent of Modified NucleotidesExemplary JAK2-V617F Targeting Inhibitory Oligonucleotides Exemplary Properties of JAK2-V617F Targeting Inhibitory Oligonucleotides ConjugatesTFR Targeting ConjugatesTFR Binding AgentsAnti-TFR (e.g., Anti-TFRl) AntibodiesExemplary Anti-TFR e.g., Anti-TFRl) AntibodiesIg Constant RegionsIg Effector FunctionAttorney Docket No. 66504.13WO01Promotion of HeterodimerizationIg Constant Region Variations for Site Specific ConjugationTFR Binding Peptides and Antibody-Like ScaffoldsExemplary TFR Binding Peptides and Antibody-Like Scaffolds Heterologous MoietiesExemplary Properties of TFR Binding AgentsMolecular Payloads Targeting JAK2 (e.g., JAK2-V617F)Inhibitory OligonucleotidesJAK2-V617F Targeting Inhibitory OligonucleotidesExemplary Properties of Molecular Payloads Targeting JAK2 Exemplary Properties of TFR Targeting ConjugatesLinkersCleavable LinkersNon-Cleavable LinkersLinker ConjugationOrientation & DARMethods of Making ProteinsMethods of Making Oligonucleotide Molecular PayloadsMethods of ConjugationVectorsCarriersCellsPharmaceutical CompositionsMethods of UseMethods of DeliveryMethods of Inhibiting Expression of Gain of Function JAK2 Variants (e.g., JAK2-V617F)Methods of Inhibiting Expression of JAK2-V617FMethods of Reducing the Level of a Population of Myeloid Cells Methods of Reducing the Level of a PlateletsMethods of Treating a DiseaseAttorney Docket No. 66504.13WO015.11.7 Methods of Treating a JAK2 Mediated Disease5.11.8 Methods of Treating a JAK2 Gain of Function Variant Mediated Disease 5.11.9 Methods of Treating a JAK2-V617F Mediated Disease5.11.10 Methods of Treating a Myeloproliferative Neoplasm5.11.11 Methods of Treating a Cancer5.11.12 Methods of Treating a Congestive Hepatopathy5.11.13 Methods of Assessing JAK2 Gain of Function Variant (e.g., JAK2-V617F) Status5.12 Kits5.1 Definitions

[0106] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0107] 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.

[0108] In this disclosure, 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.

[0109] 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 herein.

[0110] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; AAttorney Docket No. 66504.13WO01and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0111] 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.

[0112] The term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. When particular values or compositions are provided in the disclosure, unless otherwise stated, the meaning of “about” should be assumed to be within an acceptable error range for that particular value or composition.

[0113] Where proteins are described herein, it is understood that nucleic acid molecules (e.g., RNA (e.g., mRNA) or DNA nucleic acid molecules) encoding the protein are also provided herein.

[0114] Where proteins, nucleic acid molecules, vectors, earners, etc. are described herein, it is understood that isolated forms of the proteins, nucleic acid molecules, vectors, carriers, etc. are also provided herein.

[0115] Where proteins, nucleic acid molecules, etc. are described herein, it is understood that recombinant forms of the proteins, nucleic acid molecules, etc. are also provided herein.

[0116] Where polypeptides or sets of polypeptides are described herein, it is understood that proteins comprising the polypeptides or sets of polypeptides folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein and vice versa.

[0117] Where proteins are described herein, it is understood that polypeptides comprising the same amino acid sequence either linear or folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein.

[0118] As used herein, the term “administering” refers to the physical introduction of an agent (e.g., a conjugate described herein), e.g., a therapeutic agent (or a precursor of an agent e.g., a precursor of a therapeutic agent) that is metabolized or altered within the body of the subject to produce the agent (e.g., 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 self-administration.Attorney Docket No. 66504.13WO01

[0119] The terms “agent” and “moiety” are used interchangeably herein and are used generically to describe any macro or micro molecule (and any combination thereof). Exemplary agents include, but are not limited proteins, peptides, nucleic acid molecules (e.g., DNA, RNA), small molecules, carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG), conjugates (e.g., described herein), and any combination of the foregoing. Agents may contain more than one individual agent (wherein the individual agents are the same or different). For example, an agent may comprise an antibody (e.g., a targeting agent described herein) and an oligonucleotide (e.g., an oligonucleotide described herein). Agents as defined herein include e.g., conjugates described herein.

[0120] As used herein, the term “affinity” refers to the strength of the binding of one agent to another agent. For example, in the case of two proteins, 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).

[0121] 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 domainAttorney Docket No. 66504.13WO01of 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, di sulf ide-linked Fvs (sdFv), Fc fusions (e.g., Fab-Fc, scFv-Fc, VHH-Fc, (SCFV)2-FC, (VHH)2-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, IgGs, IgG4, IgAi or IgA2), or any subclass (e.g., IgG2a or IgG2b) 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 subclass 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. The term antibody as used herein also includes antibody-like scaffolds (as defined herein). As such, the term antibody as used herein encompasses both Ig based antibodies and non-Ig based antigen binding domains that function similarly to Ig based antibodies (antibody-like scaffolds). Antibodies described herein can be produced by any standard methods known in the art, e.g., recombinant production in host cells, see, e.g., § 5.4; or synthetic production.

[0122] As used herein, the term “antibody-like scaffold” refers to non-Ig based antigen binding domains that function similarly to Ig based antibodies. 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 antigenbinding 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.,Attorney Docket No. 66504.13WO01US2004132094) (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 variants) of naturally occurring antigen binders, fragments (e.g., functional fragments) of naturally occurring antigen binders, and synthetic antigen binders (i.e., not naturally occurring antigen binders).

[0123] 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 toAttorney Docket No. 66504.13WO01the 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.

[0124] As used herein, the term “antisense oligonucleotide” or “ASO” refer to the standard single stranded oligonucleotides known in the art that are e.g., capable of modulating expression of a target gene (or protein) by hybridizing to a target nucleic acid (e.g., an mRNA encoded by the target gene and encoding the target protein), in particular to a contiguous sequence on a target nucleic acid. Antisense oligonucleotides include DNA, RNA, and hybrid DNA / RNA oligonucleotides.

[0125] As used herein, the term “antisense strand” with reference to an oligonucleotide described herein (e.g., an RNAi agent (e.g., siRNA agent), an antisense oligonucleotide) refers to an oligonucleotide 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 portion of a target mRNA). In the case of single stranded oligonucleotides (e.g., antisense oligonucleotides) the antisense strand will be the only strand. In the case of double stranded oligonucleotides (e.g., siRNAs) the sense strand will typically be paired with a sense strand (as described herein).

[0126] As used herein, the term “bicyclic sugar” refers to a modified sugar (e.g., ribose, deoxyribose) 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.

[0127] As used herein, the term “bicyclic nucleoside” (“BNA”) is a nucleoside comprising a bicyclic sugar.

[0128] As used herein, the term “blunt end” refers to a double stranded oligonucleotide that does not contain any unpaired nucleotides at the end (e.g., 3' terminus, 5' terminus) of the double stranded oligonucleotide (i.e., no nucleotide overhang(s)). The double stranded oligonucleotide can have, for example, a blunt end at the 3' end, 5' end, or both the 3' and 5' end of the molecule.

[0129] 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),Attorney Docket No. 66504.13WO01the 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 art would be able to determine the CDRs as defined by another scheme, e.g., Chothia, IMGT, using ordinary methods known in the art.

[0130] 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: 118; and the amino acid sequence of an exemplary reference h!gG4 CHI region is set forth in SEQ ID NO: 131.

[0131] 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: 120; and the amino acid sequence of an exemplary reference hIgG4 CH2 region is set forth in SEQ ID NO: 133.

[0132] 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: 121; and the amino acid sequence of an exemplary reference hIgG4 CH3 region is set forth in SEQ ID NO: 134.

[0133] 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 or an antisense oligonucleotide), refers to the ability of a nucleic acid molecule comprising the first nucleotide sequence to hybridize to a nucleic acid molecule comprising the second nucleotide sequence and form a double stranded region (through base pair hydrogen bonds) under suitable in vivo or vitro conditions (e.g., under certain standard conditions, under mammalian (e.g., human) physiological conditions). A person of ordinary skill in the art would be able to select the set of conditions most appropriate for a hybridization test. Complementary sequences include, e.g., Watson-Crick base pairs. For example, complementary nucleobase pairs include adenine (A) and thymine (T); adenine (A) and uracil (U); and cytosine (C) and guanine (G). Complementary nucleobase pairs include natural and modified nucleotides, and nucleotide mimics, at least to the extent that the above hybridization requirements are fulfilled. As such, determinations of complementarity (as described herein) are independent of nucleotide chemical modifications (e.g., as described herein). For example, (C) and 5-methyl cytosine (mC) are both complementary toAttorney Docket No. 66504.13WO01(G).

[0134] As used herein, the term “conjugation” refers to the operable connection (e.g., chemical conjugation) of at least a first agent (e.g., an oligonucleotide (e.g., an oligonucleotide described herein)) with a second agent (e.g., an anti-TFR (e.g., anti-hTFR (e.g., anti-hTFRl)) antibody described herein). The first agent can be directly connected to the second agent or indirectly connected (e.g., through a linker (e.g., as described herein)). Methods of operably connected two agents (e.g., 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. Operable connection (e.g., chemical conjugation) includes both covalent and non-covalent conjugation. In some embodiments, the operable connection (e.g., chemical conjugation) comprises the covalent linkage of the first agent (e.g., an oligonucleotide (e.g., an oligonucleotide described herein)) with the second agent (e.g., an anti-TFR (e.g., anti-hTFR (e.g., anti-hTFRl)) antibody described herein).

[0135] 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.

[0136] As used herein, the term “disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology. The term disease includes infection (e.g., a viral, bacterial, fungal, protozoal infection).

[0137] 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.

[0138] As used herein, the term “double stranded oligonucleotide” refers to a complex of two nucleic acid 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 double stranded oligonucleotideAttorney Docket No. 66504.13WO01comprises a sense strand and an antisense strand.

[0139] 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, Fey R Illa, and / or FcyRIIIb (e.g., FcyRI, Fey Ila, and / or Fey Illa)), and Clq binding.

[0140] 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.

[0141] 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.

[0142] The term “Fab-Fc” as used herein refers to an antibody that comprises a Fab operably linked to an Fc region.

[0143] 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), see, e.g., §§ 5.3.1. l(ii)(a), 5.3.1. l(ii)(b). 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).

[0144] 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 theseAttorney Docket No. 66504.13WO01terms 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) may contain two Fc regions that associate e.g., via one or more covalent (e.g., disulfide) bond.

[0145] 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).

[0146] 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.

[0147] 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.

[0148] The term “functional variant” as used herein in reference to a protein refers to a proteinAttorney Docket No. 66504.13WO01that 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.

[0149] 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.

[0150] As used herein, the term “fuse” and grammatical equivalents thereof refer to the operable connection of at least a first polypeptide to a second polypeptide, wherein the first and second polypeptides are not naturally found operably connected together. For example, the first and second polypeptides are derived from different proteins. 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).

[0151] As used herein, the term “fusion protein” and grammatical equivalents thereof refers to a protein that comprises at least one polypeptide operably connected to another polypeptide, wherein the first and second polypeptides are not naturally found operably connected together. For example, the first and second polypeptides of the fusion protein are each derived from different proteins. 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 polypeptide 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).

[0152] As used herein, the term “germline mutation” refers to one or more nucleotide alteration (e.g., variation, modification (e.g., variation)) in the germline genomic DNA sequence (e.g., of a gene) of an individual and are therefore inherited from a parent.Attorney Docket No. 66504.13WO01

[0153] 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.

[0154] 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 art.

[0155] 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 (5), 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 (5), 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.

[0156] 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) (also referred to herein as hematopoietic stem cells), common myeloid progenitor cells (also referred to herein as myeloid progenitor cells), megakaryocyte erythroid progenitor cells, erythroid progenitor cells, proerythroblast cells, early erythroblast cells, intermediate erythroblast cells, late erythroblast cells, reticulocytes, megakaryocytes (early megakaryocytes, mature megakaryocytes), platelets, granulocyte monocyte progenitor cells, monoblasts, promonocytes, monocytes, macrophages, myeloblasts, promyelocytes, myelocytes, eosinophils, basophils, neutrophils,Attorney Docket No. 66504.13WO01common lymphoid progenitor cells, pro-NK lymphoblasts, NK cells, pro-B lymphoblasts, B lymphocytes, pro-T lymphoblasts, T lymphoblasts, and plasma cells.

[0157] 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.

[0158] 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: 119; and the amino acid sequence of an exemplary reference hIgG4 hinge region is set forth in SEQ ID NO: 132.

[0159] As used herein, the term “inhibitory oligonucleotide” and the like refers to an oligonucleotide capable of inhibiting, reducing, or preventing the expression and / or activity of a target DNA, RNA, or protein molecule.

[0160] As used herein, the term “isolated” with reference to an agent (e.g., a protein, nucleic acid molecule, etc.) refers to an agent (e.g., a protein, nucleic acid molecule, etc.) that is substantially free of other cellular components with which it is associated in the natural state.

[0161] As used herein, the term “Janus Kinase 2” or “JAK2” refers to the non-receptor tyrosine kinase of the Janus kinase family that functions, inter alia, in in various cellular processes, including, but not limited to, cell growth, development, differentiation, and proliferation. The mRNA sequence of a reference human JAK2 (hJAK2) gene is set forth in SEQ ID NO: 267 (NCBI Ref.: NM_004972). The amino acid sequence of a reference hJAK2 protein is set forth in SEQ ID NO: 269 (NCBI Ref.: NP_004963). The term JAK2 includes naturally occurring variants of JAK2. JAK2 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.

[0162] As used herein, the term “JAK2 gain of function variant” and the like refers to a JAK2 variant that comprises one or more variation (relative to a reference (e.g., wild-type)) that results in an increase in expression and / or activity of the JAK2 protein (relative to a reference (e.g., wild-Attorney Docket No. 66504.13WO01type)). For example, a JAK2 gain of function variant may be constitutively active. JAK2-V617F (described herein) is an example of a JAK2 gain of function variant. The term JAK2 gain of function variant is used herein to refer to both the JAK2 DNA variant and RNA variant encoding a JAK2 variant protein; and the JAK2 variant protein. Whether the term JAK2 gain of function variant is referring to DNA or RNA encoding a JAK2 variant protein, or the JAK2 variant protein, will be clear to a person of ordinary skill in the art based on the context.

[0163] As used herein, the term “JAK2-V617F” refers to JAK2 comprising a phenylalanine at amino acid position 617 (numbering according to SEQ ID NO: 269). The JAK2-V617F protein variant is known as a constitutively active gain of function variant. See, e.g., Levine, R., Pardanani, A., Tefferi, A. et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7, 673-683 (2007). https: / / doi.org / 10.1038 / nrc2210, the entire contents of which are incorporated herein by reference for all purposes. The amino acid sequence of an exemplary JAK2-V617F protein is set forth in SEQ ID NO: 272. The amino acid sequence of the JAK2-V617F protein that is set forth in SEQ ID NO: 272 is identical to the reference (wild-type) JAK2 amino acid sequence set forth in SEQ ID NO: 269 except for a V617F amino acid substitution. The term JAK2-V617F is used herein to refer to both the JAK2-V617F DNA and RNA encoding A JAK2-V617F protein; and the JAK2-V617F protein. Whether the term JAK2-V617F is referring to DNA or RNA encoding A JAK2-V617F protein, or the JAK2-V617F protein, will be clear to a person of ordinary skill in the art based on the context.

[0164] As used herein, the term “JAK.2 mediated disease” refers to a disease that is mediated and / or influenced at least in part by an alteration in JAK2 (e.g., any one or more of an alteration in expression, function, variations, etc.). For example, any one of more of the onset, severity, progression, treatment susceptibility, etc. of the disease can be mediated and / or influenced in part by an alteration in JAK2 (e.g., any one or more of an alteration in expression, function, variations, etc.). In some embodiments, the JAK2 mediated disease is characterized by the presence of one or more JAK2 mutation (somatic or germline), wherein any one of more of the onset, severity, progression, treatment susceptibility, etc. of the disease is mediated and / or influenced in part by the presence of the one or more JAK.2 mutation (somatic or germline). In some embodiments, the JAK2 mediated disease is characterized by the presence of one or more JAK2 gain of function mutation (somatic or germline), wherein any one of more of the onset, severity, progression, treatment susceptibility, etc. of the disease is mediated and / or influenced in part by the presenceAttorney Docket No. 66504.13WO01of the one or more JAK2 gain of function mutation (somatic or germline). A specific example of a JAK2-mediated disease is a JAK2-V617F mediated disease.

[0165] As used herein, the term “JAK2 gain of function variant mediated disease” refers to a JAK2 mediated disease that is mediated and / or influenced at least in part by a JAK2 gain of function variant (somatic or germline).

[0166] As used herein, the term “JAK2-V617F mediated disease” refers to a JAK2 mediated disease that is mediated and / or influenced at least in part by the gain of function JAK2-V617F mutation (somatic or germline).

[0167] As used herein, the term “modified nucleotide,” “nucleotide modification,” or use of the term “modification” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleotide comprising a chemical modification, e.g., a modified sugar moiety, a modified nucleobase, and / or a modified internucleoside linkage, or any combination thereof. Exemplary modifications are provided herein, see, e.g., § 5.2.2. In certain embodiments of the instant disclosure, inclusion of a deoxynucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within an RNA oligonucleotide is considered to constitute a modified nucleotide.

[0168] As used herein, the term “molecular payload” refers to an agent that functions to modulate a biological outcome. In some embodiments, a molecular payload is operably connected to another agent (e.g., a targeting agent (e.g., a targeting agent described herein (e.g., an anti-TFR antibody))). In some embodiments, the molecular payload is a small molecule, a protein, a peptide, or an oligonucleotide. In some embodiments, the molecular payload is an oligonucleotide (e.g., an oligonucleotide described herein, see, e.g., § 5.2.2). In some embodiments, the molecular payload functions to inhibit the transcription of a DNA molecule, to inhibit the translation of an RNA (e.g., mRNA) molecule, to inhibit the expression of a protein, or to inhibit the activity of a protein. In some embodiments, the molecular payload is an oligonucleotide that comprises a strand having a region of complementarity to a target nucleic acid molecule (e.g., an RNA molecule encoded by a target gene e.g., an mRNA molecule encoded by a target gene)).

[0169] 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.

[0170] The terms “nucleic acid molecule,” “polynucleotide,” and “oligonucleotide” are usedAttorney Docket No. 66504.13WO01interchangeably 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, non-natural, 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).

[0171] As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that extends from the double stranded region of a double stranded nucleic acid molecule. For example, when a 3'-end of one strand of a double stranded nucleic acid molecule extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang.

[0172] As used herein, the term “operably connected” refers to the linkage of two agents 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” also refers for example to the conjugation of a first agent (e.g., a protein (e.g., an antibody)) to a second agent (e.g., an oligonucleotide) wherein the first and second agent are both capable of mediating their function.

[0173] 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 ofAttorney Docket No. 66504.13WO01bases 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.

[0174] The determination of “percent identity” between two sequences (e.g., protein (amino acid sequences) or oligonucleotide (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 andXBLAST 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 acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.Attorney Docket No. 66504.13WO01

[0175] 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 (e.g., a conjugate described herein) and a pharmaceutically acceptable carrier or diluent. A “pharmaceutically acceptable carrier or diluent” means a substance intended for use in contact with the tissues of human beings and / or non-human animals, and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable therapeutic benefit / risk ratio.

[0176] 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).

[0177] As used herein, the terms “protein”, “polypeptide”, and peptide refers to a polymer of at least 2 (e.g., at least 5) amino acids linked by a peptide bond. The term “polypeptide” does not denote a specific length of the polymer chain of amino acids. It is common in the art to refer to shorter polymers of amino acids (e.g., approximately 2-50 amino acids) as peptides; and to refer to longer polymers of amino acids (e.g., approximately over 50 amino acids) as polypeptides. However, the terms “peptide” and “polypeptide” and “protein” are used interchangeably herein. In some embodiments, the protein is folded into its three-dimensional structure. Where polypeptides (e.g., in a linear (i.e., primary) structure are contemplated herein, it should be understood that proteins folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein and vice versa. Proteins include e.g., naturally occurring proteins, variant (e.g., functional variants) of naturally occurring proteins, fragments (e.g., functional fragments) of naturally occurring proteins, and synthetic proteins (i.e., not naturally occurring proteins).

[0178] 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.

[0179] 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.Attorney Docket No. 66504.13WO01

[0180] 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 or protein in a cell, e.g., a cell within a subject, such as a mammalian subject. RNAi agents include, for example, siRNAs, miRNAs. and shRNAs.

[0181] 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.

[0182] The term “(scFv)2” 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 can specifically bind the same or different antigens. In some embodiments, the first and second scFv are operably connected by a peptide linker.

[0183] 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.

[0184] 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)2 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.

[0185] As used herein, the term “sample” encompasses a variety of biological specimens obtained from a subject. Exemplary sample types include, e.g., blood, red blood cells, and other liquid samples of biological origin (including, but not limited to, whole-blood, red blood cells (e.g., isolated from whole blood), peripheral blood mononuclear cells (PBMCs). serum, plasma, urine, saliva, amniotic fluid, stool, synovial fluid, etc.), nasopharyngeal swabs, solid tissue samples suchAttorney Docket No. 66504.13WO01as biopsies (or cells derived therefrom and the progeny thereof), tissue cultures (or cells derived therefrom and the progeny thereof), and cell cultures (or cells derived therefrom and the progeny thereof). The term also includes samples that have been manipulated in any way after their procurement from a subject, such as by centrifugation, filtration, washing, precipitation, dialysis, chromatography, lysis, treatment with reagents, enriched for certain cell populations, refrigeration, freezing, staining, etc.

[0186] 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).

[0187] 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.

[0188] As used herein, the term “somatic mutation” refers to one or more nucleotide alteration (e.g., variation, modification (e.g., variation)) in a genomic DNA sequence (e.g., of a gene) that is acquired during the lifetime of a subject. It is understood in the art that somatic mutations are not present in the germline DNA of an individual and are therefore not inherited from a parent like germline polymorphisms. Somatic mutations may occur spontaneously due to e.g., the infidelity of DNA replication occurring at each cell division creating substitutions, deletions, or additions of nucleotides into the DNA of a cell. A somatic mutation may also be caused by environmental factors such as e.g., ultraviolet radiation, chemical exposure, or virial infections.

[0189] 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.,Attorney Docket No. 66504.13WO01cynomolgus, 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, 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., 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).

[0190] 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 specific preferred 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).

[0191] 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.

[0192] 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). In some embodiments, the target nucleic acid sequence is an mRNA molecule formed during the transcription of a target gene. 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 an oligonucleotide described herein (e.g., an antisense oligonucleotide, an RNAi agent, etc.).

[0193] As used herein, the term “therapeutic agent” refers to an agent (e.g., a conjugateAttorney Docket No. 66504.13WO01described 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.

[0194] 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.

[0195] 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: 3 (UniProt Accession P02787).

[0196] As used herein, the term “transferrin receptor” or “TFR” refers to the transmembrane homodimeric 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: 1 (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: 2 (UniProt Accession Q9UP52).

[0197] 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 theAttorney Docket No. 66504.13WO01intensity 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 e.g., a conjugate described herein (or a carrier, pharmaceutical composition, etc. comprising the same).

[0198] 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. The term mutation is also used herein to refer to a variation in a nucleic acid molecule or amino acid sequence.

[0199] 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 the 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. See, e.g., § 5.3.1. l(ii)(b).

[0200] As used herein, the term “variable region” refers to a portion of an antibody, generally,Attorney Docket No. 66504.13WO01a 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).

[0201] 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.

[0202] 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, 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.

[0203] 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.

[0204] 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.

[0205] 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 someAttorney Docket No. 66504.13WO01embodiments, 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.

[0206] The term “(VHH)2-Fc” as used herein refers to (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)2 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.5.2 JAK2-V617F Targeting Inhibitory Oligonucleotides

[0207] Provided herein are inhibitory oligonucleotides that target IAK2-V617F. As described elsewhere herein, the JAK2-V617F targeting inhibitory oligonucleotides useful in, inter alia, inhibiting expression and / or activity of the gain of function JAK2 variant JAK2-V617F (e.g., within a cell (e.g., a hematopoietic cell), e.g., within a cell in a subject, e.g., a mammalian subject, e.g., a human subject) (e.g., through binding to an mRNA molecule encoding the JAK2 gain of function variant JAK2-V617F variant).

[0208] JAK2 is a is a member of the Janus kinase family and a non-receptor tyrosine kinase. JAK2 functions in various cellular processes, including, but not limited to, cell growth, development, differentiation, proliferation, and survival. JAK2 also mediates signaling events in both innate and adaptive immunity, including roles in both cytokine and growth factor signalling. Alternative splicing results in multiple transcript variants encoding distinct isoforms. See, e.g., Santos FP, Verstovsek S. Therapy with JAK2 inhibitors for myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012 Oct;26(5):1083-99. doi: 10.1016 / j.hoc.2012.07.008. Epub 2012 Aug 21. PMID: 23009939; PMCID: PMC4406395, Hu. X., li. J.. Fu, M. et al. The JAK / STAT signaling pathway; from bench to clinic. Sig Transduct Target Ther 6, 402 (2021). https: / / doi.org / 10.1038 / s41392-021-00791-l, the entire contents of which are incorporated herein by reference for all purposes.

[0209] The JAK2-V617F variant (comprising a phenylalanine at amino acid position 617 (a valine in the wild-type amino acid sequence)) is known as a constitutively active gain of function variant. See, e.g., Levine, R., Pardanani, A., Tefferi, A. et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7, 673-683 (2007).Attorney Docket No. 66504.13WO01https: / / doi.org / 10.1038 / nrc2210, the entire contents of which are incorporated herein by reference for all purposes. The JAK2-V617F variant is associated with several breakpoint cluster region (BCR) / Abelson (ABL)-negative myeloproliferative disorders. See, e.g., Jedidi, Abire et al. “Selective reduction of JAK2V617F-dependent cell growth by siRNA / shRNA and its reversal by cytokines.” Blood vol. 114,9 (2009): 1842-51. doi:10.1182 / blood-2008-09-176875 (hereinafter “Jedidi 2009”), the entire contents of which are incorporated herein by reference for all purposes.

[0210] The mRNA sequence of an exemplary reference {e.g., exemplary wild-type) human JAK2 (hJAK.2) gene is set forth in SEQ ID NO: 267. The reverse complement sequence of the exemplary reference {e.g., exemplary wild-type) hJAK2 mRNA is set forth in SEQ ID NO: 268. The amino acid sequence of the exemplary reference {e.g., exemplary wild-type) hJAK2 protein encoded by the hJAK2 exemplary reference {e.g., exemplary wild-type) gene is set forth in SEQ ID NO: 269.

[0211] The mRNA sequence of a hJAK2-V617F variant gene is set forth in SEQ ID NO: 270. The reverse complement sequence of the hJAK2-V617F variant mRNA is set forth in SEQ ID NO: 271. The amino acid sequence of a variant hJAK2 protein comprising a phenylalanine at amino acid position 617 (numbering according to SEQ ID NO: 269) is set forth in SEQ ID NO: 272 (the JAK2-V617F variant). See Table 1, herein.Table 1. The Nucleic Acid and Amino Acid Sequences of Reference and Variant JAK2 Sequences.Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO01Attorney Docket No. 66504.13WO015.2.1 RNAi Agents

[0212] In specific embodiments, the JAK2-V617F targeting inhibitory oligonucleotide comprises or consists of an RNAi agent. As described above, RNAi agents include, e.g., siRNA molecules, shRNA molecules, and miRNA molecules. In some embodiments, the RNAi agent is a siRNA. In some embodiments, the RNAi agent is a miRNA. In some embodiments, the RNAi agent is a shRNA.

[0213] In some embodiments, the RNAi agent comprises one or more RNA molecule. In some embodiments, the RNAi agent comprises an antisense strand. In some embodiments, the RNAi agent comprises a sense strand. In some embodiments, the agent comprises one or more single stranded RNA (ssRNA) molecules. In some embodiments, the RNAi agent comprises a dsRNA agent.

[0214] In some embodiments, the RNAi agent comprises a dsRNA agent comprising a sense strand and an antisense strand. In some embodiments, the RNAi agent comprises a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, the 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.5.2.1.1 Antisense Strand(i) Overall Length

[0215] 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 fromAttorney Docket No. 66504.13WO01about 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, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 26-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0216] In some embodiments, the 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. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.(ii) Targeting Region

[0217] 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F mRNA)).

[0218] 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%,Attorney Docket No. 66504.13WO0190%, 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F mRNA)). 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 the target nucleic acid molecule (e.g., a target mRNA (e.g., a JAK2-V617F mRNA), a portion of a target mRNA (e.g., aJAK2-V617F 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F mRNA)).

[0219] 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 JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1 (e.g., 0) non-complementary nucleotide mismatch relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 nonAttorney Docket No. 66504.13WO01complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. Methods known in the art and described herein can be utilized to evaluate the effect of any non-complementary mismatches between an antisense strand and a target nucleic acid molecule on functional properties (e.g., inhibition of expression of the target nucleic acid molecule (e.g., a target mRNA (e.g., a JAK2-V617F mRNA), a portion of a target mRNA (e.g., a JAK2-V617F mRNA))).

[0220] 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, theAttorney Docket No. 66504.13WO01region 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.

[0221] 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 JAK2-V617F mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA {e.g., a JAK2-V617F 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).

[0222] In some embodiments, the target nucleic acid molecule is a target mRNA {e.g., a JAK2-V617F 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 JAK2-V617F mRNA). In some embodiments, the target nucleic acid molecule is at least a portion {e.g., a portion) of an mRNA {e.g., a JAK2-V617F mRNA) formed in the expression of a target gene, nucleic acid {e.g., mRNA), and / or protein {e.g., a mammalian, primate, human, non-human primate, mouse, and / or rat gene) {e.g., a JAK2-V617F gene). In some embodiments, the target nucleic acid molecule is at least a portion {e.g., a portion) of a JAK2-V617F {e.g., hJAK2-V617F) 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 JAK2-V617F {e.g., hJAK2-V617F) 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: 270 (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 encoded by a target gene, nucleic acid {e.g., mRNA), and / or protein. In some embodiments, the target nucleic acid molecule comprises at least a portion {e.g., a portion) of an mRNA encoding a JAK2-V617F {e.g., hJAK2-V617F) 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: 258 (or a variant or fragment thereof).

[0223] In some embodiments, the target nucleic acid molecule comprises or consists of fromAttorney Docket No. 66504.13WO01about 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 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.(iii) Exemplary Antisense Strands

[0224] 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 Table 2 or Table 14. 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 Table 2 or Table 14. 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 Table 2 or Table 14. 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 Table 2 or Table 14.Attorney Docket No. 66504.13WO01

[0225] 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 Table 2 or Table 14. 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 Table 2 or Table 14. 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 Table 2 or Table 14.

[0226] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or Table 14. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 14.

[0227] 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 set forth in Table 2 or Table 14 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0228] 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: 311-348 or 391-411. 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)Attorney Docket No. 66504.13WO01nucleotides from the nucleotide sequence of any one of the antisense strands set forth in SEQ ID NOS: 311-348 or 391-411. 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: 311-348 or 391-411. 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: 311-348 or 391-411.

[0229] 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 SEQ ID NO: 311. 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 set forth in SEQ ID NO: 311. 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 SEQ ID NO: 311. 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 SEQ ID NO: 311.

[0230] 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 SEQ ID NO: 312. 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 set forth in SEQ ID NO: 312. 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 SEQ ID NO: 312. 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)Attorney Docket No. 66504.13WO01nucleotides from the nucleotide sequence set forth in SEQ ID NO: 312.

[0231] 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 SEQ ID NO: 313. 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 set forth in SEQ ID NO: 313. 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 SEQ ID NO: 313. 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 SEQ ID NO: 313.

[0232] 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 SEQ ID NO: 314. 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 set forth in SEQ ID NO: 314. 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 SEQ ID NO: 314. 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 SEQ ID NO: 314.

[0233] 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 SEQ ID NO: 315. 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 nucleotideAttorney Docket No. 66504.13WO01sequence set forth in SEQ ID NO: 315. 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 SEQ ID NO: 315. 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 SEQ ID NO: 315.

[0234] 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 SEQ ID NO: 391. 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 set forth in SEQ ID NO: 391. 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 SEQ ID NO: 391. 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 SEQ ID NO: 391.

[0235] 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 SEQ ID NO: 392. 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 set forth in SEQ ID NO: 392. 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 SEQ ID NO: 392. 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 SEQ ID NO: 392.

[0236] In some embodiments, the antisense strand comprises at least 15 {e.g., 15, 16, 17, 18,Attorney Docket No. 66504.13WO0119, 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 SEQ ID NO: 393. 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 set forth in SEQ ID NO: 393. 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 SEQ ID NO: 393. 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 SEQ ID NO: 393.

[0237] 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 SEQ ID NO: 394. 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 set forth in SEQ ID NO: 394. 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 SEQ ID NO: 394. 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 SEQ ID NO: 394.

[0238] 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 SEQ ID NO: 395. 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 set forth in SEQ ID NO: 395. 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 nucleotidesAttorney Docket No. 66504.13WO01differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 395. 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 SEQ ID NO: 395.

[0239] 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: 311-348 or 391-411. 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: 311-348 or 391-411. 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: 311-348 or 391-411.

[0240] 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 SEQ ID NO: 311. 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 SEQ ID NO: 311. 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 SEQ ID NO: 311.

[0241] 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 SEQ ID NO: 312. In some embodiments, theAttorney Docket No. 66504.13WO01antisense 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 SEQ ID NO: 312. 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 SEQ ID NO: 312.

[0242] 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 SEQ ID NO: 313. 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 SEQ ID NO: 313. 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 SEQ ID NO: 313.

[0243] 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 SEQ ID NO: 314. 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 SEQ ID NO: 314. 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 SEQ ID NO: 314.

[0244] 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,Attorney Docket No. 66504.13WO0120-21 , 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 SEQ ID NO: 315. 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 SEQ ID NO: 315. 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 SEQ ID NO: 315.

[0245] 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 SEQ ID NO: 391. 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 SEQ ID NO: 391. 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 SEQ ID NO: 391.

[0246] 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 SEQ ID NO: 392. 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 SEQ ID NO: 392. 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 SEQ ID NO: 392.

[0247] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22,Attorney Docket No. 66504.13WO0115-21, 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. ., 0, 1. 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 393. 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 SEQ ID NO: 393. 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 SEQ ID NO: 393.

[0248] 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 SEQ ID NO: 394. 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 SEQ ID NO: 394. 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 SEQ ID NO: 394.

[0249] 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 SEQ ID NO: 395. 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 SEQ ID NO: 395. 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 SEQ ID NO:Attorney Docket No. 66504.13WO01395.

[0250] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 311-348 or 391-411 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: 311-348 or 391-411. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 311-348 or 391-411.

[0251] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 311 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 311. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 311.

[0252] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 312 differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 312. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 312.

[0253] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 313 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 313. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 313.

[0254] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 314 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 314. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 314.

[0255] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 315 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 315. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ IDAttorney Docket No. 66504.13WO01NO: 315.

[0256] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 391 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 391. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 391.

[0257] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 392 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 392. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 392.

[0258] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 393 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 393. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 393.

[0259] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 394 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 394. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 394.

[0260] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 395 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth SEQ ID NO: 395. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 395.

[0261] 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: 311-348 or 391-411 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-Attorney Docket No. 66504.13WO013, 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0262] 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 SEQ ID NO: 311 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0263] 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 SEQ ID NO: 312 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0264] 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 SEQ ID NO: 313 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0265] 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 SEQ ID NO: 314 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.Attorney Docket No. 66504.13WO01

[0266] 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 SEQ ID NO: 315 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0267] 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 SEQ ID NO: 391 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0268] 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 SEQ ID NO: 392 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0269] 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 SEQ ID NO: 393 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0270] 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 nucleotideAttorney Docket No. 66504.13WO01sequence set forth in SEQ ID NO: 394 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0271] 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 SEQ ID NO: 395 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0272] 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14.

[0273] 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 the antisense strand of dsRNA agent 1 as set forth in Table 2. 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,Attorney Docket No. 66504.13WO0120, 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 dsRNA agent 1 as set forth in Table 2. 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 dsRNA agent 1 as set forth in Table 2. 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 the antisense strand of dsRNA agent 1 as set forth in Table 2.

[0274] 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 the antisense strand of dsRNA agent 2 as set forth in Table 2. 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 dsRNA agent 2 as set forth in Table 2. 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 dsRNA agent 2 as set forth in Table 2. 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 the antisense strand of dsRNA agent 2 as set forth in Table 2.

[0275] 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 the antisense strand of dsRNA agent 3 as set forth in Table 2. 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 dsRNA agent 3 as set forth in Table 2. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26,Attorney Docket No. 66504.13WO0127, 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 dsRNA agent 3 as set forth in Table 2. 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 the antisense strand of dsRNA agent 3 as set forth in Table 2.

[0276] 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 the antisense strand of dsRNA agent 4 as set forth in Table 2. 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 dsRNA agent 4 as set forth in Table 2. 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 dsRNA agent 4 as set forth in Table 2. 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 the antisense strand of dsRNA agent 4 as set forth in Table 2.

[0277] 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 the antisense strand of dsRNA agent 5 as set forth in Table 2. 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 dsRNA agent 5 as set forth in Table 2. 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 dsRNA agent 5 as set forth in Table 2. In some embodiments, the antisense strand comprises at least 23 {e.g., 24,Attorney Docket No. 66504.13WO0125, 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 the antisense strand of dsRNA agent 5 as set forth in Table 2.

[0278] 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 the antisense strand of dsRNA agent 43 as set forth in Table 14. 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 dsRNA agent 43 as set forth in Table 14. 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 dsRNA agent 43 as set forth in Table 14. 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 the antisense strand of dsRNA agent 43 as set forth in Table 14.

[0279] 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 the antisense strand of dsRNA agent 44 as set forth in Table 14. 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 dsRNA agent 44 as set forth in Table 14. 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 dsRNA agent 44 as set forth in Table 14. 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 the antisense strand of dsRNA agent 44 as set forth in Table 14.Attorney Docket No. 66504.13WO01

[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 the antisense strand of dsRNA agent 45 as set forth in Table 14. 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 dsRNA agent 45 as set forth in Table 14. 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 dsRNA agent 45 as set forth in Table 14. 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 the antisense strand of dsRNA agent 45 as set forth in Table 14.

[0281] 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 the antisense strand of dsRNA agent 46 as set forth in Table 14. 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 dsRNA agent 46 as set forth in Table 14. 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 dsRNA agent 46 as set forth in Table 14. 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 the antisense strand of dsRNA agent 46 as set forth in Table 14.

[0282] 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. 66504.13WO01sequence of the antisense strand of dsRNA agent 47 as set forth in Table 14. 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 dsRNA agent 47 as set forth in Table 14. 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 dsRNA agent 47 as set forth in Table 14. 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 the antisense strand of dsRNA agent 47 as set forth in Table 14.

[0283] 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14. 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 of any one of dsRNA agents 1-84 set forth in Table 2 or Table 14.

[0284] 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 dsRNA agent 1 as set forth in Table 2. 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 moreAttorney Docket No. 66504.13WO01than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of dsRNA agent 1 as set forth in Table 2. 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 strands of dsRNA agent 1 as set forth in Table 2.

[0285] 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 dsRNA agent 2 as set forth in Table 2. 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 dsRNA agent 2 as set forth in Table 2. 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 strands of dsRNA agent 2 as set forth in Table 2.

[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 the antisense strand of dsRNA agent 1 as set forth in Table 14. 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 dsRNA agent 3 as set forth in Table 2. 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 strands of dsRNA agent 3 as set forth in Table 2.

[0287] 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,Attorney Docket No. 66504.13WO0117-20, 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 dsRNA agent 4 as set forth in Table 2. 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 dsRNA agent 4 as set forth in Table 2. 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 strands of dsRNA agent 4 as set forth in Table 2.

[0288] 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 dsRNA agent 5 as set forth in Table 2. 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 dsRNA agent 5 as set forth in Table 2. 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 strands of dsRNA agent 5 as set forth in Table 2.

[0289] 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 dsRNA agent 43 as set forth in Table 14. 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 dsRNA agent 43 as set forth in Table 14. In some embodiments, the antisense strand comprisesAttorney Docket No. 66504.13WO01from 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 strands of dsRNA agent 43 as set forth in Table 14.

[0290] 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 dsRNA agent 44 as set forth in Table 14. 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 dsRNA agent 44 as set forth in Table 14. 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 strands of dsRNA agent 44 as set forth in Table 14.

[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 dsRNA agent 45 as set forth in Table 14. 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 dsRNA agent 45 as set forth in Table 14. 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 strands of dsRNA agent 45 as set forth in Table 14.

[0292] 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)Attorney Docket No. 66504.13WO01nucleotides from the nucleotide sequence of the antisense strand of dsRNA agent 46 as set forth in Table 14. 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 dsRNA agent 46 as set forth in Table 14. 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 strands of dsRNA agent 46 as set forth in Table 14.

[0293] 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 dsRNA agent 47 as set forth in Table 14. 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 dsRNA agent 47 as set forth in Table 14. 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 strands of dsRNA agent 47 as set forth in Table 14.

[0294] 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 1-84 set forth in Table 2 or Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14.

[0295] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 1 as set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 1 set forth in Table 2.Attorney Docket No. 66504.13WO01

[0296] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 2 as set forth in Table 2 differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 2 set forth in Table 2.

[0297] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 3 as set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 3 set forth in Table 2.

[0298] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 4 as set forth in Table 2 differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 4 set forth in Table 2.

[0299] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 5 as set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 5 set forth in Table 2.

[0300] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 43 as set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 43 set forth in Table 14.

[0301] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 44 as set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 44 set forth in Table 14.

[0302] In some embodiments, the nucleotide sequence of the antisense strand comprises theAttorney Docket No. 66504.13WO01nucleotide sequence of the antisense strand of dsRNA agent 45 as set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 45 set forth in Table 14.

[0303] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 46 as set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 46 set forth in Table 14.

[0304] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strand of dsRNA agent 47 as set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of the antisense strands of dsRNA agent 47 set forth in Table 14.

[0305] 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 1-84 set forth in Table 2 or Table 14 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0306] 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 the antisense strand of dsRNA agent 1 set forth in Table 2 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0307] The disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16,Attorney Docket No. 66504.13WO0117, 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 the antisense strand of dsRNA agent 2 set forth in Table 2 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0308] 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 the antisense strand of dsRNA agent 3 set forth in Table 2 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0309] 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 the antisense strand of dsRNA agent 4 set forth in Table 2 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0310] 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 the antisense strand of dsRNA agent 5 set forth in Table 2 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.Attorney Docket No. 66504.13WO01

[0311] 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 the antisense strand of dsRNA agent 43 set forth in Table 14 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0312] 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 the antisense strand of dsRNA agent 44 set forth in Table 14 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0313] 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 the antisense strand of dsRNA agent 45 set forth in Table 14 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0314] 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 the antisense strand of dsRNA agent 46 set forth in Table 14 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 JAK2-V617F mRNA transcript targeted by theAttorney Docket No. 66504.13WO01select antisense strand.

[0315] 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 the antisense strand of dsRNA agent 47 set forth in Table 14 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 JAK2-V617F mRNA transcript targeted by the select antisense strand.

[0316] It is to be understood, that although the antisense strands set forth in Table 2 are not described as being modified {e.g., comprising chemically modified nucleotides), conjugated, etc., the disclosure includes any antisense strand set forth in Table 2 that is unmodified, unconjugated, modified {e.g., as described herein), or conjugated {e.g., as described herein).5.2.1.2 Sense Strand(i) Antisense Strand Complementarity

[0317] 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).

[0318] In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0319] 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. 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%, orAttorney Docket No. 66504.13WO01100% complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0320] 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-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 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 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 I) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity.

[0321] 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,Attorney Docket No. 66504.13WO01or 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 lengths are also contemplated to be part of the disclosure.(ii) Overall Length

[0322] 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 about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the sense strand comprises 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, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30. 26-30. 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0323] 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 aboutAttorney Docket No. 66504.13WO0119, 20, 21, 22, 23 nucleotides. Tn 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 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.(iii) Exemplary Sense Strands

[0324] 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 Table 2 or Table 14. 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 Table 2 or Table 14. 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 Table 2 or Table 14. 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 Table 2 or Table 14.

[0325] 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 Table 2 or Table 14. 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 Table 2 or Table 14. 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)Attorney Docket No. 66504.13WO01nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 14.

[0326] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or Table 14. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 14.

[0327] Table 2 or Table 14 further identifies the target nucleic acid molecule within the reference JAK2-V617F 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 any one of the sense strands set forth in Table 2 or Table 14 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0328] 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: 273-310 or 349-390. 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: 273-310 or 349-390. 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 set forth in any one of SEQ ID NOS: 273-310 or 349-390. 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: 273-310 or 349-390.

[0329] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19,Attorney Docket No. 66504.13WO0120, 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 SEQ ID NO: 1 . 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 the sense strand set forth in SEQ ID NO: 273. 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 set forth in SEQ ID NO: 273. 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 SEQ ID NO: 273.

[0330] 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 SEQ ID NO: 274. 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 the sense strand set forth in SEQ ID NO: 274. 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 set forth in SEQ ID NO: 274. 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 SEQ ID NO: 274.

[0331] 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 SEQ ID NO: 275. 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 the sense strand set forth in SEQ ID NO: 275. 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 byAttorney Docket No. 66504.13WO01no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 275. 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 SEQ ID NO: 275.

[0332] 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 SEQ ID NO: 276. 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 the sense strand set forth in SEQ ID NO: 276. 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 set forth in SEQ ID NO: 276. 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 SEQ ID NO: 276.

[0333] 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 SEQ ID NO: 277. 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 the sense strand set forth in SEQ ID NO: 277. 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 set forth in SEQ ID NO: 277. 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 SEQ ID NO: 277.

[0334] 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 forthAttorney Docket No. 66504.13WO01SEQ ID NO: 349. 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 the sense strand set forth in SEQ ID NO: 349. 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 set forth in SEQ ID NO: 349. 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 SEQ ID NO: 349.

[0335] 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 SEQ ID NO: 350. 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 the sense strand set forth in SEQ ID NO: 350. 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 set forth in SEQ ID NO: 350. 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 SEQ ID NO: 350.

[0336] 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 SEQ ID NO: 351. 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 the sense strand set forth in SEQ ID NO: 351. 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 set forth in SEQ ID NO: 351. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28,Attorney Docket No. 66504.13WO0129, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 351.

[0337] 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 SEQ ID NO: 352. 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 the sense strand set forth in SEQ ID NO: 352. 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 set forth in SEQ ID NO: 352. 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 SEQ ID NO: 352.

[0338] 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 SEQ ID NO: 353. 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 the sense strand set forth in SEQ ID NO: 353. 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 set forth in SEQ ID NO: 353. 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 SEQ ID NO: 353.

[0339] 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: 273-310 or 349-Attorney Docket No. 66504.13WO01390. 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: 273-310 or 349-390. 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: 273-310 or 349-390.

[0340] 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 SEQ ID NO: 273. 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 SEQ ID NO: 273. 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 SEQ ID NO: 273.

[0341] 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 SEQ ID NO: 274. 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 SEQ ID NO: 274. 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 SEQ ID NO: 274.

[0342] 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 SEQ ID NO: 275. In some embodiments, theAttorney Docket No. 66504.13WO01sense 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 SEQ ID NO: 275. 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 SEQ ID NO: 275.

[0343] 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 SEQ ID NO: 276. 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 SEQ ID NO: 276. 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 SEQ ID NO: 276.

[0344] 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 SEQ ID NO: 277. 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 SEQ ID NO: 277. 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 SEQ ID NO: 277.

[0345] 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 SEQ ID NO: 349. 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,Attorney Docket No. 66504.13WO0121-22, 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 SEQ ID NO: 349. 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 SEQ ID NO: 349.

[0346] 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 SEQ ID NO: 350. 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 SEQ ID NO: 350. 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 SEQ ID NO: 350.

[0347] 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 SEQ ID NO: 351. 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 SEQ ID NO: 351. 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 SEQ ID NO: 351.

[0348] 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 SEQ ID NO: 352. 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) nucleotidesAttorney Docket No. 66504.13WO01from the nucleotide sequence set forth in SEQ ID NO: 352. 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 SEQ ID NO: 352.

[0349] 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 SEQ ID NO: 353. 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 SEQ ID NO: 353. 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 SEQ ID NO: 353.

[0350] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 273-310 or 349-390 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: 273-310 or 349-390. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 273-310 or 349-390.

[0351] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 273 differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 273. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 273.

[0352] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 274 differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 274. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 274.

[0353] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 275 differing by no more than 3 {e.g., 0, 1, 2, or 3)Attorney Docket No. 66504.13WO01nucleotides from the nucleotide sequence set forth in SEQ ID NO: 275. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 275.

[0354] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 276 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 276. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 276.

[0355] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 277 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 277. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 277.

[0356] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 349 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 349. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 349.

[0357] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 350 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 350. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 350.

[0358] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 351 differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 351. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 351.

[0359] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 352 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 352. In some embodiments, theAttorney Docket No. 66504.13WO01nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 352.

[0360] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 353 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 353. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 353.

[0361] 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 set forth in any one of SEQ ID NOS: 273-310 or 349-390 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0362] 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 set forth in SEQ ID NO: 273 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0363] 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 set forth in SEQ ID NO: 274 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0364] 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))) contiguousAttorney Docket No. 66504.13WO01nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 275 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0365] 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 set forth in SEQ ID NO: 276 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0366] 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 set forth in SEQ ID NO: 277 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0367] 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 set forth in SEQ ID NO: 349 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0368] 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 set forth in SEQ ID NO: 350 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 leastAttorney Docket No. 66504.13WO01partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the JAK2-V617F mRNA transcript identical to the select sense strand.

[0369] 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 set forth in SEQ ID NO: 351 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0370] 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 set forth in SEQ ID NO: 352 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0371] 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 set forth in SEQ ID NO: 353 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 JAK2-V617F mRNA transcript identical to the select sense strand.

[0372] 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14. In some embodiments, the sense strandAttorney Docket No. 66504.13WO01comprises 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14.

[0373] 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 the sense strand of dsRNA agent 1 set forth in Table 2. 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 the sense strand of dsRNA agent 1 set forth in Table 2. 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 the sense strand of dsRNA agent 1 set forth in Table 2. 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 the sense strand of dsRNA agent 1 set forth in Table 2.

[0374] 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 the sense strand of dsRNA agent 2 set forth in Table 2. 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 the sense strand of dsRNA agent 2 set forth in Table 2. 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 the sense strand of dsRNA agent 2 set forth in Table 2. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30)Attorney Docket No. 66504.13WO01contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of dsRNA agent 2 set forth in Table 2.

[0375] 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 the sense strand of dsRNA agent 3 set forth in Table 2. 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 the sense strand of dsRNA agent 3 set forth in Table 2. 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 the sense strand of dsRNA agent 3 set forth in Table 2. 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 the sense strand of dsRNA agent 3 set forth in Table 2.

[0376] 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 the sense strand of dsRNA agent 4 set forth in Table 2. 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 the sense strand of dsRNA agent 4 set forth in Table 2. 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 the sense strand of dsRNA agent 4 set forth in Table 2. 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 the sense strand of dsRNA agent 4 set forth in Table 2.

[0377] 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 theAttorney Docket No. 66504.13WO01sense strand of dsRNA agent 5 set forth in Table 2. 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 the sense strand of dsRNA agent 5 set forth in Table 2. 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 the sense strand of dsRNA agent 5 set forth in Table 2. 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 the sense strand of dsRNA agent 5 set forth in Table 2.

[0378] 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 the sense strand of dsRNA agent 43 set forth in Table 14. 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 the sense strand of dsRNA agent 43 set forth in Table 14. 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 the sense strand of dsRNA agent 43 set forth in Table 14. 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 the sense strand of dsRNA agent 43 set forth in Table 14.

[0379] 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 the sense strand of dsRNA agent 44 set forth in Table 14. 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 the sense strand of dsRNA agent 44 set forth in Table 14. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g.,Attorney Docket No. 66504.13WO0121, 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 sense strand of dsRNA agent 44 set forth in Table 14. 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 the sense strand of dsRNA agent 44 set forth in Table 14.

[0380] 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 the sense strand of dsRNA agent 45 set forth in Table 14. 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 the sense strand of dsRNA agent 45 set forth in Table 14. 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 the sense strand of dsRNA agent 45 set forth in Table 14. 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 the sense strand of dsRNA agent 45 set forth in Table 14.

[0381] 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 the sense strand of dsRNA agent 46 set forth in Table 14. 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 the sense strand of dsRNA agent 46 set forth in Table 14. 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 the sense strand of dsRNA agent 46 set forth in Table 14. 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 the sense strand of dsRNA agent 46 set forth in Table 14.Attorney Docket No. 66504.13WO01

[0382] 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 the sense strand of dsRNA agent 47 set forth in Table 14. 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 the sense strand of dsRNA agent 47 set forth in Table 14. 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 the sense strand of dsRNA agent 47 set forth in Table 14. 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 the sense strand of dsRNA agent 47 set forth in Table 14.

[0383] 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14.

[0384] 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 the sense strand of dsRNA agent 1 set forth in TableAttorney Docket No. 66504.13WO012. 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 the sense strand of dsRNA agent 1 set forth in Table 2. 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 the sense strand of dsRNA agent 1 set forth in Table 2.

[0385] 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 the sense strand of dsRNA agent 2 set forth in Table 2. 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 the sense strand of dsRNA agent 2 set forth in Table 2. 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 the sense strand of dsRNA agent 2 set forth in Table 2.

[0386] 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 the sense strand of dsRNA agent 3 set forth in Table 2. 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 the sense strand of dsRNA agent 3 set forth in Table 2. 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 the sense strand of dsRNA agent 3 set forth in Table 2.

[0387] 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,Attorney Docket No. 66504.13WO0120-21 , 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 dsRNA agent 4 set forth in Table 2. 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 the sense strand of dsRNA agent 4 set forth in Table 2. 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 the sense strand of dsRNA agent 4 set forth in Table 2.

[0388] 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 the sense strand of dsRNA agent 5 set forth in Table 2. 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 the sense strand of dsRNA agent 5 set forth in Table 2. 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 the sense strand of dsRNA agent 5 set forth in Table 2.

[0389] 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 the sense strand of dsRNA agent 43 set forth in Table 14. 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 the sense strand of dsRNA agent 43 set forth in Table 14. 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 the sense strand of dsRNA agent 43 set forth in Table 14.

[0390] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-Attorney Docket No. 66504.13WO0121, 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. ., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the sense strand of dsRNA agent 44 set forth in Table 14. 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 the sense strand of dsRNA agent 44 set forth in Table 14. 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 the sense strand of dsRNA agent 44 set forth in Table 14.

[0391] 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 the sense strand of dsRNA agent 45 set forth in Table 14. 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 the sense strand of dsRNA agent 45 set forth in Table 14. 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 the sense strand of dsRNA agent 45 set forth in Table 14.

[0392] 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 the sense strand of dsRNA agent 46 set forth in Table 14. 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 the sense strand of dsRNA agent 46 set forth in Table 14. 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) nucleotidesAttorney Docket No. 66504.13WO01from the nucleotide sequence of the sense strand of dsRNA agent 46 set forth in Table 14.

[0393] 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 the sense strand of dsRNA agent 47 set forth in Table 14. 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 the sense strand of dsRNA agent 47 set forth in Table 14. 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 the sense strand of dsRNA agent 47 set forth in Table 14.

[0394] 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 1-84 set forth in Table 2 or Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or Table 14. 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 1-84 set forth in Table 2 or Table 14.

[0395] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 1 set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 1 set forth in Table 2.

[0396] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 2 set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 2 set forth in Table 2.

[0397] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 3 set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In someAttorney Docket No. 66504.13WO01embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 3 set forth in Table 2.

[0398] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 4 set forth in Table 2 differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 4 set forth in Table 2.

[0399] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 5 set forth in Table 2 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 5 set forth in Table 2.

[0400] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 43 set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 43 set forth in Table 14.

[0401] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 44 set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 44 set forth in Table 14.

[0402] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 45 set forth in Table 14 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 14. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 45 set forth in Table 14.

[0403] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of dsRNA agent 46 set forth in Table 14 differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the sense strand set fo...

Claims

1. Attorney Docket No. 66504.13WO01CLAIMSWhat is claimed is:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of JAK2-V617F, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and whereina. 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 SEQ ID NO: 311; 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 set forth in SEQ ID NO: 273;b. 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 SEQ ID NO: 312; 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 set forth in SEQ ID NO: 274;c. 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 SEQ ID NO: 313; 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 set forth in SEQ ID NO: 275;d. 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 SEQ ID NO: 314; 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 set forth in SEQ ID NO: 276; ore. 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 SEQ ID NO: 315; 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 set forth in SEQ ID NO: 277.Attorney Docket No. 66504.13WO012. A dsRNA agent for inhibiting expression of JAK2-V617F, 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 differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 311; 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 set forth in SEQ ID NO: 273; b. 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 SEQ ID NO: 312; 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 set forth in SEQ ID NO: 274; c. 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 SEQ ID NO: 313; 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 set forth in SEQ ID NO: 275; d. 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 SEQ ID NO: 314; 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 set forth in SEQ ID NO: 276; ore. 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 SEQ ID NO: 315; 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 set forth in SEQ ID NO: 277.

3. A dsRNA agent for inhibiting expression of JAK2-V617F, 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: 311; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 273;b. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 312; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 274;Attorney Docket No. 66504.13WO01c. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 313; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 275;d. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 314; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 276; or e. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 315; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 277.

4. A dsRNA agent for inhibiting expression of Janus kinase 2 V617F (JAK2-V617F), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and whereina. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO; 391: and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 349;b. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO; 392; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 350;c. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 393; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 351;d. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 394; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 352; or e. the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in SEQ ID NO: 395; and the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in SEQ ID NO: 353.

5. A dsRNA agent for inhibiting expression of JAK2-V617F, 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 differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in SEQ ID NO:Attorney Docket No. 66504.13WO01391 ; 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 set forth in SEQ ID NO: 349:b. 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 SEQ ID NO: 392; 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 set forth in SEQ ID NO: 350;c. 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 SEQ ID NO: 393; 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 set forth in SEQ ID NO: 351;d. 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 SEQ ID NO: 394; 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 set forth in SEQ ID NO: 352; ore. 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 SEQ ID NO: 395; 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 set forth in SEQ ID NO: 353.

6. A dsRNA agent for inhibiting expression of JAK2-V617F, 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 differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in SEQ ID NO: 391; 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 set forth in SEQ ID NO: 349; b. 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 SEQ ID NO: 392;Attorney Docket No. 66504.13WO01and 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 SEQ ID NO: 350; c. 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 SEQ ID NO: 393; 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 set forth in SEQ ID NO: 351; d. 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 SEQ ID NO: 394; 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 set forth in SEQ ID NO: 352; ore. 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 SEQ ID NO: 395; 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 set forth in SEQ ID NO: 353.

7. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of JAK2-V617F, 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 Table 2 or Table 14 or set forth in any one of SEQ ID NOS: 311-348 or 391-411.

8. The dsRNA agent of claim 7. 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 Table 2 or Table 14 or set forth in any one of SEQ ID NOS: 273-310 or 349-390.

9. The dsRNA agent of claim 7 or 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 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding sense strand set forth in Table 2 or Table 14 or the corresponding sense strand set forth in one of SEQ ID NOS: 273-310 or 349-390.

10. A dsRNA agent for inhibiting expression of JAK2-V617F, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and whereinAttorney Docket No. 66504.13WO01the 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 1-84 set forth in Table 2 or Table 14; 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 Table 2 or Table 14.

11. 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.

12. 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.

13. 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.

14. 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).

15. The dsRNA agent of any one of the preceding claims, wherein (a) the sense strand comprises at least one 2'-O-methyl and / or the antisense strand comprises at least one 2'-O-methyl and / or (b) the sense strand comprises at least one 2'-deoxy-2'-fluoro and / or the antisense strand comprises at least one 2'-deoxy-2'-fluoro.

16. The dsRNA agent of any one of the preceding claims, wherein (a) the sense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro; and the antisense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro.

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

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

19. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises at least one vinyl-phosphonate.Attorney Docket No. 66504.13WO0120. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 5' vinyl-phosphonate.

21. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine) and / or the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine) e.g., wherein the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine).

22. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 5' vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine).

23. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises an (E)-vinylphosphonate 2'-O-methylated (2’-Ome) uridine at the 5’ end.

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

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

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, 26-30, 27-30, 28-3029-30, 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, 26-30, 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.Attorney Docket No. 66504.13WO0130. 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.

31. 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).

32. 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.

33. 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.

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

35. 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).

36. 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).

37. The dsRNA agent of any one of the preceding claims, wherein the dsRNA agent selectively inhibits the expression and / or activity of JAK2-V617F.

38. The dsRNA agent of any one of the preceding claims, wherein the dsRNA agent selectively inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2.

39. The dsRNA agent of any one of the preceding claims, wherein the dsRNA agent preferentially inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2.

40. The dsRNA agent of any one of the preceding claims, wherein the dsRNA agent exhibits greater inhibition of the expression and / or activity of JAK2-V617F relative to wild-type JAK2.

41. The dsRNA agent of any one of the preceding claims, the dsRNA agent does not (or does not substantially) inhibit the expression and / or activity of wild-type JAK2.

42. The dsRNA agent of any one of the preceding claims, the dsRNA agent inhibits the expression and / or activity of JAK2-V617F through binding to an mRNA molecule encoding JAK2-V617F.Attorney Docket No. 66504.13WO0143. The dsRNA agent of any one of the preceding claims, the dsRNA agent inhibits the expression and / or activity of JAK2-V617F through selectively binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.

44. The dsRNA agent of any one of the preceding claims, the dsRNA agent inhibits the expression and / or activity of JAK2-V617F through preferentially binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.

45. The dsRNA agent of any one of the preceding claims, the dsRNA agent mediates one or more of the following degradation of the mRNA molecule, modification of the mRNA molecule, alteration in the splicing of the mRNA molecule, alteration (e.g., a decrease) in the stability of the mRNA molecule, or a block in the translation of the target mRNA molecule, or any combination of the foregoing.

46. A conjugate comprising the dsRNA agent of the preceding claims operably connected to a heterologous moiety.

47. The conjugate of claim 46, wherein the heterologous moiety is a protein, peptide, small molecule, carbohydrate, lipid, or polymer.

48. The conjugate of claim 47, wherein the heterologous moiety is a protein.

49. The conjugate of claim 48, wherein the protein is an antibody.

50. The conjugate of any one of claims 46-49, wherein the heterologous moiety comprises a means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)).

51. A conjugate comprising the dsRNA agent of any one of claims 1-45 operably connected to a means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)).

52. The conjugate of claim 51, wherein the means for binding to TFR (e.g., human TFR (hTFR) (e.g., hTFRl)) is a protein.

53. The conjugate of claim 51 or 52, wherein the means for binding to TFR (e.g., human TFR (hTFR) (e.g., hTFRl)) is an antibody (e.g., an antibody described herein).

54. A conjugate comprising:a. a means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)); operably connected tob. at least one inhibitory oligonucleotide that inhibits (e.g., selectively inhibits) the expression and / or activity of a JAK2 gain of function variant (e.g., JAK2-V617F).Attorney Docket No. 66504.13WO0155. The conjugate of claim 54, wherein the means for binding to transferrin receptor (TFR) (e.g., human TFR (hTFR) (e.g., hTFRl)) comprises a protein.

56. The conjugate of claim 55, wherein the protein is an antibody that specifically binds to the TFR e.g., hTFR (e.g., hTFRl)) (an anti-TFR antibody).

57. A conjugate comprising:a. an antibody that specifically binds to the TFR (e.g., hTFR (e.g., hTFRl)) (an anti- TFR antibody); operably connected tob. at least one inhibitory oligonucleotide that inhibits (e.g., selectively inhibits) the expression and / or activity of a JAK2 gain of function variant (e.g., JAK2-V617F).

58. The conjugate of claim 56 or 57, wherein the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody does not (or does not significantly) block binding of TF (e.g., hTF) to TFR (e.g., hTFR (e.g., hTFRl)).

59. The conjugate of any one of claims 56-58, wherein the anti-TFR (e.g., hTFR (e.g., TFR1)) 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).

60. The conjugate of any one of claims 56-59, wherein the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is an IgG (e.g., a human IgG (hlgG)) antibody.

61. The conjugate of any one of claims 56-60, wherein the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is a hlgGl, h!gG2, h!gG3, or h!gG4 antibody (e.g., a hlgGl or h!gG4 antibody).

62. The conjugate of any one of claims 56-61, wherein the antibody comprises an immunoglobulin (Ig) (e.g., a human Ig (hlg)) Fc region.

63. The conjugate of any one of claims 56-62, 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).

64. The conjugate of any one of claims 56-63, wherein the Ig (e.g., hlg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region.

65. The conjugate of any one of claims 56-64, wherein the Ig (e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region.

66. The conjugate of any one of claims 56-65, wherein the Ig is a hlg.Attorney Docket No. 66504.13WO0167. The conjugate of claim 66, wherein the hlg is a human TgG (hlgG).

68. The conjugate of claim 67, wherein the hlgG is hlgGl or h!gG4.

69. The conjugate of any one of claims 56-68, 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, Fey Ila, and / or Fcyllla))).

70. The conjugate of any one of claims 56-69, wherein the Ig (e.g., hlg) Fc region does not substantially mediate ADCC, does not substantially mediate CDC, and / or does not bind 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))).

71. The conjugate of any one of claims 56-70, wherein the conjugate does not substantially mediate ADCC, does not substantially mediate CDC. and / or does not bind 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))).

72. The conjugate of any one of claims 46-71, 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 target cell, the conjugate is internalized into the target cell; (b) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target 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 target cell, the target cell remains viable; (d) upon internalization into a target cell, the conjugate does not induce death of the target cell; (e) upon binding to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target cell, the conjugate does not induce degradation of TFR (e.g., hTFR (e.g., TFRI)); and / or (f) binding of the conjugate to TFR (e.g., hTFR (e.g., TFR1)) expressed on the surface of a target cell, does not block (or does not significantly block) binding of transferrin (TF) (e.g., hTF) to TFR (e.g., hTFR (e.g., hTFRl)) expressed by the target cell.

73. The conjugate of any one of claims 46-58, wherein binding of the conjugate to TFR (e.g., hTFR (e.g., TFRI)) expressed on the surface of a target cell, does not block (or does not significantly block) binding of transferrin (TF) (e.g., hTF) to TFR (e.g., hTFR (e.g., hTFRl)).Attorney Docket No. 66504.13WO0174. The conjugate of any one of claims 72-73, wherein the target cell is a hematopoietic cell (e.g., in the bone marrow).

75. The conjugate of any one of claims 72-74, wherein the target cell is a hematopoietic pluripotent stem cell (e.g., in the bone marrow).

76. The conjugate of any one of claims 72-75, wherein the target cell is a common myeloid progenitor cell (e.g., in the bone marrow).

77. The conjugate of any one of claims 72-76, wherein the target cell is a megakaryocyte erythroid progenitor cell or an early megakaryocyte (e.g., in the bone marrow).

78. The conjugate of any one of claims 46-77, wherein the at least one inhibitory oligonucleotide inhibits (e.g., selectively inhibits) the expression and / or activity of JAK2-V617F.

79. The conjugate of any one of claims 46-78, wherein the inhibitory oligonucleotide selectively inhibits the expression and / or activity of JAK2-V617F.

80. The conjugate of any one of claims 46-79, wherein the inhibitory oligonucleotide selectively inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2.

81. The conjugate of any one of claims 46-80, wherein the inhibitory oligonucleotide preferentially inhibits the expression and / or activity of JAK2-V617F relative to wild-type JAK2.

82. The conjugate of any one of claims 46-81, wherein the inhibitory oligonucleotide exhibits greater inhibition of the expression and / or activity of JAK2-V617F relative to wild-type JAK2.

83. The conjugate of any one of claims 46-82, wherein the inhibitory oligonucleotide does not (or does not substantially) inhibit the expression and / or activity of wild-type JAK2.

84. The conjugate of any one of claims 46-83, wherein the inhibitory oligonucleotide inhibits the expression and / or activity of JAK2-V617F through binding to an mRNA molecule encoding JAK2-V617F.

85. The conjugate of any one of claims 46-84, wherein the inhibitory oligonucleotide inhibits the expression and / or activity of JAK2-V617F through selectively binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.

86. The conjugate of any one of claims 46-85, wherein the inhibitory oligonucleotide inhibits the expression and / or activity of JAK2-V617F through preferentially binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.

87. The conjugate of any one of claims 46-86, wherein the inhibitory oligonucleotide mediates one or more of the following degradation of the mRNA molecule, modification of theAttorney Docket No. 66504.13WO01mRNA molecule, alteration in the splicing of the mRNA molecule, alteration (e.g., a decrease) in the stability of the mRNA molecule, or a block in the translation of the target mRNA molecule, or any combination of the foregoing.

88. The conjugate of any one of claims 46-87, wherein the inhibitory oligonucleotide comprises or consists of an antisense oligonucleotide (ASO), small interfering RNA (siRNA), a short hairpin RNA (shRNA), or a microRNA (miRNA).

89. The conjugate of any one of claims 46-88, wherein the inhibitory oligonucleotide comprises or consists of an siRNA.

90. The conjugate of any one of claim 46-89, wherein the inhibitory oligonucleotide comprises a sense strand and an antisense strand.

91. The conjugate of any one of claims 46-90, wherein the inhibitory oligonucleotide comprises or consists of an antisense strand comprising a region of complementarity to an mRNA molecule encoding JAK2 gain of function variant.

92. The conjugate of any one of claims 46-91, wherein the inhibitory oligonucleotide comprises or consists of an antisense strand comprising a region of complementarity to an mRNA molecule encoding JAK2-V617F.

93. The conjugate of any one of claims 46-92, wherein the inhibitory oligonucleotide is single stranded or double stranded.

94. The conjugate of any one of claims 46-93, wherein the inhibitory oligonucleotide is a DNA, RNA, or RNA and RNA hybrid molecule.

95. The conjugate of any one of claims 46-94, wherein the inhibitory oligonucleotide comprises a sense strand and an antisense strand forming a double stranded region.

96. The conjugate of any one of claims 46-95, 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).

97. The conjugate of any one of claims 46-96, wherein the sense strand and the antisense strand are separate nucleic acid molecules (i.e., connected only through the double stranded region).

98. The conjugate of any one of claims 46-97, 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-Attorney Docket No. 66504.13WO0129, 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.

99. The conjugate of any one of claims 46-98, wherein the inhibitory oligonucleotide comprises the dsRNA agent of any one of claims 1-28.

100. The conjugate of any one of claims 46-99, wherein the inhibitory oligonucleotide comprises at least one modified nucleotide.

101. The conjugate of any one of claims 46-100, 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 inhibitory oligonucleotide are modified.

102. The conjugate of any one of claims 46-101, wherein substantially all (or all) of the nucleotides in the inhibitory oligonucleotide are modified.

103. The conjugate of any one of claims 46-102, wherein at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).

104. The conjugate of any one of claims 46-103, wherein (a) the sense strand comprises at least one 2'-O-methyl and / or the antisense strand comprises at least one 2'-O-methyl and / or (b) the sense strand comprises at least one 2'-deoxy-2'-fluoro and / or the antisense strand comprises at least one 2'-deoxy-2'-fluoro.

105. The conjugate of any one of claims 46-104, wherein (a) the sense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro; and the antisense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro.

106. The conjugate of any one of claims 46-105, wherein at least one of the modified nucleotides comprises a modified nucleobase.

107. The conjugate of any one of claims 46-106, wherein the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

108. The conjugate of any one of claims 46-107, wherein the antisense strand comprises at least one vinyl-phosphonate.

109. The conjugate of any one of claims 46-108, wherein the antisense strand comprises a 5' vinyl-phosphonate.

110. The conjugate of any one of claims 46-109, wherein the sense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine) and / or theAttorney Docket No. 66504.13WO01antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine) (e.g., wherein the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine).

111. The conjugate of any one of claims 46-110, wherein the antisense strand comprises a 5' vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine).

112. The conjugate of any one of claims 46-111, wherein the antisense strand comprises an (E)-vinylphosphonate 2'-O-methylated (2’-0me) uridine at the 5’ end.

113. The conjugate of any one of claims 46- 112, wherein the sense strand comprises at least one phosphorothioate and / or the antisense strand comprises at least one phosphorothioate.

114. The conjugate of any one of claims 46-113, wherein the sense strand comprises at least one phosphorothioate and the antisense strand comprises at least one phosphorothioate.

115. The conjugate of conjugate of any one of claims 46-114, wherein the at least one modified nucleotide is a 2’ modified nucleotide (e.g., a 2'-fluoro (2'-F), 2'-O-methyl (2'-0-Me), 2'-O-methoxyethyl (2'-M0E). 2 -0- aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-0-DMAOE), 2'-0-dimethylaminopropyl (2'-0-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), 2'-O-N-methylacetamido (2'-0-NMA), locked nucleic acid (LNA), ethylene-bridged nucleic acid (ENA), and (S)- constrained ethyl-bridged nucleic acid (cEt) (e.g., a 2' modified nucleotide is 2'- O-methyl or 2'-fluoro (2'-F))).

116. The conjugate of any one of claims 46- 115, wherein upon internalization into a target cell the conjugate inhibits (e.g., selectively inhibits) the expression and / or activity of JAK2-V617F.

117. The conjugate of any one of claims 46- 116, wherein upon internalization into a target cell the conjugate selectively inhibits the expression and / or activity of JAK2-V617F.

118. The conjugate of any one of claims 46-117, wherein upon internalization into a target cell the conjugate selectively inhibits the expression and / or activity of JAK2-V617F relative to wildtype JAK2.

119. The conjugate of any one of claims 46-118, wherein upon internalization into a target cell the conjugate does not (or does not substantially) inhibit the expression and / or activity of wildtype JAK.2.

120. The conjugate of any one of claims 46-119, wherein upon internalization into a target cell the conjugate inhibits the expression and / or activity of JAK2-V617F through binding to an mRNA molecule encoding JAK2-V617F.Attorney Docket No. 66504.13WO01121. The conjugate of any one of claims 46-120, wherein upon internalization into a target cell the conjugate inhibits the expression and / or activity of JAK2-V617F through selectively binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK.2.

122. The conjugate of any one of claims 46-121, wherein upon internalization into a target cell the conjugate inhibits the expression and / or activity of JAK2-V617F through preferentially binding to an mRNA molecule encoding JAK2-V617F relative to an mRNA encoding wild-type JAK2.

123. The conjugate of any one of claims 46-122, wherein upon internalization into a target cell the conjugate mediates one or more of the following degradation of the mRNA molecule, modification of the mRNA molecule, alteration in the splicing of the mRNA molecule, alteration (e.g., a decrease) in the stability of the mRNA molecule, or a block in the translation of the target mRNA molecule, or any combination of the foregoing.

124. The conjugate of any one of claims 46-123, wherein (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is non-covalently conjugated to (b) the at least one inhibitory oligonucleotide.

125. The conjugate of any one of claims 46-124, wherein (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is covalently conjugated to (b) the at least one inhibitory oligonucleotide.

126. The conjugate of any one of claims 46-125, wherein (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is directly conjugated to (b) the at least one inhibitory oligonucleotide.

127. The conjugate of any one of claims 46-126, wherein (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody is indirectly conjugated to (b) the at least one inhibitory oligonucleotide through (c) a linker.

128. The conjugate of any one of claims 46-127, wherein the linker is cleavable or non-cleavable.

129. The conjugate of any one of claims 46-128, wherein the wherein (b) comprises at least 2, 3, 4, 5, 6. or more inhibitory oligonucleotides.

130. The conjugate of any one of claims 46-129, wherein each of the at least 2, 3, 4, 5, 6, or more inhibitory oligonucleotides are individually conjugated to (a) the anti-TFR (e.g., hTFR (e.g., TFR1)) antibody.

131. 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 1-45.Attorney Docket No. 66504.13WO01132. A carrier comprising the dsRNA agent of any one of claims 1 -45, the conjugate of any one of claims 46-130, or the vector of claim 131.

133. A carrier conjugated to the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, or the vector of claim 131.

134. The carrier of claim 132 or 133, wherein the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, as dendrimer, a cationic delivery system, or a hydrogel.

135. The carrier of claim 134, wherein the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome. or a micelle.

136. A cell (or population of cells) comprising the dsRNA agent of any one of claims 1-46, the conjugate of any one of claims 46-130, or the carrier of any one of claims 132-135.

137. The cell (or population of cells) of claim 136, wherein the cell (or population of cells) is in vitro, ex vivo, or in vivo.

138. A pharmaceutical composition comprising the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, or the cell (or population of cells) of any one of claims 136-137, and a pharmaceutically acceptable excipient.

139. A kit comprising the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138.

140. A method of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell (or a population of cells), the method comprising introducing into a cell (or the population of cells) the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell (or the population of cells).

141. The method of claim 140, wherein the cell is in vitro, ex vivo, or in vivo.

142. The method of claim 140 or 141, wherein the cell is a subject (e.g., a human subject).

143. 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 agentAttorney Docket No. 66504.13WO01of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby deliver the dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to the subject.

144. A method of reducing and / or inhibiting expression and / or activity of a JAK2 gain of function variant (e.g., JAK2-V617F) in a cell (or population of cells), the method comprising introducing into the cell (or the population of cells) the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby reduce and / or inhibit expression and / or activity of the JAK2 gain of function variant (e.g., JAK2-V617F) in the cell (or population of cells).

145. The method of claim 144, wherein the cell (or a population of cells) is in vitro, ex vivo, or in vivo.

146. The method of any one of claims 144-145, wherein the cell (or a population of cells) is a subject (e.g., a human subject).

147. A method of reducing and / or inhibiting expression and / or activity of a JAK2 gain of function variant (e.g., JAK2-V617F) in a cell (or a population of cells) in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45. the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby reduce and / or inhibit expression and / or activity of the JAK2 gain of function variant (e.g., JAK2-V617F) in the cell (or a population of cells) in the subject.

148. The method of any one of claims 140-147, wherein the JAK.2 gain of function variant is JAK2-V617F.

149. A method of reducing and / or inhibiting expression and / or activity of JAK2-V617F in a cell (or population of cells), the method comprising introducing into the cell (or the population of cells) the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) ofAttorney Docket No. 66504.13WO01any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby reduce and / or inhibit expression and / or activity of JAK2-V617F in the cell (or population of cells).

150. The method of any one of claims 140-149, wherein the cell (or a population of cells) is in vitro, ex vivo, or in vivo.

151. The method of any one of claims 140-150, wherein the cell (or a population of cells) is a subject (e.g., a human subject).

152. A method of reducing and / or inhibiting expression and / or activity of JAK2-V617F in a cell (or a population of cells) in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby reduce and / or inhibit expression and / or activity of the JAK2-V617F in the cell (or a population of cells) in the subject.

153. The method of any one of claims 140-152, wherein the cell (or a population of cells) comprises a hematopoietic cell (or a population of hematopoietic cells).

154. The method of any one of claims 140-153, wherein the cell (or a population of cells) comprises a hematopoietic pluripotent stem cell (or a population of hematopoietic pluripotent stem cells).

155. The method of any one of claims 140-154, wherein the cell (or population of cells) comprises one or more myeloid cell (or a population of one or more myeloid cell) (e.g., myeloblasts, erythrocytes, megakaryocytes (e.g., early megakaryocytes), megakaryocyte erythroid progenitor cells, neutrophils, and / or monocytes).

156. A method of reducing the level of a population of myeloid cells in a subject, the method comprising administering to the subject, the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby reduce the level of a population of myeloid cells in the subject.

157. The method of claim 156, wherein the population of myeloid cells comprises myeloblasts, erythrocytes, megakaryocytes (e.g., early megakaryocytes), megakaryocyte erythroid progenitor cells, neutrophils, and / or monocytes.Attorney Docket No. 66504.13WO01158. A method of reducing the level of a platelets in a subject, the method comprising administering to the subject, the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby reduce the level of platelets in the subject.

159. A method of treating, ameliorating, or preventing a disease in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby treat, ameliorate, or prevent the disease in the subject.

160. The method of claim 159. wherein the disease is a myeloproliferative neoplasm, a cancer, or a congestive hepatopathy.

161. The method of claim 159, wherein the disease is polycythemia vera, essential thrombocythemia, primary myelofibrosis, acute myeloid leukemia, or Budd-Chiari syndrome.

162. A method of treating, ameliorating, or preventing a JAK2-V617F mediated disease in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the earner of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby treat, ameliorate, or prevent the JAK2-V617F mediated disease in the subject.

163. The method of claim 162, wherein the JAK2-V617F mediated disease is a myeloproliferative neoplasm, a cancer, or a congestive hepatopathy.

164. The method of claim 162 or 163, wherein the JAK2-V617F mediated disease is polycythemia vera, essential thrombocythemia, primary myelofibrosis, acute myeloid leukemia, or Budd-Chiari syndrome.

165. A method of treating, ameliorating, or preventing a myeloproliferative neoplasm in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the earner of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby treat, ameliorate, or prevent the myeloproliferative neoplasm in the subject.Attorney Docket No. 66504.13WO01166. The method of claim 165, wherein the myeloproliferative neoplasm is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm.

167. The method of claim 165 or 166. wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or primary myelofibrosis.

168. A method of treating, ameliorating, or preventing a cancer in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45. the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby treat, ameliorate, or prevent the cancer in the subject.

169. The method of claim 168, wherein the cancer is a myeloid leukemia.

170. The method of claim 168 or 169. wherein the cancer is acute myeloid leukemia.

171. A method of treating, ameliorating, or preventing a congestive hepatopathy in a subject, the method comprising administering to the subject the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-130, the vector of claim 131, the carrier of any one of claims 132-135, the cell (or population of cells) of any one of claims 136-137, or the pharmaceutical composition of claim 138, to thereby treat, ameliorate, or prevent the congestive hepatopathy in the subject.

172. The method of claim 171, wherein the congestive hepatopathy is Budd-Chiari Syndrome.

173. The method of claims 140-172, further comprising detecting, or having detected, the presence or absence of a genomic (e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2 gain of function variant.

174. The method of claims 140-173, further comprising detecting, or having detected, the presence or absence of a genomic (e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2-V617F variant.

175. The method of claims 140-174, further comprising detecting, or having detected in DNA, RNA, or protein isolated and purified from a sample obtained from the subject, the presence or absence of a genomic (e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2-V617F variant.

176. The method of claims 140-175, wherein the subject has been determined to be homozygous or heterozygous for a genomic (e.g., germline or somatic) mutation in JAK2 that results in expression of a JAK2-V617F variant.Attorney Docket No. 66504.13WO01177. The method of claims 140-176, wherein the genomic (e.g., germline or somatic) mutation in JAK2 comprises the C.1849G>T single nucleotide polymorphism.

178. The method of claims 140-177, wherein the genomic mutation in JAK2 is a germline mutation.

179. The method of claims 140-178, wherein the genomic mutation in JAK2 is a somatic mutation.

180. The method of claims 140-179, wherein the somatic mutation in JAK2 is determined to be present in a subpopulation of cells in the subject.

181. The method of claim 180, wherein the subpopulation of cells comprises hematopoietic cells.

182. The method of any one of claims 181-181, wherein the subpopulation of cells comprises hematopoietic pluripotent stem cells.

183. The method of any one of claims 181-182, wherein the subpopulation of cells comprises common myeloid progenitor cells.

184. The method of any one of claims 181-183, wherein the sample is a blood sample or a bone marrow sample.

185. The method of any one of claims 181-184, wherein the subject is a human.

Images