ACVR2a and ACVR2b RNA interference agents

Abstract

Provided herein are Activin Receptor type 2A (ACVR2A) and Activin Receptor Type 2B (ACVR2B) RNAi agents. Also provided herein are compositions comprising the ACVR2A and / or the ACVR2B RNAi agents conjugated to human transferrin receptor (TfR) binding proteins via a linker or a direct bond. Also provided herein are methods of using ACVR2A RNAi agent(s) in separate, simultaneous, or sequential combination with ACVR2B RNAi agent(s) for treating metabolic disorders, including for example, obesity, overweight, Type 2 diabetes mellitus (T2DM), and metabolic associated steatohepatitis (MASH) in a patient

Description

ACVR2A AND ACVR2B RNA INTERFERENCE AGENTSSEQUENCE LISTNG

[0001] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled 30771_WO.xml created 5 / 13 / 2025 and is 6.76 MB in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.BACKGROUND

[0002] Activin Receptor Type-2A (ACVR2A) and Activin Receptor Type-2B (ACVR2B) genes encode receptors that mediate the functions of activins and other ligands which are members of the transforming growth factor-beta (TGF-beta) superfamily involved in diverse biological processes. For example, several ligands, such as myostatin, GDF-11 and activin A, signal through complexes formed of the ACVR2A and / or ACVR2B type 2 receptors together with type 1 receptors to regulate muscle growth. Studies have shown that blocking ACVR2A and ACVR2B may increase muscle mass while decreasing fat mass, making these two targets promising for the treatment of obesity with the additional benefit of preservation of lean mass (Tsuchida et. al, Cell Commun Signal 7:15, 2009; Heymsfield et. al, JAMA Netw Open 4;4(1), 2021 ; Garito et. al, Diabetes, Obesity and Metabolism, 2018).

[0003] While compounds that block signaling via the ACVR2A and ACVR2B receptors are known in the art, current therapies require once monthly, or even weekly, dosing. Therefore, there remains a need for alternative treatment options to induce targeted, therapeutic weight loss requiring fewer doses. Furthermore, current treatments for weight loss may also cause some incidental loss of lean mass. Therefore, there remains an unmet need for a treatment option that is particularly efficacious at preserving lean mass while inducing loss of fat mass.

[0004] There remains a need for therapeutic agents that can decrease or adjust the expression of the ACVR2A and / or ACVR2B genes, thereby decreasing expression of ACVR2A and / or ACVR2B protein. RNA interference (RNAi) is a highly conserved regulatory mechanism in which RNA molecules are involved in sequence-specific suppression of gene expression bydouble-stranded RNA molecules (dsRNA) (Fire et. al, Nature 391:806-811, 1998). Such RNAi agents are useful in the treatment of diseases involving the regulation of ACVR2A and ACVR2B expression and function, such as obesity and overweight.SUMMARY OF INVENTION

[0005] Provided herein are Activin Receptor Type-2A (ACVR2A) and Activin Receptor Type-2B (ACVR2B) RNAi agents. Also provided herein are RNAi agents that are conjugates of the Formula: R-L-TBP, wherein R is a dsRNA comprising a sense strand and an antisense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic sequence, wherein L is a linker or a direct bond, and wherein TBP is a protein comprising a transferrin receptor (TfR) binding protein (“TBP”).

[0006] Also provided herein are compositions comprising the ACVR2A and the ACVR2B RNAi agents that are conjugates of the above formula. Also provided herein are methods of using an ACVR2A RNAi agent of the above formula in separate, simultaneous, or sequential combination with an ACVR2B RNAi agent of the above formula for treating metabolic disorders, including for example, obesity, overweight, Type 2 diabetes mellitus (T2DM), and metabolic associated steatohepatitis (MASH) in a patient.

[0007] RNAi agents of the present disclosure have one or more of the following advantages: the ability to induce weight loss with preservation of lean mass, improvement of A1C (i.e., lowering or stabilizing A1C values), and extended time of action (i.e., durability) to allow for an extended period of time between doses. Certain RNAi agents of the present disclosure also provide for targeted delivery to muscle via the transferrin receptor and have suitable potency and CMC characteristics to allow for subcutaneous dosing.DETAILED DESCRIPTION

[0008] Provided herein are Activin Receptor Type-2A (ACVR2A) and Activin Receptor Type-2B (ACVR2B) RNAi agents. In some embodiments, the RNAi agents are comprised of a dsRNA comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence. In some embodiments, the RNAi agents provided herein are pharmaceutical compositions comprising a dsRNA comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence.

[0009] In other embodiments, provided herein are RNAi agents that are conjugates of the Formula : R-L-P, wherein R is a dsRNA comprising a sense strand and an antisense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic sequence, wherein L is a linker or a direct bond, and wherein TBP is a protein comprising a TfR binding protein. dsRNA Sequences

[0010] In some embodiments, the dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand is complementary to a target mRNA of ACVR2A of SEQ ID NO:1. In some embodiments, provided herein is an ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:3 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:33; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:4 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:34; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:5 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:35;d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID N0:6 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:36; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:7 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:37; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:8 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:38; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:9 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:39; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:10 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:40; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 11 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:41; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:12 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:42; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 13 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:43; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 14 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:44; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:15 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:45; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 16 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:46; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:17 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:47; p. the first nucleic acid sequence has least 95% sequence identity to SEQ ID NO: 18 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:48; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:19 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:49;r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:20 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:50; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:21 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:51 ; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:22 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:52; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:23 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:53; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:24 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:54; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:25 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:55; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:26 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:56; y. the first nucleic acid sequence has least 95% sequence identity to SEQ ID NO:27 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:57; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:28 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:58; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:29 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:59; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:30 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:60; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:31 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:61; and dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:32 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 62.

[0011] In some embodiments, provided herein is an ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence that has at least 95% sequence identity to the sequence of a sense strand of any one of dsRNA Duplex No. 123-181 as disclosed herein and the antisense strand comprises a second nucleic acid sequence that has at least 95% sequence identity to the sequence of an antisense strand of any one of dsRNA Duplex No. 123-181 as disclosed herein. For example, the first nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 313 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 372, as in dsRNA Duplex No. 123; or the first nucleic acid may have at least 95% sequence identity to SEQ ID NO: 314 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 373, as in dsRNA Duplex No. 124, and so forth; that is, wherein the first nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 313-371, and the second nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 372-430.

[0012] In some embodiments, provided herein is an ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO: 3 and the second nucleic acid sequence comprises SEQ ID NO:33; b. the first nucleic acid sequence comprises SEQ ID NO:4 and the second nucleic acid sequence comprises SEQ ID NO:34; c. the first nucleic acid sequence comprises SEQ ID NO:5 and the second nucleic acid sequence comprises SEQ ID NO:35; d. the first nucleic acid sequence comprises SEQ ID NO:6 and the second nucleic acid sequence comprises SEQ ID NO:36;e. the first nucleic acid sequence comprises SEQ ID NO:7 and the second nucleic acid sequence comprises SEQ ID NO:37; f. the first nucleic acid sequence comprises SEQ ID NO: 8 and the second nucleic acid sequence comprises SEQ ID NO:38; g. the first nucleic acid sequence comprises SEQ ID NO:9 and the second nucleic acid sequence comprises SEQ ID NO:39; h. the first nucleic acid sequence comprises SEQ ID NO: 10 and the second nucleic acid sequence comprises SEQ ID NO:40; i. the first nucleic acid sequence comprises SEQ ID NO: 11 and the second nucleic acid sequence comprises SEQ ID NO:41; j. the first nucleic acid sequence comprises SEQ ID NO: 12 and the second nucleic acid sequence comprises SEQ ID NO:42; k. the first nucleic acid sequence comprises SEQ ID NO: 13 and the second nucleic acid sequence comprises SEQ ID NO:43; l. the first nucleic acid sequence comprises SEQ ID NO: 14 and the second nucleic acid sequence comprises SEQ ID NO:44; m. the first nucleic acid sequence comprises SEQ ID NO: 15 and the second nucleic acid sequence comprises SEQ ID NO:45; n. the first nucleic acid sequence comprises SEQ ID NO: 16 and the second nucleic acid sequence comprises SEQ ID NO:46; o. the first nucleic acid sequence comprises SEQ ID NO: 17 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:47; p. the first nucleic acid sequence comprises SEQ ID NO: 18 and the second nucleic acid sequence comprises SEQ ID NO:48; q. the first nucleic acid sequence comprises SEQ ID NO: 19 and the second nucleic acid sequence comprises SEQ ID NO:49; r. the first nucleic acid sequence comprises SEQ ID NO:20 and the second nucleic acid sequence comprises SEQ ID NO:50;s. the first nucleic acid sequence comprises SEQ ID NO:21 and the second nucleic acid sequence comprises SEQ ID NO:51; t. the first nucleic acid sequence comprises SEQ ID NO: 22 and the second nucleic acid sequence comprises SEQ ID NO:52; u. the first nucleic acid sequence comprises SEQ ID NO:23 and the second nucleic acid sequence comprises SEQ ID NO:53; v. the first nucleic acid sequence comprises SEQ ID NO:24 and the second nucleic acid sequence comprises SEQ ID NO:54; w. the first nucleic acid sequence comprises SEQ ID NO:25 and the second nucleic acid sequence comprises SEQ ID NO:55; x. the first nucleic acid sequence comprises SEQ ID NO:26 and the second nucleic acid sequence comprises SEQ ID NO:56; y. the first nucleic acid sequence comprises SEQ ID NO:27 and the second nucleic acid sequence comprises SEQ ID NO:57; z. the first nucleic acid sequence comprises SEQ ID NO:28 and the second nucleic acid sequence comprises SEQ ID NO:58; aa. the first nucleic acid sequence comprises SEQ ID NO:29 and the second nucleic acid sequence comprises SEQ ID NO:59; bb. the first nucleic acid sequence comprises SEQ ID NO:30 and the second nucleic acid sequence comprises SEQ ID NO:60; cc. the first nucleic acid sequence comprises SEQ ID NO:31 and the second nucleic acid sequence comprises SEQ ID NO:61; and dd. the first nucleic acid sequence comprises SEQ ID NO:32 and the second nucleic acid sequence comprises SEQ ID NO:62.

[0013] In some embodiments, provided herein is an ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence of a sense strand of any one of dsRNA Duplex No. 123-181 as disclosed herein andthe antisense strand comprises a second nucleic acid sequence of an antisense strand of any one of dsRNA Duplex No. 123-181 as disclosed herein. For example, the first nucleic acid sequence may comprise SEQ ID NO: 313 and the second nucleic acid sequence may comprise SEQ ID NO: 372, as in dsRNA Duplex No. 123; or the first nucleic acid may comprise SEQ ID NO: 314 and the second nucleic acid sequence may comprise SEQ ID NO: 373, as in dsRNA Duplex No. 124, and so forth.

[0014] In some embodiments, the present disclosure provides for an ACVR2 RNAi agent wherein the antisense strand comprises a 3’ overhang of two nucleotides. In some embodiments, the sense and antisense strands each comprise one or more modified nucleotides. In some embodiments, the one or more modified nucleotides is a 2 ’fluoro modified nucleotide or a 2’ O-methyl modified nucleotide.

[0015] In some embodiments, the present disclosure provides for an RNAi agent wherein the sense and antisense strands each comprise one or more modified intemucleotide linkages. In some embodiments, one or more modified internucleotide linkages are phosphorothioate linkages.

[0016] In some embodiments, the antisense strand further comprises an abasic or inverted abasic moiety of Table 15. In some embodiments, the abasic structure is comprised of the following structure:

[0017] In some embodiments, the antisense sense strand further comprises an inverted abasic moiety. In some embodiments, the inverted abasic structure is comprised of the following structure:

[0018] In some embodiments, the antisense strand is between 15 and 50 nucleotides in length. In some embodiments, the sense strand is between 15 and 50 nucleotides in length. In some embodiments, the antisense strand is between 18 and 23 nucleotides in length. In some embodiments, the sense strand is between 18 and 21 nucleotides in length. In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In some embodiments, the region of complementarity is at least 18 nucleotides in length.

[0019] In some embodiments, the antisense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, and 184.

[0020] In some embodiments, the antisense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 678, 680, 682,684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718,720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754,756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790,792, and 794.

[0021] In some embodiments, the antisense strand has a nucleotide sequence selected from the group consisting of SEQ ID NOs: 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, and 184, or a sequence having at least 90% sequence identity thereto.

[0022] In some embodiments, the antisense strand has a nucleotide sequence selected from the group consisting of SEQ ID NOs: 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732,734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, and 794, or a sequence having at least 90% sequence identity thereto.

[0023] In some embodiments, the sense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, and 183. In some embodiments, the antisense strand has a nucleotide sequence selected from the group consisting of SEQ ID NOs: 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, and 183, or a sequence having at least 90% sequence identity thereto.

[0024] In some embodiments, the sense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 677, 679, 681 ,683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 713, 715, 717,719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753,755, 757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789,791, and 793. In some embodiments, the antisense strand has a nucleotide sequence selected from the group consisting of SEQ ID NOs: 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731,733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767,769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, and 793, or a sequence having at least 90% sequence identity thereto.

[0025] In some embodiments, the duplex region between the sense strand and the antisense strand comprises 0, 1, 2, or 3 mismatches.

[0026] In some embodiments, the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of:a. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 125 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 126; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 127 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 128; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 129 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 130; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 131 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 132; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 133 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 134; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:135 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 136; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 137 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 138; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 139 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 140; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 141 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 142;j. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 143 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 144; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 145 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 146; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 147 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 148; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 149 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 150; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 151 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 152; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:153 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 154; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 155 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 156; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 157 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 158; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 159 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 160;s. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 161 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 162; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 163 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 164; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 165 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 166; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 167 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 168; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 169 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 170; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 171 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 172; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 173 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 174; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ IDNO: 175 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 176; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 177 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 178;bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 179 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 180; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 181 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 182; and dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 183 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 184.

[0022] In some embodiments, provided herein is an ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence that has at least 95% sequence identity to the sequence of a sense strand of any one of dsRNA Duplex No. 305-363 as disclosed herein and the antisense strand comprises a second nucleic acid sequence that has at least 95% sequence identity to the sequences of an antisense strand of any one of dsRNA Duplex No. 305-363 as disclosed herein. For example, the first nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 677 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 678, as in dsRNA Duplex No. 305; or the first nucleic acid may have at least 95% sequence identity to SEQ ID NO: 679 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 680, as in dsRNA Duplex No. 306, and so forth.

[0023] In some embodiments, the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid comprises SEQ ID NO: 125 and the second nucleic acid sequence comprises SEQ ID NO: 126; b. the first nucleic acid comprises SEQ ID NO:127 and the second nucleic acid sequence comprises SEQ ID NO: 128;c. the first nucleic acid comprises SEQ ID NO: 129 and the second nucleic acid sequence comprises SEQ ID NO: 130; d. the first nucleic acid comprises SEQ ID NO: 131 and the second nucleic acid sequence comprises SEQ ID NO: 132; e. the first nucleic acid comprises SEQ ID NO: 133 and the second nucleic acid sequence comprises SEQ ID NO: 134; f. the first nucleic acid comprises SEQ ID NO: 135 and the second nucleic acid sequence comprises SEQ ID NO: 136; g. the first nucleic acid comprises SEQ ID NO: 137 and the second nucleic acid sequence comprises SEQ ID NO: 138; h. the first nucleic acid comprises SEQ ID NO: 139 and the second nucleic acid sequence comprises SEQ ID NO: 140; i. the first nucleic acid comprises SEQ ID NO: 141 and the second nucleic acid sequence comprises SEQ ID NO: 142; j. the first nucleic acid comprises SEQ ID NO: 143 and the second nucleic acid sequence comprises SEQ ID NO: 144; k. the first nucleic acid comprises SEQ ID NO: 145 and the second nucleic acid sequence comprises SEQ ID NO: 146; l. the first nucleic acid comprises SEQ ID NO: 147 and the second nucleic acid sequence comprises SEQ ID NO: 148; m. the first nucleic acid comprises SEQ ID NO: 149 and the second nucleic acid sequence comprises SEQ ID NO: 150; n. the first nucleic acid comprises SEQ ID NO:151 and the second nucleic acid sequence comprises SEQ ID NO: 152; o. the first nucleic acid comprises SEQ ID NO: 153 and the second nucleic acid sequence comprises SEQ ID NO: 154; p. the first nucleic acid comprises SEQ ID NO: 155 and the second nucleic acid sequence comprises SEQ ID NO: 156;q. the first nucleic acid comprises SEQ ID NO: 157 and the second nucleic acid sequence comprises SEQ ID NO: 158; r. the first nucleic acid comprises SEQ ID NO: 159 and the second nucleic acid sequence comprises SEQ ID NO: 160; s. the first nucleic acid comprises SEQ ID NO: 161 and the second nucleic acid sequence comprises SEQ ID NO: 162; t. the first nucleic acid comprises SEQ ID NO: 163 and the second nucleic acid sequence comprises SEQ ID NO: 164; u. the first nucleic acid comprises SEQ ID NO: 165 and the second nucleic acid sequence comprises SEQ ID NO: 166; v. the first nucleic acid comprises SEQ ID NO: 167 and the second nucleic acid sequence comprises SEQ ID NO: 168; w. the first nucleic acid comprises SEQ ID NO: 169 and the second nucleic acid sequence comprises SEQ ID NO: 170; x. the first nucleic acid comprises SEQ ID NO: 171 and the second nucleic acid sequence comprises SEQ ID NO: 172; y. the first nucleic acid comprises SEQ ID NO: 173 and the second nucleic acid sequence comprises SEQ ID NO: 174; z. the first nucleic acid comprises SEQ ID NO: 175 and the second nucleic acid sequence comprises SEQ ID NO: 176; aa. the first nucleic acid comprises SEQ ID NO: 177 and the second nucleic acid sequence comprises SEQ ID NO:178; bb. the first nucleic acid comprises SEQ ID NO:179 and the second nucleic acid sequence comprises SEQ ID NO: 180; cc. the first nucleic acid comprises SEQ ID NO: 181 and the second nucleic acid sequence comprises SEQ ID NO:182; and dd. the first nucleic acid comprises SEQ ID NO: 183 and the second nucleic acid sequence comprises SEQ ID NO: 184.

[0023] In some embodiments, provided herein is an ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence of a sense strand of any one of dsRNA Duplex No. 305-363 and the antisense strand comprises a second nucleic acid sequence of an antisense strand of any one of dsRNA Duplex No. 305-363 as disclosed herein. For example, the first nucleic acid sequence may comprise SEQ ID NO: 677 and the second nucleic acid sequence may comprise SEQ ID NO: 678, as in dsRNA Duplex No. 305; or the first nucleic acid may comprise SEQ ID NO: 679 and the second nucleic acid sequence may comprise SEQ ID NO: 680, as in dsRNA Duplex No. 306, and so forth.

[0024] In some embodiments, the 5’ terminal nucleotide of the antisense strand comprises a phosphate group, a vinyl phosphonate, a phosphate analog, or a hydroxyl group. In some embodiments, the phosphate analog is vinyl phosphonate. In some embodiments, the RNAi agent decreases the expression of the ACVR2A gene in a muscle cell, as compared to a control.

[0025] In some embodiments, the RNAi agent of the present disclosure is of the Formula: R-L-TBP, wherein R is the RNAi agent, L is a linker or a direct bond, and TBP is a transferrin receptor binding protein.

[0026] In some embodiments, the dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand is complementary to a target mRNA of ACVR2B of SEQ ID NO:2. In some embodiments, the present disclosure provides for an ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 63 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:94;b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 64 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:95; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 65 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:96; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 66 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:97; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 67 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:98; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 68 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:99; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 69 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 100; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:70 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:101; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:71 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 102; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:72 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:103;k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:73 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 104; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:74 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 105; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:75 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:106; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:76 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:107; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:77 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 108; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:78 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 109; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:79 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:110; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 80 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 111; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 81 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:112;t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 82 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:113; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 83 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 114; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 84 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:115; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 85 and the second nucleic sequence has at least 95% sequence identity to SEQ ID NO:116; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 86 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 117; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 87 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:118; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 88 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:119; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 89 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 120; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:90 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:121;cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:91 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:122; dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:92 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 123; and ee. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:93 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 124.

[0026] In some embodiments, provided herein is an ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence that has at least 95% sequence identity to the sequence of a sense strand of any one of dsRNA Duplex No. 182-304 and the antisense strand comprises a second nucleic acid sequence that has at least 95% sequence identity to the sequences of an antisense strand of any one of dsRNA Duplex No. 182-304 as disclosed herein. For example, the first nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 431 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 554, as in dsRNA Duplex No. 182; or the first nucleic acid may have at least 95% sequence identity to SEQ ID NO: 432 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 555, as in dsRNA Duplex No. 183, and so forth; that is, wherein the first nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 431-553, and the second nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 554-676.

[0027] In some embodiments, the present disclosure provides for an ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the firstnucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO:63 and the second nucleic acid sequence comprises SEQ ID NO:94; b. the first nucleic acid sequence comprises SEQ ID NO:64 and the second nucleic acid sequence comprises SEQ ID NO:95; c. the first nucleic acid sequence comprises SEQ ID NO:65 and the second nucleic acid sequence comprises SEQ ID NO:96; d. the first nucleic acid sequence comprises SEQ ID NO:66 and the second nucleic acid sequence comprises SEQ ID NO:97; e. the first nucleic acid sequence comprises SEQ ID NO:67 and the second nucleic acid sequence comprises SEQ ID NO:98; f. the first nucleic acid sequence comprises SEQ ID NO:68 and the second nucleic acid sequence comprises SEQ ID NO:99; g. the first nucleic acid sequence comprises SEQ ID NO:69 and the second nucleic acid sequence comprises SEQ ID NO: 100; h. the first nucleic acid sequence comprises SEQ ID NO:70 and the second nucleic acid sequence comprises SEQ ID NO: 101 ; i. the first nucleic acid sequence comprises SEQ ID NO:71 and the second nucleic acid sequence comprises SEQ ID NO: 102; j. the first nucleic acid sequence comprises SEQ ID NO:72 and the second nucleic acid sequence comprises SEQ ID NO:103; k. the first nucleic acid sequence comprises SEQ ID NO:73 and the second nucleic acid sequence comprises SEQ ID NO: 104; l. the first nucleic acid sequence comprises SEQ ID NO:74 and the second nucleic acid sequence comprises SEQ ID NO: 105; m. the first nucleic acid sequence comprises SEQ ID NO:75 and the second nucleic acid sequence comprises SEQ ID NO: 106;n. the first nucleic acid sequence comprises SEQ ID NO:76 and the second nucleic acid sequence comprises SEQ ID NO: 107; o. the first nucleic acid sequence comprises SEQ ID NO:77 and the second nucleic acid sequence comprises SEQ ID NO: 108; p. the first nucleic acid sequence comprises SEQ ID NO:78 and the second nucleic acid sequence comprises SEQ ID NO: 109; q. the first nucleic acid sequence comprises SEQ ID NO:79 and the second nucleic acid sequence comprises SEQ ID NO:110; r. the first nucleic acid sequence comprises SEQ ID NO:80 and the second nucleic acid sequence comprises SEQ ID NO: 111 ; s. the first nucleic acid sequence comprises SEQ ID NO:81 and the second nucleic acid sequence comprises SEQ ID NO:112; t. the first nucleic acid sequence comprises SEQ ID NO:82 and the second nucleic acid sequence comprises SEQ ID NO: 113; u. the first nucleic acid sequence comprises SEQ ID NO:83 and the second nucleic acid sequence comprises SEQ ID NO: 114; v. the first nucleic acid sequence comprises SEQ ID NO:84 and the second nucleic acid sequence comprises SEQ ID NO:115; w. the first nucleic acid sequence comprises SEQ ID NO:85 and the second nucleic sequence comprises SEQ ID NO: 116; x. the first nucleic acid sequence comprises SEQ ID NO:86 and the second nucleic acid sequence comprises SEQ ID NO:117; y. the first nucleic acid sequence comprises SEQ ID NO:87 and the second nucleic acid sequence comprises SEQ ID NO: 118; z. the first nucleic acid sequence comprises SEQ ID NO:88 and the second nucleic acid sequence comprises SEQ ID NO:1 19; aa. the first nucleic acid sequence comprises SEQ ID NO:89 and the second nucleic acid sequence comprises SEQ ID NO: 120;bb. the first nucleic acid sequence comprises SEQ ID NO:90 and the second nucleic acid sequence comprises SEQ ID NO: 121 ; cc. the first nucleic acid sequence comprises SEQ ID NO:91 and the second nucleic acid sequence comprises SEQ ID NO: 122; dd. the first nucleic acid sequence comprises SEQ ID NO:92 and the second nucleic acid sequence comprises SEQ ID NO: 123; and ee. the first nucleic acid sequence comprises SEQ ID NO:93 and the second nucleic acid sequence comprises SEQ ID NO: 124.

[0027] In some embodiments, provided herein is an ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence of a sense strand of any one of dsRNA Duplex No. 182-304 and the antisense strand comprises a second nucleic acid sequence of an antisense strand of any one of dsRNA Duplex No. 182-304 as disclosed herein. For example, the first nucleic acid sequence may comprise SEQ ID NO: 431 and the second nucleic acid sequence may comprise SEQ ID NO: 554, as in dsRNA Duplex No. 182; or the first nucleic acid may comprise SEQ ID NO: 432 and the second nucleic acid sequence may comprise SEQ ID NO: 555, as in dsRNA Duplex No. 183, and so forth; that is, wherein the first nucleic acid sequence comprises one of SEQ ID NOs: 431-553, and the second nucleic acid sequence comprises one of SEQ ID NOs: 554- 676.

[0028] In some embodiments, the present disclosure provides for an ACVRB RNAi agent wherein the antisense strand comprises a 3’ overhang of two nucleotides. In some embodiments, the sense and antisense strands each comprise one or more modified nucleotides. In some embodiments, the one or more modified nucleotides is a 2’fluoro modified nucleotide or a 2’ O-methyl modified nucleotide.

[0029] In some embodiments, the present disclosure provides for an RNAi agent wherein the sense and antisense strands each comprise one or more modified intemucleotide linkages. In some embodiments, one or more modified internucleotide linkages are phosphorothioate linkages.

[0030] In some embodiments, the antisense strand further comprises an abasic or inverted abasic moiety. In some embodiments, the abasic structure is comprised of the following structure:

[0031] In some embodiments, the antisense sense strand further comprises an inverted abasic moiety. In some embodiments, the inverted abasic structure is comprised of the following structure:

[0032] In some embodiments, the antisense strand is between 15 and 50 nucleotides in length. In some embodiments, the sense strand is between 15 and 50 nucleotides in length. In some embodiments, the antisense strand is between 18 and 23 nucleotides in length. In some embodiments, the sense strand is between 18 and 21 nucleotides in length. In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In some embodiments, the region of complementarity is at least 18 nucleotides in length.

[0033] In some embodiments, the antisense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, and 246.

[0034] In some embodiments, the antisense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 796, 798, 800,802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836,838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872,874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908,910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944,946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980,982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, and 1040.

[0035] . In some embodiments, the antisense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, and 246, or a sequence having at least 90% sequence identity thereto.

[0036] In some embodiments, the antisense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850,852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886,888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922,924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958,960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994,996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, and 1040, or a sequence having at least 90% sequence identity thereto.

[0037] In some embodiments, the sense strand comprises at least 18 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, and 245.

[0038] In some embodiments, the sense strand comprises at least 18 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859, 861, 863, 865, 867,869, 871, 873, 875, 877, 879, 881, 883, 885, 887, 889, 891, 893, 895, 897, 899, 901, 903,905, 907, 909, 911, 913, 915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939,941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975,977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009,1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, and 1039.

[0039] In some embodiments, the sense strand has a nucleotide sequence selected from the group consisting of SEQ ID NOs: 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, and 245, or a sequence having at least 90% sequence identity thereto.

[0040] In some embodiments, the sense strand has a nucleotide sequence selected from the group consisting of SEQ ID NOs: 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849,851, 853, 855, 857, 859, 861, 863, 865, 867, 869, 871, 873, 875, 877, 879, 881, 883, 885,887, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913, 915, 917, 919, 921,923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957,959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993,995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, and 1039, or a sequence having at least 90% sequence identity thereto.

[0041] In some embodiments, the duplex region between the sense strand and the antisense strand comprises 0, 1, 2, or 3 mismatches.

[0042] In some embodiments, the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:185 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 186;b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 187 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:188; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 189 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 190; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 191 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:192; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 193 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:194; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 195 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 196; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 197 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:198; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 199 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:200; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:201 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:202; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:203 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:204;k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:205 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:206; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:207 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:208; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:209 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:210; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:211 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:212; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:213 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:214; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:215 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:216; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:217 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:218; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:219 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:220; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:221 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:222;t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:223 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:224; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:225 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:226; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:227 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:228; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:229 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:230; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:231 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:232; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:233 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:234; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:235 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:236; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:237 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:238; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:239 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:240;cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:241 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:242; dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:243 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:244; and ee. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:245 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:246.

[0038] In some embodiments, provided herein is an ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence that has at least 95% sequence identity to the sequence of a sense strand of any one of dsRNA Duplex No. 364-486 and the antisense strand comprises a second nucleic acid sequence that has at least 95% sequence identity to the sequences of an antisense strand of any one of dsRNA Duplex No. 364-486 as disclosed herein. For example, the first nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 795 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 796, as in dsRNA Duplex No. 364; or the first nucleic acid may have at least 95% sequence identity to SEQ ID NO: 797 and the second nucleic acid sequence may have at least 95% sequence identity to SEQ ID NO: 798, as in dsRNA Duplex No. 365, and so forth.

[0039] In some embodiments, the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO: 185 and the second nucleic acid sequence comprises SEQ ID NO:186; b. the first nucleic acid sequence comprises SEQ ID NO: 187 and the second nucleic acid sequence comprises SEQ ID NO: 188;c. the first nucleic acid sequence comprises SEQ ID NO: 189 and the second nucleic acid sequence comprises SEQ ID NO: 190; d. the first nucleic acid sequence comprises SEQ ID NO: 191 and the second nucleic acid sequence comprises SEQ ID NO: 192; e. the first nucleic acid sequence comprises SEQ ID NO: 193 and the second nucleic acid sequence comprises SEQ ID NO: 194; f. the first nucleic acid sequence comprises SEQ ID NO: 195 and the second nucleic acid sequence comprises SEQ ID NO: 196; g. the first nucleic acid sequence comprises SEQ ID NO: 197 and the second nucleic acid sequence comprises SEQ ID NO: 198; h. the first nucleic acid sequence comprises SEQ ID NO: 199 and the second nucleic acid sequence comprises SEQ ID NO:200; i. the first nucleic acid sequence comprises SEQ ID NO:201 and the second nucleic acid sequence comprises SEQ ID NO:202; j. the first nucleic acid sequence comprises SEQ ID NO:203 and the second nucleic acid sequence comprises SEQ ID NO:204; k. the first nucleic acid sequence comprises SEQ ID NO:205 and the second nucleic acid sequence comprises SEQ ID NO:206; l. the first nucleic acid sequence comprises SEQ ID NO:207 and the second nucleic acid sequence comprises SEQ ID NO:208; m. the first nucleic acid sequence comprises SEQ ID NO:209 and the second nucleic acid sequence comprises SEQ ID NO:210; n. the first nucleic acid sequence comprises SEQ ID NO:211 and the second nucleic acid sequence comprises SEQ ID NO:212; o. the first nucleic acid sequence comprises SEQ ID NO:213 and the second nucleic acid sequence comprises SEQ ID NO:214; p. the first nucleic acid sequence comprises SEQ ID NO:215 and the second nucleic acid sequence comprises SEQ ID NO:216;q. the first nucleic acid sequence comprises SEQ ID NO:217 and the second nucleic acid sequence comprises SEQ ID NO:218; r. the first nucleic acid sequence comprises SEQ ID NO:219 and the second nucleic acid sequence comprises SEQ ID NO:220; s. the first nucleic acid sequence comprises SEQ ID NO:221 and the second nucleic acid sequence comprises SEQ ID NO:222; t. the first nucleic acid sequence comprises SEQ ID NO:223 and the second nucleic acid sequence comprises SEQ ID NO:224; u. the first nucleic acid sequence comprises SEQ ID NO:225 and the second nucleic acid sequence comprises SEQ ID NO:226; v. the first nucleic acid sequence comprises SEQ ID NO:227 and the second nucleic acid sequence comprises SEQ ID NO:228; w. the first nucleic acid sequence comprises SEQ ID NO:229 and the second nucleic acid sequence comprises SEQ ID NO:230; x. the first nucleic acid sequence comprises SEQ ID NO:231 and the second nucleic acid sequence comprises SEQ ID NO:232; y. the first nucleic acid sequence comprises SEQ ID NO:233 and the second nucleic acid sequence comprises SEQ ID NO:234; z. the first nucleic acid sequence comprises SEQ ID NO:235 and the second nucleic acid sequence comprises SEQ ID NO:236; aa. the first nucleic acid sequence comprises SEQ ID NO:237 and the second nucleic acid sequence comprises SEQ ID NO:238; bb. the first nucleic acid sequence comprises SEQ ID NO:239 and the second nucleic acid sequence comprises SEQ ID NO:240; cc. the first nucleic acid sequence comprises SEQ ID NO:241 and the second nucleic acid sequence comprises SEQ ID NO:242; dd. the first nucleic acid sequence comprises SEQ ID NO:243 and the second nucleic acid sequence comprises SEQ ID NO:244; andee. the first nucleic acid sequence comprises SEQ ID NO:245 and the second nucleic acid sequence comprises SEQ ID NO:246.

[0039] In some embodiments, provided herein is an ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence of a sense strand of any one of dsRNA Duplex No. 364-486 and the antisense strand comprises a second nucleic acid sequence of an antisense strand of any one of dsRNA Duplex No. 364-486 as disclosed herein. For example, the first nucleic acid sequence may comprise SEQ ID NO: 795 and the second nucleic acid sequence may comprise SEQ ID NO: 796, as in dsRNA Duplex No. 364; or the first nucleic acid may comprise SEQ ID NO: 797 and the second nucleic acid sequence may comprise SEQ ID NO: 798, as in dsRNA Duplex No. 365, and so forth.

[0040] In some embodiments, the 5’ terminal nucleotide of the antisense strand comprises a phosphate group, a vinyl phosphonate, a phosphate analog, or a hydroxyl group. In some embodiments, the phosphate analog is vinyl phosphonate. In some embodiments, the RNAi agent decreases the expression of the ACVR2B gene in a muscle cell, as compared to control.Human TfR binding proteins

[0041] In some embodiments, the RNAi agent further comprises a transferrin receptor (TfR) binding protein. In one aspect, provided herein are proteins comprising human TfR binding domain (“human TfR binding proteins” or “TBPs”). In some embodiments, the TBP is conjugated to the 3’ end of the sense strand, optionally via a linker. In some embodiments, the TBP is conjugated to the 3’ end of the sense strand via a linker. In other embodiments, provided herein are RNAi agents that are conjugates of the Formula : R-L-TBP, wherein R is a dsRNA comprising a sense strand and an antisense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic sequence, wherein L is a linker or direct bond, and wherein TBP is a protein comprising human TfR binding domain (“human TfR binding proteins” or “TBPs”) of anyone of Tables 1-14. In some embodiments, the TBP of the formula above is selected from the group consisting of TBP1, TBP2, TBP3, TBP4, TBP5, TBP6, TBP7, TBP8, TBP9, TBP10, TBP11, TBP12, TBP13, TBP14, TBP15, TBP16, TBP17, TBP18, TBP19, TBP20, TBP21, TBP22, TBP23, TBP24, TBP25, TBP26, TBP27, TBP28, TBP29, TBP30, TBP31, and TBP32. In some embodiments, the TBP of the formula above is selected from the group consisting of TBP 33, TBP 34, TBP 35, TBP 36, TBP 37, TBP 38, TBP 39, TBP 40, and TBP 41. In some embodiments, the RNAi agent is an ACVR2A RNAi agent comprising a TBP and optionally a linker. In some embodiments, the RNAi agent is an ACVR2B RNAi agent comprising a TBP and optionally a linker.

[0042] In some embodiments provided herein are proteins comprising human transferrin receptor (TfR) binding domain, wherein the human TfR binding domain binds an epitope of human TfR. In some embodiments provided herein are proteins comprising human transferrin receptor (TfR) binding domain, wherein the human TfR binding domain binds an epitope comprising, for example, one or more residues of FGNMEGDCPSDWKTDSTCR- (SEQ ID NO:257) of human TfR.

[0043] The TfR binding proteins described herein can be recombinantly produced in a host cell, for example, using an expression vector. For example, an expression vector may include a sequence that encodes one or more signal peptides that facilitate secretion of the polypeptide(s) from a host cell. Expression vectors containing a polynucleotide of interest (e.g., a polynucleotide encoding a heavy chain or light chain of the TfR binding proteins) may be transferred into a host cell by well-known methods. Additionally, expression vectors may contain one or more selection markers, e.g., tetracycline, neomycin, and dihydrofolate reductase, to aid in detection of host cells transformed with the desired polynucleotide sequences.

[0044] A host cell includes cells stably or transiently transfected, transformed, transduced or infected with one or more expression vectors expressing all or a portion of the TfR binding proteins described herein. According to some embodiments, a host cell may be stably or transiently transfected, transformed, transduced or infected with an expression vector expressing HC polypeptides and an expression vector expressing LC polypeptides ofthe TfR binding proteins described herein. According to some embodiments, a host cell may be stably or transiently transfected, transformed, transduced or infected with an expression vector expressing LC polypeptides of the TfR binding proteins described herein. In some embodiments, a host cell may be stably or transiently transfected, transformed, transduced or infected with an expression vector expressing HC and LC polypeptides of the TfR binding proteins described herein. The TfR binding proteins may be produced in mammalian cells such as CHO, NSO, HEK293 or COS cells according to techniques well known in the art.

[0045] Assignment of amino acid residues to the CDRs may be done according to the well-known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available on atseeLefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0046] Medium, into which the TfR binding proteins has been secreted, may be purified by conventional techniques, such as mixed-mode methods of ion-exchange and hydrophobic interaction chromatography. For example, the medium may be applied to and eluted from a Protein A or G column using conventional methods; mixed-ode methods of ion exchange and hydrophobic interaction chromatography may also be used. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. Various methods of protein purification may be employed, and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182: 83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rdEdition, Springer, NY (1994).

[0047] In some embodiments, the TBP is an antibody, e.g., a monoclonal antibody. In some embodiments, the TBP is an antibody fragment, e.g., Fab, scFv, Fv, or scFab (singlechain Fab). In some embodiments, the TBP is a Fab which further comprises a VHH that binds to human serum albumin (HSA). In some embodiments, the TBP is a VHH. In some embodiments, the TBP is a VHH which further comprises a VHH that binds to human serum albumin, i.e., VHH-albVHH. In some embodiments, the TBP is a peptide.

[0048] In one embodiment, the TBP is the Fab of Table 1. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, the TBP comprises a VH comprising HCDR1, HCDR2, and HCDR3, and a VL comprising LCDR1, LCDR2, and LCDR3, selected from Table 1.

[0049] In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDCR2 comprises SEQ ID NO:251, LCDR3 comprises SEQ ID NO:252. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a sequence having at least 95% sequence identity to SEQ NO:253 and VL comprises a sequence having at least 95% sequence identity to SEQ ID NO:254. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254. In some embodiments, the TBP further comprises a heavy chain constant region and a light chain region. In some embodiments, the TBP further comprises a heavy chain (HC) and light chain (LC), wherein the HC comprises SEQ ID NO:291 and the LC comprises SEQ ID NO:256.Table 1. Human TfR binding protein 1 (Fab)

[0050] In one embodiment, the TBP comprises a Fab and a VHH that binds to human serum albumin (HS A). In one embodiment, the TBP is the Fab- VHH of Table 2, wherein the VHH binds to human serum albumin. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1 , LCDR2, and LCDR3. In some embodiments, the TBP comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3, selected from Table 2.

[0051] In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDCR2 comprises SEQ ID NO:251, LCDR3 comprises SEQ ID NO:252. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a sequence having at least 95% sequence identity to SEQ NO:253 and VL comprises asequence having at least 95% sequence identity to SEQ ID NO:254. In some embodiments, the TBP comprises a VH and VL, wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254. In some embodiments, the TBP comprises a heavy chain constant region and a light chain region. In some embodiments, the TBP further comprises a heavy chain (HC) and light chain (LC), wherein the HC comprises SEQ ID NO:255 and the LC comprises SEQ ID NO:256.Table 2. Human TfR binding protein 2 (TBP2) (Fab-alb VHH)

[0052] In some embodiments, the human TfR binding proteins described herein are heterodimeric antibodies that comprise a first arm comprising a human TfR binding domain and a second arm that does not bind any known target (e.g., an isotype arm). Heterodimeric antibodies such as heteromab, orthomab, or duobody have been described in WO2014150973, WO2016118742, WO2018118616, WO2011131746. In one embodiment, the TBP is the one-arm heteromab of Table 3. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3,and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, the TBP comprises a VH comprising HCDR1, HCDR2, and HCDR3, and a VL comprising LCDR1, LCDR2, and LCDR3, selected from Table 3.

[0053] In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDCR2, and LCDCR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDR2 comprises SEQ ID NO:251, and LCDCR3 comprises SEQ ID NO:252. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a sequence having at least 95% sequence identity to SEQ ID NO: 253 and the VL comprises a sequence having at least 95% sequence identity to SEQ ID NO:254. In some embodiments, the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254. In some embodiments, the TBP has two heavy chains (HC1 and HC2) and one light chain (LC). In some embodiments, the TBP further comprises two heavy chains, (HC1) and (HC2), and one light chain (LC), wherein HC1 comprises SEQ ID NO:263, HC2 comprises SEQ ID NO:264, and the LC comprises SEQ ID NO:256.Table 3. Human TfR binding protein 3 (TBP3) (One arm heteromab)

[0054] In some embodiments, the human TfR binding proteins described herein further comprise a half-life extender, e.g., a VHH that binds human serum albumin (HSA), referred to herein as “alb VHH”. In some embodiments, the VHH also binds cynomologous monkey, mouse, and rat albumin. In some embodiments, the VHH is linked to the TBP through a peptide linker, e.g., GGGGQGGGGQGGGGQGGGGQGGGGQ (SEQ ID NO:262). In some embodiments, this peptide linker is further attached to albVHH, e.g., EVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQAPGKGREFVAGIGGGVDI TYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCGARPGRPLITSKVADLYP YWGQGTLVTVSSPP (SEQ ID NO:261). In some embodiments the albumin-binding VHH comprises a CDR1 comprising SEQ ID NO: 258. In some embodiments the albumin-binding VHH comprises a CDR2 comprising SEQ ID NO: 259. In some embodiments the albuminbinding VHH comprises a CDR3 comprising SEQ ID NO: 260. In some embodiments the albumin-binding VHH comprises a CDR1 comprising SEQ ID NO: 258, and a CDR2 comprising SEQ ID NO: 259, and a CDR3 comprising SEQ ID NO: 260.

[0055] In one embodiment, the TBP is a VHH of Table 4 (containing TBPs 4, 5, and 6). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:265, CDR2 comprising SEQ ID NO:266, and CDR3 comprising SEQ ID NO:267. In some embodiments, the TBP comprises SEQ ID NO:268. In some embodiments, the TBP comprises SEQ ID NO:269. In some embodiments, the TBP comprises SEQ ID NQ:270.Table 4. Exemplary sequences of VHH that binds human TfR (TBPs 4, 5, and 6)

[0056] In one embodiment, the TBP is a VHH of Table 5 (containing TBPs 7, 8, and9). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:273. In some embodiments, the TBP comprises SEQ ID NO:274. In some embodiments, the TBP comprises SEQ ID NO:275. In some embodiments, the TBP comprises SEQ ID NO:276.Table 5. Exemplary sequences of VHH that binds human TfR (TBPs 7, 8, and 9)

[0057] In one embodiment, the TBP is a VHH of Table 6 (containing TBPs 10, 11, and 12). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:279, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:277. In some embodiments, the TBP comprises SEQ ID NO:280. In some embodiments, the TBP comprises SEQ ID NO:292. In some embodiments, the TBP comprises SEQ ID NO:293.Table 6. Exemplary Sequences of VHH that binds human TfR (TBP 10, 11, and 12)

[0058] In one embodiment, the TBP is a VHH of Table 7 (containing TBPs 13, 14, and 15). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:281, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:277. In some embodiments, the TBP comprises SEQ ID NO:282. In some embodiments, the TBP comprises SEQ ID NO:294. In some embodiments, the TBP comprises SEQ ID NO:295.Table 7. Exemplary Sequences of VHH that binds human TfR (TBP 13, 14, and 15)

[0059] In one embodiment, the TBP is a VHH of Table 8 (containing TBPs 16, 17, and 18). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:283, and CDR3 comprising SEQ ID NO:277. In some embodiments, the TBP comprises SEQ ID NO:284. In some embodiments, the TBP comprises SEQ ID NO:296. In some embodiments, the TBP comprises SEQ ID NO:297.Table 8. Exemplary Sequences of VHH that binds human TfR (TBPs 16, 17, and 18)

[0060] In one embodiment, the TBP is a VHH of Table 8 (containing TBPs 19, 20, and 21). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:285, and CDR3 comprising SEQ ID NO:277. In some embodiments, the TBP comprises SEQ ID NO:286. In some embodiments, the TBP comprises SEQ ID NO:298. In some embodiments, the TBP comprises SEQ ID NO:299.Table 9. Exemplary Sequences of VHH that binds human TfR (TBP 19, 20, and 21)

[0061] In one embodiment, the TBP is a VHH of Table 9 (containing TBPs 22, 23, and 24). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:287, and CDR3 comprising SEQ ID NO:277. In some embodiments, the TBP comprises SEQ ID NO:288. In some embodiments, the TBP comprises SEQ ID NQ:300. In some embodiments, the TBP comprises SEQ ID NQ:301.Table 10. Exemplary Sequence of a VHH that binds human TfR (TBP 22, 23, and 24)

[0062] In one embodiment, the TBP is a VHH of Table 10 (containing TBPs 25, 26, and 27). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:289, and CDR3 comprising SEQ ID NO:277. In some embodiments, the TBP comprises SEQ ID NQ:290. In some embodiments, the TBP comprises SEQ ID NO:302. In some embodiments, the TBP comprises SEQ ID NO:303.Table 11. Exemplary Sequence of a VHH that binds human TfR (TBP 25, 26, and 27)In one embodiment, the TBP is a VHH of Table 11 (containing TBP 28). In some embodiments, the TBP comprises: a. a CDR1 comprising AQSGPX1FSX2YAMA (SEQ ID NO:304), wherein Xi is Q or T and X2is A or S, b. a CDR2 comprising AVSGX1X2GRTX3 (SEQ ID NO:305), wherein Xi is N or S, X2is A, G, or T, and X3 is R or Y, and c. a CDR3 comprising SEQ ID NO:277.In some embodiments, the TBP comprises SEQ ID NO:306. In some embodiments, the TBP comprisesEVQLLESGGGLVQPGGSLRLSC AQS GPX i FSX2YAM AWFRQ APGKEREFVGAVS GX3X4GRTX5YADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCARHYFYSTSGFFV DYSQVDEFDYWGQGTLVTVSSC (SEQ ID NO: 306), wherein Xi is Q or T, A or S, X3is N or S, X4 is A, G or T, and X5 is R or Y.Table 12. Exemplary Sequence of a VHH that binds human TfR (TBP 28)

[0063] In one embodiment, the TBP is a VHH of Table 12-1 (containing TBPs 33, 34, and 35). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO: 1042, CDR2 comprising SEQ ID NO:287, and CDR3 comprising SEQ ID NO: 1043. In some embodiments, the TBP comprises SEQ ID NO: 1044. In some embodiments, the TBP comprises SEQ ID NO: 1045. In some embodiments, the TBP comprises SEQ ID NO: 1046.Table 12-1. Exemplary Sequence of a VHH that binds human TfR (TBP 33, 34, and 35)

[0064] In one embodiment, the TBP is a VHH of Table 12-2 (containing TBPs 36, 37, and 38). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO: 1047, CDR2 comprising SEQ ID NO: 272, and CDR3 comprising SEQ ID NO: 1048. In some embodiments, the TBP comprises SEQ ID NO: 1049. In some embodiments, the TBP comprises SEQ ID NO: 1050. In some embodiments, the TBP comprises SEQ ID NO: 1051.Table 12-2. Exemplary Sequence of a VHH that binds human TfR (TBP 36, 37, and 38)

[0065] In one embodiment, the TBP is a VHH of Table 12-3 (containing TBPs 39, 40, and 41). In some embodiments, the TBP comprises a CDR1 comprising SEQ ID NO: 271, CDR2 comprising SEQ ID NO: 272, and CDR3 comprising SEQ ID NO: 277. In some embodiments, the TBP comprises SEQ ID NO: 1052. In some embodiments, the TBP comprises SEQ ID NO: 1053. In some embodiments, the TBP comprises SEQ ID NO: 1054.Table 12-3. Exemplary Sequence of a VHH that binds human TfR (TBP 39, 40, and 41)In one embodiment, the TBP is a peptide of Table 13 (containing TBPs 29-32).In some embodiments, the TBP comprises SEQ ID NO:307. In some embodiments, the TBP comprising SEQ ID NO:307 further comprises a disulfide bond between the cysteines at positions 4 and 13. In some embodiments, the TBP comprising SEQ ID NQ:307 further comprises a C-terminal amide.In some embodiments, the TBP comprises SEQ ID NO:308. In some embodiments, the TBP comprising SEQ ID NQ:3O8 further comprises a disulfide bond between the cysteines at positions 4 and 13. In some embodiments, the TBP comprising SEQ ID NQ:308 further comprises a C-terminal amide.In some embodiments, the TBP comprises SEQ ID NQ:309. In some embodiments, the TBP comprising SEQ ID NQ:309 further comprises a disulfide bond between the cysteines at positions 4 and 13. In some embodiments, the TBP comprising SEQ ID NO:309 further comprises a C-terminal amide.In some embodiments, the TBP comprises SEQ ID NQ:310. In some embodiments, the TBP comprising SEQ ID NQ:307 further comprises a disulfide bond between the cysteines at positions 4 and 13. In some embodiments, the TBP comprising SEQ ID NO:310 further comprises a C-terminal amide.Table 13. Exemplary Sequences of TfR Binding Peptides (TBPs 29-32)

[0062] Optionally, the compounds comprising SEQ ID N0s:307-310 further comprise an additional element to extend the time action profile of these compounds. These additional elements may include, with or without a linker and at any suitable position in the sequence, the Fc portion of an immunoglobulin, fragments of the Fc portion of an immunoglobulin, human serum albumin (HSA), a variant of VHH, including a variant that can further bind HSA, peptides or plasma proteins, including peptides or plasma proteins that can further bind HSA, a nanobody, fragments of HSA, a C6-C22 monoacid, a C6-C22 diacid, or a polyethylene glycol (PEG) moiety or other types of high molecular weight polymers.Linkers

[0063] In some embodiments, provided herein are RNAi agents that are conjugates of the formula: R-L-TBP, wherein R is a dsRNA comprising a sense strand and an antisense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic sequence, wherein L is a linker or absent, and wherein TBP is a protein comprising a human transferrin receptor (TfR) binding domain (“human TfR binding proteins” or “TBPs”). In some embodiments, the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP.

[0064] In some embodiments, the dsRNA is conjugated to the human TfR binding protein through a linker. In some embodiments, the linker is selected from any one of linkers 1-6 shown in Table 14. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 1. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 2. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 3. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 4. In one embodiment, the dsRNA is conjugated to the human TI R binding protein via linker 5. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 6. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 7. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 8. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 9. In one embodiment, the dsRNA is conjugated to the human TfRbinding protein via linker 10. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 11. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 12. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 13. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 14. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 15. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 16. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 17. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 18. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 19. In one embodiment, the dsRNA is conjugated to the human TfR binding protein via linker 20.Table 14. Exemplary Linker Structures

[0065] The conjugates described herein can be made by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the preparations and examples herein. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjugation with steps from different schemes, to prepare conjugates. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art.

[0066] In some embodiments, the present disclosure provides for a pharmaceutical composition comprising an ACVR2A RNAi agent. In some embodiments, the present disclosure provides for a pharmaceutical composition comprising an ACVR2B RNAi agent. In some embodiments, the present disclosure provides for a pharmaceutical composition comprising an ACVR2A RNAi agent and an ACVR2B RNAi agent.

[0067] In some embodiments, the present disclosure provides for a method of treating a subject having a disease associated with an elevated level of ACVR2A gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2A RNAi agent. In some embodiments, the present disclosure provides for a methodof treating a subject having a disease associated with an elevated level of ACVR2B gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2B RNAi agent.

[0068] In some embodiments, the present disclosure provides for a method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2A, the method comprising administering to the subject a therapeutically effective amount of the ACVR2A RNAi agent. In some embodiments, the present disclosure provides for a method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2B, the method comprising administering to the subject a therapeutically effective amount of the ACVR2B RNAi agent.

[0069] In some embodiments, the present disclosure provides for the ACVR2A RNAi agent or the pharmaceutical composition thereof for use in the treatment of a disease associated with ACVR2A gene expression. In some embodiments, the present disclosure provides for the ACVR2B RNAi agent or the pharmaceutical composition thereof for use in the treatment of a disease associated with ACVR2B gene expression.

[0070] In some embodiments, the present disclosure provides for the ACVR2A RNAi agent for use or the pharmaceutical composition thereof wherein the disease associated with ACVR2A gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS. In some embodiments, the present disclosure provides for the ACVR2B RNAi agent for use or the pharmaceutical composition thereof wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

[0071] In some embodiments, the present disclosure provides for the use of the ACVR2A RNAi agent, wherein the disease associated with ACVR2A gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS. In some embodiments, the present disclosure provides for the use of the ACVR2B RNAi agent, wherein the disease associated withACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.[000721 In some embodiments, the present disclosure provides for a pharmaceutical composition comprising: a. a first ACVR2A RNAI agent, and b. a second ACVR2B RNAi agent.

[0073] In some embodiments, the present disclosure provides for a method of treating a subject having a disease associated with an elevated level of ACVR2A and ACVR2B gene expression, the method comprising administering to the subject a therapeutically effective amount of two RNAi agents: a. a first ACVR2A RNAi agent, and b. a second ACVR2B RNAi agent.

[0074] In some embodiments, the present disclosure provides for a method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2A and ACVR2B, the method comprising to the subject a therapeutically effective amount of two RNAi agents: a. a first ACVR2A RNAi agent, and b. a second ACVR2B RNAi agent.

[0075] In some embodiments, the present disclosure provides for an ACVR2A RNAi agent or the pharmaceutical composition thereof for use in the treatment of a disease associated with ACVR2A gene expression administered simultaneously with an ACVRB RNAi agent or the pharmaceutical composition thereof for use in the treatment of a disease associated with ACVR2B gene expression.

[0076] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which the disclosure pertains. Although methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the interfering RNA molecules, pharmaceutical compositions, and methods, the preferred methods and materials are described herein.

[0077] Moreover, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.”

[0078] As is known in the art, “ACVR2” is an alias of, and refers to, ACVR2A.

[0079] As used herein, “abasic” or “inverted abasic” (iAb) refers to the following structures, which may be attached to the 3’ end of the sense or antisense strand. As used herein “abasic” or “inverted abasic” moieties refer to non-natural structures that prevent nucleases from recognizing it and metabolizing the molecule.Table 15. Abasic or inverted abasic (iAb) moieties

[0080] As used herein, “about” means within a statistically meaningful range of a value or values such as, for example, a stated concentration, length, molecular weight, pH, sequence identity, time frame, temperature, or volume. Such a value or range can be within an order of magnitude typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The allowable variation encompassed by “about” will depend upon the particular system under study, and can be readily appreciated by one of skill in the art.

[0081] As used herein, “antisense strand” means a single-stranded oligonucleotide that is complementary to a region of a target sequence.

[0082] As used herein, “body mass index” (BMI) refers to an individual’s weight in kilograms divided by the square of a person’s height in meters.

[0083] As used herein, “cachexia” refers to a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, including but not limited to cancer, congestive heart failure, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and AIDS.

[0084] As used herein, “cardiovascular events” are associated with minor or major heart-related problems that may be caused by, e.g., obesity or overweight. Major “cardiovascular events” includes, but is not limited to, cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

[0085] As used herein, “chronic kidney disease” (CKD) refers to the loss of kidney function over time. A person with CKD may be affected by one or more of the following signs or symptoms due to loss of kidney function: nausea, vomiting, loss of appetite, fatigue, weakness, sleep problems, urinating more than normal, muscle cramps, swelling of feet or ankles, high blood pressure, or shortness of breath.

[0086] As used herein, “complementary” or “complementarity” means a structural relationship between two nucleotides, nucleosides, or nucleobases( e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid string e.g., a hairpin) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. Complementary nucleotides can base pair in the canonical Watson-Crick manner, which means adenine pairing with thymine or uracil, and guanine pairing with cytosine, or in any other manner that allows for the formation of stable duplexes. Likewise, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity.

[0087] As used herein, “deoxyribonucleotide” means a nucleotide having a hydrogen in place of a hydroxyl at the 2’ position of its pentose sugar when compared to a ribonucleotide. A modified deoxyribonucleotide has one or more modifications or substitutions of atoms other than hydroxyl at the 2’ position, including modifications or substitutions in the nucleobase, sugar, or phosphate group.

[0088] As used herein, “diabetes” or “diabetes mellitus” refers to a group of endocrine diseases characterized by high blood sugar levels. Diabetes herein refers to either the pancreas of the body not producing enough insulin, or the cells of the body becoming unresponsive to the hormone’s effect. Diabetes herein also refers to type 2 diabetes mellitus (T2DM), which is characterized by high blood sugar, insulin resistance, and / or relative lack of insulin. As used herein, diabetes also refers to high blood sugar levels developed by a woman during pregnancy, known as gestational diabetes.

[0089] As used herein, “double- stranded oligonucleotide” or “ds oligonucleotide” means an oligonucleotide that is in duplex form. The complementary base-pairing of duplex region(s) of a ds oligonucleotide can be formed between antiparallel sequences of nucleotides of covalently separate nucleic acid strands. Likewise, complementary base-pairing of duplex region(s) of a ds oligonucleotide can be formed between antiparallel sequences of nucleotides of nucleic acid strands that are covalently linked. Moreover, complementary base-pairing of duplex region(s) of a ds oligonucleotide can be formed from single nucleic acid strand that is folded (e.g., via a hairpin) to provide complementary antiparallel sequences of nucleotides that base pair together. A ds oligonucleotide can include two covalently separate nucleic acid strands that are fully duplexed with one another. However, a ds oligonucleotide can include two covalently separate nucleic acid strands that are partially duplexed (e.g., having overhands at one or both ends). A ds oligonucleotide can include an antiparallel sequence of nucleotides that are partially complementary, and thus, may have one or more mismatches, which may include internal mismatches or end mismatches.

[0090] As used herein, “duplex” and “duplex region” in reference to nucleic acids (e.g., oligonucleotides), means a structure formed through complementary base pairing of two antiparallel sequences of nucleotides, whether formed by two covalently separate nucleicacid strands or by a single, folded strand (e.g., a hairpin). A duplex may form despite not having full complementarity between the two strands, or when an abasic moiety is present.

[0091] As used herein, “dyslipidemia” refers to abnormally high levels of lipids (fats) in the blood. Dyslipidemia also refers to high levels of cholesterol in the blood.

[0092] As used herein, “effective amount” means an amount, concentration or dose of one or more interfering RNAs described herein, which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment. An effective amount can be readily determined by one of skill in the art through the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered including, but not limited to the species of the mammal; its size, age, and general health; the specific disease or disorder involved; the degree of involvement of or the severity of the disease or disorder; the response of the individual patient; the particular polypeptide administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of a concomitant medication; and other relevant circumstances.

[0093] As used herein, “iRNA,” “iRNA agent,” “RNAi,” “RNAi agent” and “RNA interference agent” means an agent that contains RNA and mediates the targeted cleavage of a RNA transcript via RNA interference, e.g., through a RNA-induced silencing complex (RISC) pathway. In some embodiments, the RNAi agent has a sense strand and an antisense strand, and the sense strand and the antisense strand form a duplex. In some embodiments, the sense and antisense strands of RNAi agent are 21-23 nucleotides in length. In other embodiments, the sense and antisense strands can be longer, for example 25-30 nucleotides in length, in which case the longer RNAi sequences are first processed by the Dicer enzyme. The RNAi attenuates, inhibits, modulates, or reduces ACVR2a and / or ACVR2b expression in the cell. In some embodiments, the RNAi agent described herein further comprises a delivery moiety. In some embodiments, the RNAi agent described herein further comprises a linker attached to the delivery moiety.

[0094] As used herein, “linker” means a structure used to conjugate a nucleotide (e.g., oligonucleotide) to a targeting ligand or a delivery moiety. In some embodiments, a linker can be “labile” or “cleavable” meaning a linker that can be cleaved (e.g., by acidic pH or enzyme). In other embodiments, a linker can be “stable” or “non-cleavable” meaning a linker that is not cleaved in physiological conditions.

[0095] The term, “linked to” or “linked with”, as used herein, refers to a first nucleotide (or polynucleotide) or peptide being associated, attached, connected or otherwise joined to a second nucleotide (or polynucleotide) or peptide.

[0096] As used herein, “metabolic syndrome” refers to a group of health conditions leading to an increased risk of heart disease and / or related problems. A person with a metabolic syndrome has three or more of the following health conditions: (1) high blood sugar levels, (2) low levels of HDL cholesterol, (3) high levels of triglycerides in the blood, (4) a large waist circumference, and (5) high blood pressure.

[0097] As used herein, “metabolic syndrome” refers to a group of health conditions leading to increased risk of heart disease and related problems. A person with metabolic syndrome has three or more of the following health conditions (1) high blood sugar levels, (2) low levels of HDL cholesterol, (3) high levels of triglycerides in the blood, (4) large waist circumference, and (5) high blood pressure.

[0098] As used herein, “modified intemucleotide linkage” means an intemucleotide linkage having one or more chemical modifications when compared with a reference internucleotide linkage having a phosphodiester bond. A modified intemucleotide linkage can be a non-naturally occurring linkage.

[0099] As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyrihonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide. A modified nucleotide can be a non-naturally occurring nucleotide. A modified nucleotide can have, for example, one or more chemical modifications in its sugar, nucleobase, and / or phosphate group. Additionally,or alternatively, a modified nucleotide can have one or more chemical moieties conjugated to a corresponding reference nucleotide. Exemplary modifications include, for example, 2’0 methyl modified ribose on the listed nucleotide or 2’F modified ribose on the listed nucleotide.[000100] As used herein, “modulate,” “modulating,” and the like means that expression of a target gene, or level of a RNA molecule encoding a target protein or a protein subunit, or activity of a protein or protein subunit is upregulated or downregulated, such that expression, level or activity is greater than or less than that observed in the absence of the oligonucleotide. For example, “modulate” with regard to siRNA can mean to inhibit or downregulate expression of a target gene or its protein product.[000101] As used herein, “nonalcoholic steatohepatitis” (“NASH”) refers to fatty liver disease. “NASH” also refers to a subtype of nonalcoholic fatty liver disease (“NAFLD”). NASH is further synonymous with “MASH” or “metabolic associated steatohepatitis.” [000102] As used herein, “nucleotide” means an organic compound having a nucleoside (a nucleobase, for example, adenine, cytosine, guanine, thymine, or uracil; and a pentose sugar, for example ribose or 2’ -deoxyribose) and a phosphate group. A “nucleotide” can serve as a monomeric unit of nucleic acid polymers such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).[000103] As used herein “obesity” refers to a disorder involving excess body fat that increases the risk of health problems. The term “obesity” also refers to weight that is higher than what is considered heavy weight for a given height. The term “obesity” also refesr to a BMI greater than 30.0 or a BMI of 27.0 or greater (overweight) with at least one weight- related comorbid condition (e.g., hypertension, T2DM, dyslipidemia)[000104] As used herein, “obstructive sleep apnea” (OSA) refers to a sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep.[000105] As used herein, “osteoarthritis” (OA) is a form of arthritis causing inflammation of one or more joints. “Osteoarthritis” may refer to arthritis that affects joints in the hand, spine, knees, and hips.[000106] As used herein, “oligonucleotide” means a polymer of linked nucleotides, each of which can be modified or unmodified. An oligonucleotide is typically less than about 100 nucleotides in length. An oligonucleotide may be single-stranded (ss) or double stranded (ds). An oligonucleotide may or may not have duplex regions.[000107] As used herein, “overhang” means a terminal nucleotide(s) resulting from one strand or region extending beyond the terminus of a complimentary strand with which one strand or region forms a duplex. An overhang may include one or more unpaired nucleotides extending from a duplex region at the 5’ terminus or 3’ terminus of a ds oligonucleotide. The overhand can be a 3’ or 5’ overhang on the antisense strand or sense strand of a ds oligonucleotide.[000108] As used herein, “overweight” refers to having more body fat than is optimally healthy. The term “overweight” refers to a BMI overweight over 27.0. As used herein, the term “overweight” also refers to a patient who may require medical treatment in addition to a reduced calorie diet and increased physical activity to maintain a BMI below 27.0, i.e., chronic weight management.[000109] The term “percentage sequence identity” with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical with the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs, for example, those described in Current Protocols in Molecular Biology (Ausubel et. Al, eds. 1987, Supp. 30, section 7.7.18, Table 7.7.1), including BLAST, BLAST- 2, ALIGN, Megalign (DNASTAR), Clustal W2.0 or ClustalX2.0 software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percentage of “sequence identity” can be determined by comparing two optimally designed sequences over a comparison window, where the fragment of the nucleic acidsequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical nucleotide, nucleoside, or nucleobase occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence.[000110] As used herein, “phosphate analog” means a chemical moiety that mimics the electrostatic and / or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5’ terminal nucleotide of an oligonucleotide in place of a 5’ phosphate. A 5’ phosphate analog can include a phosphatase-resistant linkage. Examples of phosphate analogs include, but are not limited to, 5’ phosphonates, such as 5’ methylene phosphonate (5’ MP) and 5 ’-(E)- vinylphosphonate (5’VP). An oligonucleotide can have a phosphate analog at a 4’-carbon position of the sugar (referred to as a “4’-phosphate analog”) at a 5’ -terminal nucleotide. An example of a 4’ -phosphate analog is oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4’ carbon) or analog thereof. See, e.g., Inti. Patent Application Publication No. WO 2018 / 045317. Other modifications have been developed for the 5’ end of oligonucleotides (see, e.g., Inti. Patent Application No. WO 2011 / 133871; US Patent No. 8,927,513; and Prakash et. Al. (2015) Nite. Acids Res. 43:2992-3011).[00011 1] As used herein, “polycystic ovarian syndrome” (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS also refers to a woman who may have one or more of the following symptoms: cysts on the ovaries, irregular menstrual periods, heavy periods, excess hair, difficulty getting pregnant, or insulin resistance.[000112] As used herein, “quality of weight loss” refers to a decrease in fat mass but a preservation of lean mass.[000113] As used herein, “sarcopenia” refers to a progressive and generalized skeletal muscle disorder involving the accelerated loss of muscle mass and function.[000114] As used herein, “sarcopenic obesity” refers to a person who has both sarcopenia (loss of muscle) and obesity. Sarcopenic obesity also refers to the presence of low muscle mass or strength along with high fat mass.[000115] As used herein, “reduced expression,” and with respect to a gene (e.g., ACVR2A and / or ACVR2B) means a decrease in the amount or level of RNA transcript (e.g., ACVR2A or ACVR2B mRNA) or protein encoded by the gene and / or a decrease in the amount or level of activity of the gene in a call, a population of cells, a sample, or a subject, when compared to an appropriate reference (e.g., a reference cell, population of cells, sample, or subject). For example, introducing an oligonucleotide herein (e.g., an oligonucleotide having an antisense strand having a nucleotide sequence that is complementary to a nucleotide sequence including ACVR2A and / or ACVR2B mRNA) into a cell may result in a decrease in the amount or level of mRNA, protein, and / or activity (e.g., via degradation of ACVR2A and / or ACVR2B mRNA by the RNAi pathway) when compared to a cell that is not treated with the ds oligonucleotide. Similarly, and as used herein, “reducing expression” means an act that results in reduced expression of a gene (e.g., ACVR2A and / or ACVR2B). Specifically, and as used herein, “reduction of ACVR2A and / or ACVR2B expression” means a decrease in the amount or level of ACVR2A and / or ACVR2B mRNA, ACVR2A and / or ACVR2B protein, and / or ACVR2A and / or ACVR2B activity in a cell, a population of cells, a sample, or a subject when compared to an appropriate reference (e.g., a reference cell, population of cells, tissue, or subject).[000116] As used herein, “ribonucleotide” means a nucleotide having a ribose as its pentose sugar, which contains a hydroxyl group at its 2’ position. A modified ribonucleotide is a ribonucleotide having one or more modifications or substitutions of atoms other than hydrogen at the 2’ position, including modifications or substitutions in or of the nucleobase, sugar, or phosphate group.[000117] As used herein, “sense strand” means a single-stranded oligonucleotide that is complementary to a region of an antisense strand.[000118] As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through internucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). A strand can have two free ends (e.g., a 5’ end and a 3’ end). [000119] As used herein, “subject” means any mammal, including cats, dogs, mice, rats, primates, and humans. Preferably subject means humans. Moreover, “individual” or “patient” may be used interchangeably with “subject.”[000120] As used herein, “synthetic” refers to a nucleic acid or other compound that is artificially synthesized (e.g., using a machine such as, for example, a solid phase nucleic acid synthesizer) or that is otherwise not derived from a natural source (e.g., a cell or organism) that normally produces the nucleic acid or other compound.[000121] As used herein, “targeting ligand” [“delivery moiety”] means a chemical moiety that facilitates the entry of an oligonucleotide or RNAi agent into a cell. It can be a compound (e.g., an amino sugar, carbohydrate, cholesterol, lipid, or polypeptide) that selectively binds to a cognate compound (e.g., a receptor) of a tissue or cell of interest and that is conjugatable to another substance for targeting another substance to the tissue or cell of interest. For example, a targeting ligand may be conjugated to an oligonucleotide herein for purposes of targeting the oligonucleotide to a specific tissue or cell of interest. A targeting ligand can selectively bind to a cell surface receptor. Accordingly, a targeting ligand, when conjugated to an oligonucleotide, facilitates delivery of the oligonucleotide into a particular cell through selective binding to a receptor expressed on the surface of the cell and endosomal internalization by the cell of the complex comprising the oligonucleotide, targeting ligand, and receptor. Moreover, a targeting ligand can be conjugated to an oligonucleotide via a linker that is cleaved following or during cellular internalization such that the oligonucleotide is released from the targeting ligand in the cell.[000122] As used herein, “transferrin receptor (TfR) binding protein” (TBP) refers to antibodies or antigen-binding fragments, peptides, or other proteins that bind the transferrin receptor in tissues and / or cells that express TfR. As used herein, the TfR shuttles are used to deliver an RNAi agent to a target cell or tissue (e.g., a cell or tissue that expresses TfR). Theamino acid sequence of the human transferrin receptor protein (hTFR) can be found at NP_001121620.1:1 MMDQARSAFS NLFGGEPLSY TRFSLARQVD GDNSHVEMKL AVDEEENADN NTKANVTKPK61 RCSGSICYGT IAVIVFFLIG FMIGYLGYCK GVEPKTECER LAGTESPVRE EPGEDFPAAR121 RLYWDDLKRK LSEKLDSTDF TGTIKLLNEN SYVPREAGSQ KDENLALYVENQFREFKLSK181 VWRDQHFVKI QVKDSAQNSV I IVDKNGRLV YLVENPGGYV AYSKAATVTG KLVHANFGTK241 KDFEDLYTPV NGS IVIVRAG KITFAEKVAN AESLNAIGVL IYMDQTKFPI VNAELSFFGH301 AHLGTGDPYT PGFPSFNHTQ FPPSRSSGLP NIPVQTI SRA AAEKLFGNME GDCPSDWKTD361 STCRMVTSES KNVKLTVSNV LKEIKILNIF GVIKGFVEPD HYWVGAQRD AWGPGAAKSG421 VGTALLLKLA QMFSDMVLKD GFQPSRSI IF ASWSAGDFGS VGATEWLEGY LSSLHLKAFT481 YINLDKAVLG TSNFKVSASP LLYTLIEKTM QNVKHPVTGQ FLYQDSNWAS KVEKLTLDNA541 AFPFLAYSGI PAVSFCFCED TDYPYLGTTM DTYKELIERI PELNKVARAA AEVAGQFVIK601 LTHDVELNLD YERYNSQLLS FVRDLNQYRA D IKEMGLSLQ WLYSARGDFF RATSRLTTDF661 GNAEKTDRFV MKKLNDRVMR VEYHFLSPYV SPKESPFRHV FWGSGSHTLP ALLENLKLRK721 QNNGAFNETL FRNQLALATW TIQGAANALS GDVWD IDNEF (SEQ ID NO: 311).The amino acid sequence of the mouse transferrin receptor protein (mTFR) can be found at NP 001344227.1:1 MMDQARSAFS NLFGGEPLSY TRFSLARQVD GDNSHVEMKL AADEEENADN NMKASVRKPK61 RFNGRLCFAA IALVIFFLIG FMSGYLGYCK RVEQKEECVK LAETEETDKSETMETEDVPT121 SSRLYWADLK TLLSEKLNS I EFADTIKQLS QNTYTPREAG SQKDESLAYY IENQFHEFKF181 SKVWRDEHYV KIQVKSS IGQ NMVTIVQSNG NLDPVESPEG YVAFSKPTEV SGKLVHANFG241 TKKDFEELSY SVNGSLVIVR AGEI TFAEKV ANAQSFNAIG VLIYMDKNKF PVVEADLALF301 GHAHLGTGDP YTPGFPSFNH TQFPPSQSSG LPNIPVQTI S RAAAEKLFGK MEGSCPARWN361 IDSSCKLELS QNQNVKLIVK NVLKERRILN IFGVIKGYEE PDRYWVGAQ RDALGAGVAA421 KSSVGTGLLL KLAQVFSDMI SKDGFRPSRS I IFASWTAGD FGAVGATEWL EGYLSSLHLK481 AFTYINLDKV VLGTSNFKVS ASPLLYTLMG KIMQDVKHPV DGKSLYRDSN WI SKVEKLSF541 DNAAYPFLAY SGIPAVSFCF CEDADYPYLG TRLDTYEALT QKVPQLNQMV RTAAEVAGQL601 I IKLTHDVEL NLDYEMYNSK LLSFMKDLNQ FKTDIRDMGL SLQWLYSARG DYFRATSRLT661 TDFHNAEKTN RFVMREINDR IMKVEYHFLS PYVSPRESPF RHIFWGSGSH TLSALVENLK721 LRQKNI TAFN ETLFRNQLAL ATWTIQGVAN ALSGD IWNID NEF (SEQ ID NO: 312).[000123] As used herein, “treatment” or “treating” refers to all processes wherein there may be a slowing, controlling, delaying, or stopping of the progression of the disorders or disease disclosed herein, or ameliorating disorder or disease symptoms, but does not necessarily indicate a total elimination of all disorder or disease symptoms. Treatment includes administration of a nucleic acid or vector or composition for treatment of a disease or condition in a patient, particularly in a human.[000124] The dsRNA can include modifications. The modifications can be made to one or more nucleotides of the sense and / or antisense strand or to the intemucleotide linkages, which are the bonds between two nucleotides in the sense or antisense strand. For example, some 2’ -modifications of ribose or deoxyribose can increase RNA or DNA stability and half-life. Such 2’ -modifications can be 2’-fluoro, 2’-O-methyl (i.e., 2’-methoxy), or 2'-O-alkyl (e.g., 2’-O-C16 alkyl).[000125] In some embodiments, one or more nucleotides of the sense strand and / or the antisense strand are independently modified nucleotides, which means the sense strand and the antisense strand can have different modified nucleotides. In some embodiments, each nucleotide of the sense strand is a modified nucleotide. In some embodiments, each nucleotide of the antisense strand is a modified nucleotide. In some embodiments, the modified nucleotide is a 2'-fluoro modified nucleotide, 2’-O-methyl modified nucleotide, or 2'-O-alkyl (e.g., 2’-O- Ci6 alkyl) modified nucleotide. In some embodiments, each nucleotide of the sense strand and the antisense strand is independently a modified nucleotide, e.g., a 2'-fluoro modified nucleotide, 2'-O-methyl modified nucleotide, or 2'-O-alkyl (e.g., 2’-O-Ci6 alkyl) modified nucleotide.[000126] In some embodiments, the sense strand has four 2'-fluoro modified nucleotides, e.g., at positions 7, 9, 10, 11 from the 5’ end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has four 2'-fluoro modified nucleotides, e.g., at positions 2, 6, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2'-O-methyl modified nucleotides.[000127] In some embodiments, the sense strand has three 2'-fluoro modified nucleotides, e.g., at positions 9, 10, 11 from the 5’ end of the sense strand. In some embodiments, the other nucleotides of the sense strand are 2'-O-methyl modified nucleotides. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides, e.g., at positions 2, 5, 7, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the antisense strand has five 2'- fluoro modified nucleotides, e.g., at positions 2, 5, 8, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the antisense strand has five 2'-fluoro modified nucleotides, e.g., at positions 2, 3, 7, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the antisense strand has three 2'-fluoro modified nucleotides, e.g., at positions 2, 14, 16 from the 5’ end of the antisense strand. In some embodiments, the other nucleotides of the antisense strand are 2'-O-methyl modified nucleotides.[000128] In some embodiments, the 5’ end of the antisense strand has a phosphate analog, e.g., 5 ’ -vinylphosphonate (5’-VP).[000129] In some embodiments, the sense strand and the antisense strand have one or more modified intemucleotide linkages. In some embodiments, the modified internucleotide linkage is phosphorothioate linkage. In some embodiments, the sense strand has four or five phosphorothioate linkages. In some embodiments, the antisense strand has four or five phosphorothioate linkages. In some embodiments, the sense strand and the antisense strand each has four or five phosphorothioate linkages. In some embodiments, the sense strand has four phosphorothioate linkages and the antisense strand has five phosphorothioate linkages. [000130] Certain abbreviations as used herein are defined as follows: “Aib” refers to 2- aminoisobutyric acid; ““SMCC” refers to succinimidyl-4-(N-maleimidomethyl)cyclohexane- 1 -carboxylate; “MSPT” refers to 4-(5-methylsulfonyl-lH-tetrazole-lyl)phenol; “OD” refers to 4-(5-(methylsulfonyl)-l,3,4-oxadiazol-2-yl)phenol; “DBCO” refers to DibenzocyclooctyneEXAMPLESExample 1. Synthesis of Acyr2a RNAi Agents[000131] The sequence of antisense oligonucleotides were designed using 15 to 50 nucleotides of the following ACVR2A transcript (SEQ ID NO: 1), where T nucleotides are replaced by U nucleotides, and where one or more nucleotides and one or more internucleotide linkages are optionally further modified as described herein.[000132] Single strands (sense and antisense) of the dsRNA duplexes were synthesized on solid support via a MerMade™ 12 (LGC Biosearch Technologies). The sense strands were synthesized using phthalamido amino C6 Icaa CPG 500 A (Chemgenes) or standard support (LGC Biosearch Technologies) whereas the antisense strands used standard support (LGC Biosearch Technologies). The oligonucleotides were synthesized via phosphoramidite chemistry at either 5, 10, or 50 pmol scales.[000133] Standard reagents were used in the oligo synthesis, where 0. IM xanthane hydride in pyridine was used as the sulfurization reagent and 20% DEA in ACN was used asan auxiliary wash post synthesis. All monomers were made at 0.1 M in ACN and contained a molecular sieves trap bag.[000134] The oligonucleotides were cleaved and deprotected (C / D) at 45 °C for 20 hours. The sense strands were C / D from the CPG using cold 50% (methylamine / ammonia hydroxide 28-30%) at RT for 3 hrs, whereas 3% DEA in ammonia hydroxide (28-30%, cold) was used for the antisense strands. C / D was determined complete by IP-RP LCMS when the resulting mass data confirmed the identity of sequence. Dependent on scale, the CPG was filtered via 0.45 um PVDF syringeless filter, 0.22 um PVDF Steriflip® vacuum filtration or 0.22 um PVDF Stericup® Quick release. The CPG was back washed / rinsed with either 30% EtOH / RNAse free water then filtered through the same filtering device and combined with the first filtrate. This was repeated twice. The material was then divided evenly into 50 mL falcon tubes to remove organics via Genevac™. After concentration, the crude oligonucleotides were diluted back to synthesized scale with RNAse free water and filtered either by 0.45 pm PVDF syringeless filter, 0.22 μ PVDF Steriflip® vacuum filtration or 0.22 pm PVDF Stericup® Quick release.[000135] The crude oligonucleotides were purified via AKTA™ Pure purification system using anion-exchange (AEX). For AEX, an ES Industry Source™ 15Q column with MPA: 20mM NaH2PO4, 15% ACN, pH 7.4 and MPB: 20 mM NaH2PO4, IM NaBr, 15% ACN, pH 7.4. Fractions which contained a mass purity greater than 85% without impurities >5% where combined.[000136] The purified oligonucleotides were desalted using 15 mL 3K MWCO centrifugal spin tubes at 3500xg for ~30 min. The oligonucleotides were rinsed with RNAse free water until the eluent conductivity reached < 100 usemi / cm. After desalting was complete, 2-3 mL of RNAse free water was added then aspirated 10x, the retainment was transferred to a 50 mL falcon tube, this was repeated until complete transfer of oligo by measuring concentration of compound on filter via nanodrop. The final oligonucleotide was then nano filtered 2x via 15 mL 100K MWCO centrifugal spin tubes at 3500xg for 2 min. The final desalted oligonucleotides were analyzed for concentration (nanodrop at A260), characterized by IP-RP LC / MS for mass purity and UPLC for UV-purity.Table 16. Oligonucleotide Synthesis ReagentsTable 17. PhosphoramiditesACVR2A Transcript, SEQ ID NO:11 gtctgggctt ccgaatatgt tttatgacgg ttgattttac accaggaggt ttgtctccga61 ggaagaccca gggaactgga tatctagcga gaacttcctc cggattcccc ggcgcctcgg121 gaaaatggga gctgctgcaa agttggcgtt tgccgtcttt cttatctcct gttcttcagg181 tgctatactt ggtagatcag aaactcagga gtgtcttttc tttaatgcta attgggaaaa241 agacagaacc aatcaaactg gtgttgaacc gtgttatggt gacaaagata aacggcggca301 ttgttttgct acctggaaga atatttctgg ttccattgaa atagtgaaac aaggttgttg361 gctggatgat atcaactgct atgacaggac tgattgtgta gaaaaaaaag acagccctga421 agtatatttt tgttgctgtg agggcaatat gtgtaatgaa aagttttctt attttccgga481 gatggaagtc acacagccca cttcaaatcc agttacacct aagccaccct attacaacat541 cctgctctat tccttggtgc cacttatgtt aattgcgggg attgtcattt gtgcattttg601 ggtgtacagg catcacaaga tggcctaccc tcctgtactt gttccaactc aagacccagg661 accaccccca ccttctccat tactaggttt gaaaccactg cagttattag aagtgaaagc721 aaggggaaga tttggttgtg tctggaaagc ccagttgctt aacgaatatg tggctgtcaa781 aatatttcca atacaggaca aacagtcatg gcaaaatgaa tacgaagtct acagtttgcc841 tggaatgaag catgagaaca tattacagtt cattggtgca gaaaaacgag gcaccagtgt901 tgatgtggat ctttggctga tcacagcatt tcatgaaaag ggttcactat cagactttct961 taaggctaat gtggtctctt ggaatgaact gtgtcatatt gcagaaacca tggctagagg1021 attggcatat ttacatgagg atatacctgg cctaaaagat ggccacaaac ctgccatatc1081 tcacagggac atcaaaagta aaaatgtgct gttgaaaaac aacctgacag cttgcattgc1141 tgactttggg ttggccttaa aatttgaggc tggcaagtct gcaggcgata cccatggaca1201 ggttggtacc cggaggtaca tggctccaga ggtattagag ggtgctataa acttccaaag1261 ggatgcattt ttgaggatag atatgtatgc catgggatta gtcctatggg aactggcttc1321 tcgctgtact gctgcagatg gacctgtaga tgaatacatg ttgccatttg aggaggaaat1381 tggccagcat ccatctcttg aagacatgca ggaagttgtt gtgcataaaa aaaagaggcc1441 tgttttaaga gattattggc agaaacatgc tggaatggca atgctctgtg aaaccattga1501 agaatgttgg gatcacgacg cagaagccag gttatcagct ggatgtgtag gtgaaagaat1561 tacccagatg cagagactaa caaatattat taccacagag gacattgtaa cagtggtcac1621 aatggtgaca aatgttgact ttcctcccaa agaatctagt ctatgatggt tgcgccatct1681 gtgcacacta agaaatggga ctctgaactg gagctgctaa gctaaagaaa ctgcttacag1741 tttattttct gtgtaaaatg agtaggatgt ctcttggaaa tgttaagaaa gaagaccctt1801 tgttgaaaaa tgttgctctg ggagacttac tgcattgccg acagcacaga tgtgaaggac1861 atgagactaa gagaaacctt gcaaactcta taaagaaact tttgaaaaag tgtacatgaa1921 gaatgtagcc ctctccaaat caaggatctt ttggacctgg ctaatggagt gtttgaaaac1981 tgacatcaga tttcttaatg tctgtcagaa gacactaatt ccttaaatga actactgcta2041 ttttttttaa atcaaaaact tttcatttca gattttaaaa agggtaactt gtttttattg2101 catttgctgt tgtttctata aatgactatt gtaatgccaa tatgacacag cttgtgaatg2161 tttagtgtgc tgctgttctg tgtacataaa gtcatcaaag tggggtacag taaagaggct2221 tccaagcatt actttaacct ccctcaacaa ggtatacctc agttccacgg ttgctaaatt2281 ataaaattga aaacactaac aaaatttgaa taataaatcg atccatgttt tgtaacaaat2341 tcactgtgtt atttaaggaa aaaaaggtaa gctatgctta gtgccaacaa taagtggcca2401 ttcgtaaagc agtgttttag catttcttgt gctggcttgt aatgtaggga aaaaaagtgc2461 tgttttttga aaagatggtg tcatttcccc cttcttccca tgttttaaag ccccatctta2521 tatccagttc ccaaaatttg catacttacc taagtatttt ttttaggtgt gctgtgtttg2581 gggaatattt gaaaatttaa agcatgattt aaaatttttt aaagtgagct gtgacactgg2641 aaagctcttc attttatctt ttaaaataga gttttttcta tttatatatg taaaattgta2701 gtgtatttct tttcaccaaa cagtgtgtgg gacattcttt atcactgttt taggatcacc2761 tcaggaagtg tcgttaccca gaattcccca ctgtctgcta tgagacttgt aactttatca2821 ctatacttct gcttggtgcc atcttgtcag agtaatattt gatgtctgtg atatgtaaag2881 aattatccta ggataaagat attaaacttt aagcagattt cagatgttac tgctttaaaa2941 caaatcaggg ataacaaatt aaacgtataa cttaaaatat gcaatgacat ttagaggtaa3001 ccaatgttga tataggtagc atagcctagc ctcctcccca aaattgcttt tacaactaac3061 actgatacta atttaggata gttcatgcct tatccttgct aagaaaatgg aattgatggt3121 aggcaggtgc taaagtgctt ttcaaaacaa tattacgtta gaatacaatt ggattcttcc3181 tcaaatttat acaggccaaa aagtaaaaca ttaattttct gaatttccag attaccaatc3241 aattaatcaa caaatagcca gtattatgct gtgtatttct gtcaggtcat tttaaaatcc3301 atgttaattt tataaaagaa ttttttacat gtcactgtca ggagctcact gtgaatgtgt3361 tgtcttcaaa tggttattta accacacagt acactacatt ttacatatat gtacgtaatc3421 tctgggaata gtaaattaat tatgttattt ataaacaata cataggtcaa cagactttaa3481 gcagggagga aaagaagagt aatagcgtct gtgtgctgca gaccattcag aactgtcacg3541 tgtgtcccca tggtctcatt cattgtattc ctagcaattc ccttttcaat gttgagttca3601 cctctttatt tcacaaagta cttggtctct caatttcttg atctggtttt gcttccattt3661 aaaaactaat caagaaggga aaatattgag aatgtgcata caagaaaatc attaatttcc3721 tgaagatgaa tttctacctg ttgtgaacat ttaactttct ttttaaaagt taaacaaaaa3781 taaacaaggg atattatgat gaatgtttgg cttatgtgag tactagagat aaaattttta3841 aacccagtta ttcacaatat aaaatgtttt caagttagaa aaaattttta gaaatcctgg3901 gtattgtatt taactgtagc taaccaattt taaaacttgt attcttttga gaactattat3961 taatagaaaa actttttata agcagtaaaa taagaatgtt ccagtgacta cctgtcctta4021 tacctagtct tgttaaaact ttcttttgca gggtatttag tgtttggttt acagtcagtg4081 cagagtgggc aagttaacag aaagtttgag ctagagatac tggaaaaaaa aaagatcaaa4141 gaatgagaaa aatggtgatc cattttgggg caaactgaga ccccccaaat aactctttcc4201 tcatgtgtat ggtgctcctc atgactcgtc ttgtattttg cctttctgat acccatcaga4261 actgctgctg ctctaactta tactctttac cttgcccaga tctccgcgta aggaatgctt4321 tatgatcaac ttgccatagg actgatggat taaccagtgt tcggctttat ttgaagtcta4381 tgccctgcac agctcttgta tgtattttag atgctagaag tttttttagc atgtgatgtg4441 tgattcttgt ttgaattcta ggtaccttgt gaattccaga aaaagagact gtgcttcacg4501 attgttagtc ccatgaactt gcactatcta tctttcatgg tgatgttttg aaaatacaat4561 caggaaaaaa cccaacacct ttggaattta aaatagaatc atatcatgaa atttaaaaag4621 aatctcttct gttgcatttc ctcaccccta agtaacagct acatttaagt aaaatgcagg4681 tggtagggga aaaaaaacca tggcgagatg gtggtttagt ggaataaact gattactggt4741 ttttttgttt tttttttttt ttttaaagaa agaagcttca tcacagatac tttccagttt4801 ctcttttata cttttttgaa agattacttt ttaggaacat ttggtatgat atgcataaaa4861 ttatttatcc atttatgggc aaaatgatac aagtagcatc ttgattgaac atcatttacc4921 tcagatattc aaccagcagt acgtttttta tgcagtctca acccatatcc catttgttac4981 ctctcagaat attggtaagc agttattttc gctttactct gtatttcttg tgttttgggc5041 acaggttatt gtactactgt caaatcgtac ttgctatttt ttctgcaagt atttaacaga5101 aagcttaaaa tccccataaa accccacctt ggataagtga ttgttaaata ttgtacaaat5161 aaaatgtatg ctatccccat tccatcccca agttaaataa aaaaatgaat acggTable 18. Exemplary sense and antisense strands of Acvr2a RNAi agentsTable 19. Exemplary Modified Acvr2a dsRNA Sequencesm indicates 2’O-methyl modified ribose on the listed nucleotide f indicates 2’F modified ribose on the listed nucleotide“■“indicates a phosphorothioate bond (in place of a phosphodiester bond)Example 2. Synthesis of Acvr2b RNAi agents[000137] The sequence of antisense oligonucleotides are designed using [15 to 50] nucleotides of the following Acvr2b transcript (SEQ ID NO:2), where T nucleotides are replaced by U nucleotides, and where one or more nucleotides and one or more internucleotide linkages are optionally further modified as described herein.[000138] The synthesis of ACVR2B RNAi agents was performed following the same procedure as outlined in Example 1.SEQ ID NO:2 ACVR2b Transcript1 ggctcggctc cgtggccgcc gctcaggagc cattttggac tcggttcagc tcccctcccc61 cccacccctc cccccgttca tggcccctcc ggactcggcc cctgcgcccg gggcccgggc121 ccagccccgc cgcgctatgc ctgagtcggg cgcgccccgg cccgtgcccc gccgccgccc181 cccggccccc gcgtcgcccc ggagcccggg ccgcagcctg cgccgcccgc agcggccctg241 agcccggccc cgccgaccgg cccttggagc ccgaacgctg ctcggggacg aaggcgcagg301 aagcgcgcag ggaacgagac cgaaggaagg agcgggaagg agagcgcagc cgccgcctgg361 ccctgcgcgc cccgggagcg ccgtgcggcc ctgcccgcgg gctccgggtg tgcgcggggc421 ggcgccgcgg aacatgacgg cgccctgggt ggccctcgcc ctcctctggg gatcgctgtg481 cgccggctct gggcgtgggg aggctgagac acgggagtgc atctactaca acgccaactg541 ggagctggag cgcaccaacc agagcggcct ggagcgctgc gaaggcgagc aggacaagcg601 gctgcactgc tacgcctcct ggcgcaacag ctctggcacc atcgagctcg tgaagaaggg661 ctgctggcta gatgacttca actgctacga taggcaggag tgtgtggcca ctgaggagaa721 cccccaggtg tacttctgct gctgtgaagg caacttctgc aacgaacgct tcactcattt781 gccagaggct gggggcccgg aagtcacgta cgagccaccc ccgacagccc ccaccctgct841 cacggtgctg gcctactcac tgctgcccat cgggggcctt tccctcatcg tcctgctggc901 cttttggatg taccggcatc gcaagccccc ctacggtcat gtggacatcc atgaggaccc961 tgggcctcca ccaccatccc ctctggtggg cctgaagcca ctgcagctgc tggagatcaa1021 ggctcggggg cgctttggct gtgtctggaa ggcccagctc atgaatgact ttgtagctgt1081 caagatcttc ccactccagg acaagcagtc gtggcagagt gaacgggaga tcttcagcac1141 acctggcatg aagcacgaga acctgctaca gttcattgct gccgagaagc gaggctccaa1201 cctcgaagta gagctgtggc tcatcacggc cttccatgac aagggctccc tcacggatta1261 cctcaagggg aacatcatca catggaacga actgtgtcat gtagcagaga cgatgtcacg1321 aggcctctca tacctgcatg aggatgtgcc ctggtgccgt ggcgagggcc acaagccgtc1381 tattgcccac agggacttta aaagtaagaa tgtattgctg aagagcgacc tcacagccgt1441 gctggctgac tttggcttgg ctgttcgatt tgagccaggg aaacctccag gggacaccca1501 cggacaggta ggcacgagac ggtacatggc tcctgaggtg ctcgagggag ccatcaactt1561 ccagagagat gccttcctgc gcattgacat gtatgccatg gggttggtgc tgtgggagct1621 tgtgtctcgc tgcaaggctg cagacggacc cgtggatgag tacatgctgc cctttgagga1681 agagattggc cagcaccctt cgttggagga gctgcaggag gtggtggtgc acaagaagat1741 gaggcccacc attaaagatc actggttgaa acacccgggc ctggcccagc tttgtgtgac1801 catcgaggag tgctgggacc atgatgcaga ggctcgcttg tccgcgggct gtgtggagga1861 gcgggtgtcc ctgattcgga ggtcggtcaa cggcactacc tcggactgtc tcgtttccct1921 ggtgacctct gtcaccaatg tggacctgcc ccctaaagag tcaagcatct aagcccagga1981 catgagtgtc tgtccagact cagtggatct gaagaaaaaa ggaaaaaaag ttgtgttttg2041 ttttggaaat cccataaaac caacaaacac ataaaatgca gctgctattt taccttgact2101 ttttattatt attattataa ttattataat tattattatt aatattattt tttggattgg2161 atcagttttt accagcatat tgctctactg tatcacaaac agcggacacg tcagcaggcg2221 ttgaggtgct gagctgtgga tgcagaacca gcgccatgct gaagagcctc agccacctcc2281 tgtcctttgg gattcgtttt tcccgctttc tctttgtttg tcgtctcaga atctgtgaca2341 caaagaaacc catctcctgt cttaggaaac ctaatgctgc aaactctacc tagaggaacc2401 tttgaagact gttacataag aacatacctt cctcagaaga ggagtttcct ctgccctctg2461 cccttctccc ctgcctccct ccctcccctc cttttatttt gttttagtga gcttaagaaa2521 cagcagatgt gtctttcacg gatctaacgg gtgttgtcct gatcgagaaa aaaactggga2581 tgagaatggt ttggactgga gttggaaggg gaggacggta ctgggggtag ggtttggaac2641 agagctacac tggactcggg cacattcgga gcagcatcct ttagtatgga ggctacttct2701 caggtaacca ggaattgagg ggaaggacct tgtggaggcc gagcattaac agcaagagcg2761 gggtttggag aaagtctgag attgggtgca gccctgactt acctgctggc cctgaccagt2821 ttcttttcac taacttggcc ttgggcatag gatgaaacat tttttctgcc ctaattttaa2881 aactaggtga gggtagaatc atcacaggtt aggaatacat tcttcataag acacgatgct2941 gtaaataccc ttaatggacg aaaagttgaa atacttttgt ttcctcttgg agcagttcag3001 ggaaatgccc acaggggatt gtcctgcaca gatagggcaa gaggatttcc tgggtggagt3061 ctgccaaggc ctgcctcgct ggggacccca gagtcctgca cctctggttc cgccccaggt3121 ggtgacatta ctgtccccgt tctgtggctc gtggacaaga ctttctccag accccttaaa3181 gtggtacata ttctaaaaaa ctgtttttct attatgccat aaccttgctc tagtcagtga3241 atgttcctaa tgctgctgtt tcaacatttg aattcttttt aatttatgaa acatgctaaa3301 tttttttttt caaacaaaac acacacatcc acatatacac atgcttcgct atgtggcttc3361 caaggtttaa attttgaaaa gtaaaagaat taaaacttca cgaccacaga tcacctcaaa3421 ccagaaatac ctcagaattt tctacttatg taaggtttat tatatatttt gttagttgtg3481 ttgtcttgta gtaagtatat tttaatgtaa gttggctttt gtgacaagga agtttaaaag3541 aaatagagaa aaagaaaaaa gtttgcatct tctagggagt gctaccattt ttgtttgata3601 acgccccctt gtaaataatt gtcatcaact gtaggttggc tgtctgggcc aagtctgggc3661 atttatcagt cttgtttgtg aaggcttttc cttctggttt ctttagatca ttttatttaa3721 aaacagtgca tctcttcatc gtgagggtag gcaaggcggg ggccgtgggg agaggttgac3781 ctgggtgaga actgaagagg ccgcctcctc ttgggttgtt tggagcttca catgtaattc3841 acatgtaaca tgtaacttga tcggtcagtg ttcagaatga caagtaaccc cgcttaaact3901 tggtagaagg atggccctta gacctgaatg gggtgatttt acttgggatt taacttcttc3961 agcaaattaa cagcaacgtt ggaagagatc tgtggcgcct ctgtgaagca caccgtgact4021 caggccagtc ttttagtgca gcgtgtctgg gagtgaaggg ttttgccctt gctggtcttg4081 gagtccacag tgtgaggggc actgcacatg cctgggcatc tacctagtgt gctatgttca4141 gtgtctgggg cttactgccc cggggtcctt tcctctgggt gttggggcac agggtgctat4201 gggaggccca tttgcttccc tctcggagct cagtttttgc ttcatgggtc aaaatgtggg4261 ctggccaagt ggttacagga acagggtttc ggtaagctat gttgtctttt tttttttttt4321 tttttttttt tttaatggtt tgattttgtg ctgtggtatt ttttttccct tagaataatt4381 tttaatggca aaacaggcct tacagcagtt gcttttcttt accatttatt tctttaagaa4441 gctttaaaat atttattgaa aagtgccata tctaatttct ttagctttcg cctcaggcag4501 tgcaggcatc tttacttttc atcctcagaa gaaacaaacg actaacaaat gtagcaaatt4561 tactgcagga atagttaggt catgatacta cctgaacact aaaccccagc ctctttgttt4621 ggttttagtt cctctgggtg gtttttcttt tgtgtgctgg cttgattctt gtgagaagtt4681 ttgacctggc caagggaggg ttgagccatg gttctggtgt gggactttgc ggtcaagaca4741 cagtacagac aggtcaggcc tgcgtgcctt ttctctgggt ggcctccccg ttaggcccac4801 cgtacgctca gccactatag tgtccctgtg gggccttgcc atcagattgt gtgtcaggag4861 atggtacctt tttggtgtgg ctggggagga gtgtggtcca tgccagttct ttgggcttca4921 ggccactctt cccctcatgc tgtggtgtaa agtgcaccca tcaggtggta tatctggttc4981 tgatggcaag aagaaggtgg gggatctcct tatagggcat gggtctagga gcacagatgg5041 gccttttgcc ccgggtaaat gcttgtctgt ttgctgtcat gtgttctttg aggagtgagc5101 catctcgagc cctgctttga atttactggg tcatagagcc tctgcctgtg ctcttttcca5161 taatgacttc atgtgacatg cacttttggt gggctcagat aattggtttc tttttgtttt5221 tgacctcagg ctctgtggca gactggggaa aatggggcct ggcatcattt tccctgtcaa5281 tgggaggggc tgttccatgc agggtgggag gggaccaagt tagcagagag tagccaagga5341 tccttgcttc ttcctttcta gtgtgctgtc atccaagcag gctcctggct gtagggatgg5401 gccttgggga agaatcttct ttgaaagcat ctatgataac tgagaagtca tccctagttg5461 gagaaatcca gtaatgagca gaaggaggaa gcaagtgagg acagaggcca ttgtattaca5521 gtgtcacgca gagggccctc aatgatgggg cattggggaa ggctgtagac atagtcatca5581 gaacatcctg gcctggcata agctgggttt tctcctggga ccattggtcc tcagcaggag5641 ttctttgcat gagttgctca ggggcaaggg ctgcaagtgg gctgtgctta ggagaaagtg5701 acacctggca gtgagggaag atggtgagca ttattagcct ttgttgtcca gcatggcctt5761 cttgtcctgt ctgctctgga gaggagcctg tgggaccagt cctgcctggg gagggcatac5821 ccacacgtgc cagctgattc tgactctgaa tacatcatgt ccggacttgg gggtgtttct5881 gcagaaaaag gaggttgttt ttcagccttg aacatcttca ggaggataga gactcttgct5941 cacatattct tagcaaaggg aagggtctct catctccagg ccacagagat agttcttcca6001 ttgccctaag aggctaggct aaccctcttg acataactta gacagcaaag cacttcatcc6061 tgtagttggg ctctgtcacc tttctcttca gttggccaca ttctcgtttc ctccatcctg6121 ctatgctttg tgtgctcggg ctgtgtgtgg ggtttttccc tggtggaagg aagcccagct6181 gtgtattgaa tgtccttcat gtgttgtgtg tggctcagaa agcctgtcac ttggcccctg6241 tgctctgagc cgtgagggtg gggaggtggc tgttccatta aagtgggagt attggatggc6301 cctcttgaaa ctagaatttt gcctttttta gtatgcagta taaagtttcc agcatctatt6361 ggtaacacaa agatttgctg gtttttaaaa taatacagta agcataagta tgtaagtttt6421 tagaattggt actagaagtt ggacagctag ttattctcga gaactttatt tcactagaaa6481 aatatactaa ttggaaagca gtttccagga gttaactcag tttaattttc agtctcagtt6541 attttagcct gttgagtttt tgatggcaca cctttggaga gatggccacg cctgattccc6601 atttcagggg catcagacca taccttttta agaagctccg tgaatctagt catctaccct6661 tcatcctggg cgaacagcca aaaagagaag gggacaaggt gtctttttct ccttctcact6721 ggggtgacat gaattctttt agttaatggc tgtttgcaaa ttctaaacta atgaaatact6781 tagcagctaa catgttcaat ctagtaatga tgagtttaaa tctcaattga cagtaatgtt6841 ttagataaac aggcccagta attcagttga tgaactgtat atcttctcag tctagatttg6901 taaatgttta atgaattcag ggttataagc atagttcttt aagtaagatt ccagatagtt6961 gatttgcaac cagcagtcta cctatgaatg tatcccaaac ctttagaaga ttggaaaaga7021 tttttgaaat aatgatttag ttttgtagga aaaacacccc cttgaaaatt aattcggttg7081 acccagtaac attttttaaa acaattggtg gctccaaaag gcctgccaac aaagaaaagt7141 ccaaattatc tagtgggaca ttttgaatgt tttatgttta ttttgggtcc actgtaaact7201 ttggttcaaa aaagaatttg aatttaaaga atttaccatt atttaaatta ttaccaagtt7261 tttacatttt catgatggta ttttccaggt atgaatgaaa catgactttt tgattgtggt7321 acttcctgta tcccctgtag tgccaaaacc agtgatactt tatttgctcc tatggcagct7381 catagaggta accgaagtga tttttcctca gtaattgaaa cacatattct ctaaatgcca7441 atgtgtggtg atgggccctg cactgccttc atttctctag ggcagtgtct ttggattgtc7501 tagggcctag gtaattctga gaactactgt aaaccaacca cagggcacta aagcaatgta7561 ca caeca etc tttgtgtgta tggaaggggt tatataaacc tgggctatgc tggacatcta7621 cagaagagta ttacattcac ttgcaaagtt tacatttttg agctcacagt tatgaaaaat7681 atgacccaca agtttttcag gcaggtgagg atgggtcttc ttgcaaatgc atgagttctg7741 tcttgagtcc tgggaacttc tctgttggtt gagtgtgggc tcattccctg actctcctaa7801 tcatgtttgc gtcagaatgt tagcattgta aataaaagaa taggttgtat aatagataca7861 caacacttga aactttactt taaaaaaatc gatagtteta catatatatt tagttatatc7921 acttgacaga tttcttctac acagtgtgga gattgtttta taccacagat tatttttata7981 aagttagtga atttgaatga ttttgtaatc agagetaatg agctttacct ttcaagagaa8041 acgtacactg gagcatgagt ggtgtggaac ttttacttag tgtttatatg gattcttgtg8101 atacactggc agaetggagt caatttgcgg gtcttttttg gccaaaactc cacttgtggt8161 tgtgtaggac agtgatattc agctcagctt cttgtggatt gggaggagag agggeetgea8221 atgtgtttta cattggtgct tcctcctgag atttctgttg aacaaagggt tetgaggtea8281 aaaattagtt tgtaageett tgccatagga catagtcatg tgagagtgtt tgggggaaca8341 gaaattgtat aggggtgcct attggggtgg gatgggactc gaataagatt caggtacaaa8401 aactttgaaa tgagaatctg gtggtttgag taatccacca gaetgaatta tetaagatea8461 cattatccag gttggggggc agaattaccc agttaagtaa ttgttcagaa aagtggggag8521 ggtggcatgt ggatgcagtg atccaattaa atggagaget gccaggcaca ttttgtcctc8581 tetggteagt gagaatggtt gggttggctc gctgcttcaa tctgtggaat cagccaggag8641 cccagtgagg aagctcagaa ccccagtaac agcagagcat ctttcagata gctccagagt8701 tttcctgctt ttctgaggaa gctcagcatc actgccacaa tacggaaagt ggtcttcatt8761 ttagcctatt tatttttagg cagagagtgg atggttattt gtgtgggact tttggtggcg8821 atatataatg aataattaag ttaatttctg gtatgcataa tggccagtcc tgaggcccag8881 ctgaagacct gtcccccaga ccctgcccgc tggcttcagg ctgctgcttc tagacagagg8941 tgcactggac gggatagttt tatcaagaga atccctaatg tgtcatttta aaccagctgt9001 gctttttatt cattctggtt gagcgtatag gtttacactt tacccttttt atacttggaa9061 taaatttagt tccagcagat ctagtagcac tccagaaacc aaccccatct gttccccata9121 aaaagaacat tttctctgct ctccagccac gtgtcttgga atgtaattct gttgtgcctt9181 tgtttttatc actctcttcg ccccaaaagc aactgctgta agcttttttc tacttgtctt9241 ttctagtccc caacctctac ctttttcctt tttcccagcc ctaatttctg gatgcacttc9301 tgtgatccag gtattttaag aaccagttac ctcagacctc atgttgaaca gtgtcgccat9361 ctgggtcctc ttgatactgc agacttttaa cgtacacatg caggaaccct gctgagcgtg9421 ggcacttgtt ttaaagcaaa actcttccca aggactgaag aaagggcttc tggcaagctc9481 gtcatggcat tgtggtggga tgggtctaga gtgtcatctg aatggtgctt cctgtgttcc9541 tctttgaatt ctgccatttt cagtattctt gtgtgtctga ataggcaaag cgatttaatt9601 ggctggtctt gcacgcaaat tagttccaaa gataagctct ttgtaacaca tttccagtcg9661 ctaatgctca aatgtagaac attcctttaa atggcaggat aaaaaaccca ctatccacca9721 tagtgcattt tgggaagatg tctgtagcat atgttgctgt gaaattaggc cttgtgggat9781 atggctgttt gtcattttga tgtattttaa ataaatatat atatttttta aagagccttt9841 tttaccagtt caaaaagttt aattaaccag cagtcaccgc atctgaattt ttgtctctgg9901 ggcatagatg gcagaccaag attaaaagtg gtaactcagc tatacgagca tgggctacct9961 tcctgggctc tcctgcagtc ctgtagacct gctgttccgc agaccatggg acacaaggtc10021 agtgtgttcc cagtgagggt cccaagtcag tcatcttaag tgtttgttct ctgccccatt10081 cagtggactg ttgacttcag tccctgcaag tgctttagcc cgagtggggt tttctcagag10141 cactgccacg agttaagtgt gtgtttagcc aaataatttc tccgtaaggg aaaaatgcag10201 tcacccaaat tttaccaaca atgacagaga tgagagtaga aaagattagg caacatctga10261 gttttaactt gaaaagtgtc caagtcatca tgaaaggccg actgggagca agtgattatt10321 agagattctt caggagacct catctgaaaa tgttaagact gccagtgagg gaaggaattg10381 ttaaaatgcc agcggctttt ttttcctctt tttttctgta attctgtaaa aatgcagaga10441 aagttgagtg gtacttcaga attgagggag agggttaccg cagagtagaa atatatttct10501 agatttcagt tccacaccac aaatccacaa caatgccatt tttcaactgt acaaaaatct10561 gcttatgaac tggacatgat cttaatggta gtgtcaaagg ccaagttttt cacctgttaa10621 tatttttcca catttgtcct tgaatctgaa taactttata cagtactgta aatttaactt10681 acatcgagtt tgttgtcaat tcttatgaaa agagctttct gcatgtaaca catacggtta10741 aagaacacag caaaggacaa aatttgcagg aacagttttg gaaccaacag aaaatgtcac10801 cttttatttg ccatcttata tatatctatc agttttacca gctacttcta aatttgtaca10861 ttatttgtaa gggaaagaag gaaaacccta agacttgtct aacttagtgg agaatgtgtg10921 tgttgggctt aggatggata gctaagtctt attgagctgt gttacctaac ttgtatataa10981 aaattgtaat taaaagtttg ggttcacctg tttctcacag tttaaaatga tgagtaattg11041 caaactctgg aaatgtgact agtatatgat ttaaggctgt agaagcaagg aagctctttc11101 aagtgctaaa actaaagact tctagttttt ggctcaaata agtactgttt gtataccagg11161 atatgtgaga tgtaaatgta gtaggtcact tttcaccctt gtagctataa aataaaaatt11221 ttgtagaaca gaaatagctt gtactactga attaacaaaa gttatactaa agtatcatgt11281 ttaaaaaaaa tatatatata tatacagagt taagcttgtt gctgttaccc tgtctggatt11341 tgaaaagtgt gctgatttat atatatatat tacacacaca cacacacaca cacacacaca11401 cacacacaca cacacacaca cacacacaca cacacacaca cacatacacc taaaatggcc11461 taaagcagac atccatgtaa ttacagttgc aaaatgaaaa cattttggaa agaacattgt11521 atcatagttc attcatttgc agtggatctt tgttcctttt tactgtggta attttagaaa11581 tgagtgtcaa gtttgaaatt agatctgcta agttggggtt ttgctgcttg aactctgcac11641 tgggtcctca aataaaccga tgtgaatgta gttttttccc cctgtgtgaa gaagcagtta11701 caccccaaca ataggaggaa aaatctagaa ctatttcaag ttttatcttt ttgtatatga11761 aaataaaata ataataaaac aaTable 20. Exemplary sense and antisense strands of Acvr2b RNAi agentsTable 21. Exemplary modified Acvr2b Sequences-Ill-m indicates 2’O-methyl modified ribose on the listed nucleotide f indicates 2’F modified ribose on the listed nucleotide *indicates a phosphorothioate bond (in place of a phosphodiester bond)Example 3. In vitro knockdown of human ACVR2A mRNA in N2 cells with cholesterol- conjugated ACVR2A dsRNA[000139] Knockdown of human ACVR2A mRNA by the cholesterol-conjugated ACVR2A dsRNA with a 5 ’-phosphate group on the antisense strand was assayed using the following procedure: On day 1, N2 cells (ATCC) were added to Corning 96-well plates at 4,000 cells per well in growth media, on day 2, the culture media was replaced with ACCELL Media (Dharmacon) and dsRNA were added directly to the well. For single point (SP) screening, luM (1,000 nM) of cholesterol-conjugated dsRNA was used. To generate concentration / dose response curves final concentrations of 1000, 333, 111, 37, 12.4, 4. 12, 1 .37, 0.46, 0.15, 0.051 , and 0.017 nM of cholesterol-conjugated dsRNA concentration was used.[000140] Treated cells were lysed directly into the 96 well plate and RNA was isolated using the Quick- RNA 96 Kit (Zymo Research). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen) and using the following steps in a thermocycler: 37C for 30 minutes, 95C for 5 minutes, and 4C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan RT PCR (Life Technologies) using the following cycles temperatures and times: 50C for 2 minutes, 95C for 10 minutes, 40 cycles of 95C for 15 seconds and 60C for 1 minute.[000141] The human ACVR2A mRNA levels were normalized to human RPLPO (Life Technologies) mRNA and represent the relative knockdown of human ACVR2A mRNA as compared to vehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit.Table 22. In vitro knockdown of human ACVR2A mRNA in N2 cells with cholesterol - conjugated ACVR2A dsRNA[000142] Table 22 shows the result of a single dose screen in N2 cells by free uptake with the indicated cholesterol conjugated ACVR2A dsRNA. Data are expressed as percent of rnRNA knockdown relative to untreated cells. The IC50 and percent maximum knockdown of top hits from single point screening followed by concentration / dose response curves are included as well.Example 4. In vitro knockdown of human ACVR2B mRNA in N2 cells with cholesterol- conjugated ACVR2B siRNA[000143] Knockdown of human ACVR2B mRNA by the cholesterol-conjugated ACVR2B dsRNA with a 5’ -phosphate group on the antisense strand was assayed using the following procedure: On day 1, N2 cells (ATCC) were added to Corning 96-well plates at 4,000 cells per well in growth media, on day 2, the culture media was replaced with ACCELL Media (Dharmacon) and dsRNA were added directly to the well. For single point (SP) screening, luM (1,000 nM) of cholesterol-conjugated dsRNA was used. To generate concentration / dose response curves final concentrations of 1000, 333, 111, 37, 12.4, 4.12, 1.37, 0.46, 0.15, 0.051, and 0.017 nM of cholesterol-conjugated dsRNA concentration was used.[000144] Treated cells were lysed directly into the 96 well plate and RNA was isolated using the Quick- RNA 96 Kit (Zymo Research). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen) and using the following steps in a thermocycler: 37C for 30 minutes, 95C for 5 minutes, and 4C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan RT PCR (Life Technologies) using the following cycles temperatures and times: 50C for 2 minutes, 95C for 10 minutes, 40 cycles of 95C for 15 seconds and 60C for 1 minute.[000145] The human ACVR2B mRNA levels were normalized to human RPLP0 (Life Technologies) mRNA and represent the relative knockdown of human ACVR2B mRNA as compared to vehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit.Table 23. In vitro knockdown of human ACVR2B mRNA in N2 cells with cholesterol- conjugated ACVR2B dsRNA[000146] Table 23 shows the result of a single dose screen in N2 cells by free uptake with the indicated cholesterol conjugated ACVR2B dsRNA. Data are expressed as percent of mRNA knockdown relative to untreated cells. The IC5o and percent maximum knockdown of top hits from single point screening followed by concentration / dose response curves are included as well.Example 5. Expression, Purification and Conjugation of dsRNA to TfR binding proteins.Expression and Purification of TfR binding proteins[000147] TBP cDNA sequences were cloned in a GS-containing expression plasmid backbone (pEE12.4-based plasmids, Lonza Biologies Inc.). The cDNA sequence was fused in frame with the coding sequence of a signal peptide sequence,METDTLLLWVLLLWVPGSTG (SEQ ID 1041).[000148] For generating TBPs via transient transfection, CHOKl-derived cells were cultured in a bioreactor up to densities between 35-50 x 106vc / mL. The cells were transfected with an equal stoichiometric ratio of the recombinant expression plasmids for TBPs with multiple chains or single plasmid when appropriate using a PEI-based method. Briefly, the appropriate volume of CHOKl-derived suspension cells at a density of 20 x 106cells / mL was transferred in shake flasks, and both PEI and recombinant plasmid DNA are added to the cells. Cells were incubated in a suspension culture at 32 °C for 7-days. At the end of the production period, cells were removed by centrifugation and the TBP was purified from the clarified medium.[000149] Alternatively, and for generating the TBP via stable transfections, CHOKl- derived cells were stably transfected using lipid-based transfection reagent and the appropriate amount of recombinant expression plasmid, and the transfected cells are maintained in suspension culture at an adequate cell density. Selection of the transfected cells is accomplished by growth in 25 pM MSX-containing chemically defined serum-free medium and incubated at 32-37 °C and 5-7% CO2. Subsequently, cells are removed by centrifugation and the TBP is purified from the clarified medium.[000150] TBP1 secreted into the media from the CHO cells was purified by CHI affinity chromatography followed by size-exclusion chromatography. Specifically, TBP1 from harvested media was captured onto CaptureSelect CHI -XL resin (Thermo Fisher). The resin then was briefly washed with a running buffer, such as a phosphate-buffered saline (PBS; pH 7.2) or a running buffer containing Tris, to remove non-specifically bound material. TBP1 was eluted from the resin with a low pH solution, such as 50mM acetate pH 4.Fractions containing TBP1 were pooled. The pH was neutralized by adding a base such as IM Tris pH 8.0. TBP1 was further purified by size exclusion chromatography using resins such as Superdex75 (Cytiva) with isocratic elution in PBS pH 7.2.[000151 ] TBP2 and 4-28 secreted into the media from the CHO cells was purified by Protein A affinity chromatography followed by size-exclusion chromatography. Specifically, TBP2 and 4-28 from harvested media were captured onto MabSelect PrismA resin (Cytiva). The resin then was briefly washed with a running buffer, such as a phosphate-buffered saline(PBS; pH 7.2) or a running buffer containing Tris, to remove non-specifically bound material. In some cases, NaCl was added in the wash buffer to retain the VHH polypeptide on the column before elution. The TBP2 and 4-28 were eluted from the resin with a low pH solution, such as lOmM citrate pH3. Fractions containing the TBPs were pooled. The pH was neutralized for TBP2 by adding a base such as IM Tris pH 8.0. Alternatively, for TBP 4-28 the pH was neutralized by adding Tris base to pH5. TBPs were further purified by size exclusion chromatography using resins such as Superdex75 (Cytiva) with isocratic elution in PBS pH 7.2 for TBP2 or Acetate buffer pH5 with NaCl and EDTA for TBP 4-28.[000152] TBPS secreted into the media from CHO cells was purified by Protein A affinity chromatography (PrismA) followed by depth filtration (XOSP millipore) at pH 5.25. Elution from affinity was pH based using a pH < 3.0 to elute. Protein A mainstream was neutralized with a 500mM Tris Base before proceeding to depth filtration. After depth filtration, protein was run on two chromatography columns, CEX (poros 50 HS) and HIC (capto phenyl impres) respectively. Elution from CEX was obtained by an increasing NaCl gradient maximizing on the ionic properties of the molecule. The HIC column eluted based on decreasing hydrophobicity in the system in a gradient fashion. Material was then processed through a buffer exchange and concentration into 20mM Tris 150mM NaCl pH 7.0 buffer.Conjugation of dsRNA to TfR binding proteins[000153] Site-specific native or engineered cysteine amino acid residues in the TfR binding proteins were used to conjugate dsRNA. Cysteines can be engineered into the primary amino acid sequence of the TfR binding proteins (TBP1-3), e.g., heavy chain I24C (EU nomenclature). The approach of introducing cysteines as a means for conjugation has been described in WO 2018 / 232088. which is both incorporated by reference in its entirety and incorporated specifically in relation to conjugation via cysteine residues. Alternatively, for TBP4-28, a single Cysteine amino acid was added at the C-terminus of either the TfRbinding VHH or at the C-terminus of a fusion protein containing the TfR binding VHH fused to an albumin-binding VHH.|000154| For engineered cysteine conjugation, the TfR binding proteins were first reduced with 4 (TBP1-2) or 40 (TBP3) molar equivalents reducing agent dithiothreitol (DTT) at room temperature overnight, followed by desalting to remove reducing agent via dialysis or desalting columns. This was followed by re-oxidation of the TfR binding protein to reform the structural disulfides with 10 molar equivalent dehydroascorbic acid (DHAA) incubation at room temperature for two hours.[000155] Alternatively, for TBP 4-28, the pH was increased using 1 / 10 volume addition of IM Tris pH8. After pH adjustment, the TfR binding VHH polypeptides were reduced with 10 molar equivalents reducing agent tris(2-carboxyethyl)phosphine (Thermo Scientific Bond- Breaker™ TCEP Solution, Neutral pH) at room temperature for 10-20 minutes, followed by desalting to remove reducing agent quickly. Conjugation of dsRNA onto TBP 4-28 was done immediately after reducing agent removal in order to prevent dimer reformation while TBP 1-3 did not require immediate conjugation.Conjugation Scheme[000156] All siRNAs prepared for the conjugation procedure were synthesized with an antisense 5’vinylphosphonate modification. The conjugation method utilized the SMCC- functionalized or MSPT-functionalized dsRNA for conjugating onto the engineered or added cysteine of the TfR binding proteins. For this method, TfR binding protein was prepared similarly as above to make the engineered or added thiol available for conjugation by undergoing a reduction and oxidation process (when appropriate) of the TfR binding proteins. This is followed by incubating the SMCC-dsRNA or MSPT-dsRNA with the TfR binding proteins at 1.2 molar equivalents for 2hr conjugation at room temperature.TfR binding protein conjugation with SMCC linkerTfR binding protein conjugation with MSPT linker[000157] Conjugation was monitored using analytical anion exchange chromatography. A ProPac™ SAX- 10 HPLC Column, 10pm particle, 4mm diameter, 50mm length was utilized with the following method. Flow rate of 1 mL / min, Buffer A: 20mM Acetate pH5.0,Buffer B: 20 mM Acetate pH 5.0 + l.M NaCl, at room temperature for TBP1-3. A 1 mLPOROS™ GoPure™ XQ Pre-packed Column, 0.5 x 5 cm was utilized with the following method. Flow rate of 0.5 mL / min, Buffer A: 20mM Acetate pH5.0, Buffer B: 20 mM Acetate pH 5.0 + 1.0 M NaCl, at room temperature for TBP 4-28. This analytical method was used for siRNA-TBP conjugates synthesized with linkers 1 and 2.Table 24. HPLC gradient used to assess dsRNA conjugation to TBPs 1-3Table 25. HPLC gradient used to asses dsRNA conjugation to TBP 4-28[000158] Drug / dsRNA to antibody / protein ratio (DAR) was calculated based on peak area % from the analytical anion exchange (aAEX) chromatogram.[000159] Post conjugation of dsRNA to the TfR binding protein, excess dsRNA and unconjugated protein was removed by further purification. Preparative anion exchange chromatography and preparative size exclusion chromatography (SEC) was utilized for purification of the final conjugate. Anion exchange, e.g., ThermoFisher POROS™ XQ, was used with starting buffer of 20mM TRIS pH 7.0 and eluting with 20 column volume gradient with a buffer containing 20mM TRIS pH 7.0 and IM NaCl. Preparative SEC was performed using Cytiva Superdex® 200 in IX PBS pH 7.2 under an isocratic condition. In some cases, for instance when the TBP is not expressed with a VHH that binds human serum albumin, e.g, TBPs 4-28, Mab Select PrismA resin (Cytiva) in place of POROS™ XQ is used as the primary purification step. The conjugate is captured on the column under high salt conditions (20mM TRIS pH 7.0 and IM NaCl), washed and eluted by removing the salt using 20mM TRIS pH 7.0 buffer followed by SEC polishing.[000160] These resulted in purified TfR binding protein-dsRNA conjugate devoid of excess dsRNA and minimal unconjugated protein. The resulting conjugate profile was analyzed by analytical anion exchange for final DAR quantitation.Conjugation of dsRNA to TBPs 29-32[000161] TBPs 29-32 were synthesized on a Symphony Classic instrument using standard Fmoc protection and 1-3 hour oxyma / DIC coupling chemistries. Side chain azides were added via HFIP-deprotection of an added Lys(Mtt) moiety at the C-terminus followed by a standard coupling with the appropriate azide-containing reagent. The crude linear peptides were cyclized via disulfide formation in DMSO / water buffered with sodium acetate at pH=6.5. The cyclized peptides were purified via RPLC on a Shimadzu instrument using a Waters SymmetryPrep 7mm Cl 8 column.[000162] Conjugation of the C6-NH2 oligonucleotide to a DBCO-containing linker was accomplished by addition of excess DBCO reagent with an appended NHS ester in THF to a solution of oligonucleotide and 20x borate buffer in water. Upon completion of the reaction, the mixture was centrifuged in a 3,000 molecular weight-cutoff spin filter to remove excess reagent and salts.[000163] TBPs 29-32 were conjugated to the oligonucleotides via DBCO-azide click chemistry. TBPs 29-32 were dissolved in water / acetonitrile and added to an aqueous solution of the DBCO-functionalized oligonucleotide at ambient temperature. The conjugates were purified via RPLC on a Shimadzu instrument using a Waters XBridge® Protein BEH C4 Prep 300A column.TfR binding protein (TBP 29-32) conjugation with DBCO- Azide linkerExample 6: In vitro knockdown of human ACVR2A and ACVR2B mRNA in EFO-21 cells with TfR-binding protein conjugated ACVR2A and ACVR2B dsRNAs[000164] Knockdown of human ACVR2A or ACVR2B mRNA by the TfR-binding protein conjugated ACVR2A or ACVR2B dsRNAs in EFO21 cells was assayed using the following procedure.Table 26. In vitro knockdown of human ACVR2A or ACVR2B mRNA in EFO-21 cells with TfR-binding protein conjugated ACVR2A or ACVR2B dsRNAs[000165] On day 1, EFO-21 cells (eClipse, Germany) were added to 96-well plates at 8000 cells per well in cell culture growth media. On day 2, the culture media was replaced with ACCELL Media (Dharmacon) and the TfR binding protein ACVR2A or ACVR2B dsRNA conjugates were added directly to the well. To generate concentration / dose response curves, final concentrations of 1000, 200, 40, 8, 1.6, 0.32, 0.06, O.OlnM of TfR binding protein ACVR2A or ACVR2B dsRNA conjugates were used. On day 5, treated cells were lysed directly in the 96 well plate using Cells-to-CT™ Bulk Lysis Reagents (Invitrogen). cDNA was synthesized from lysates using Cells-to-CT™ Bulk RT Reagents (Invitrogen) using the following steps in a thermocycler: 37 °C for 1 hour, 95 °C for 5 minutes, and 4 °C hold. cDNA samples were used immediately or stored frozen. Quantitative Polymerase Chain Reaction (qPCR) performed using TaqMan Fast Advanced Master Mix (Applied Biosystems) with ACVR2A (Hs00155658_m l) and ACVR2B (Hs00609603_ml) primers. The following cycle temperatures and times were used: 50 °C for 2 minutes, 95 °C for 20 seconds, 40 cycles of 95 °C for 1 second and 60 °C for 20 seconds. The human ACVR2A or 2B mRNA levelswere normalized to human GAPDH (Applied Biosystems) mRNA to represent the relative knockdown of human AC VR2A or 2B mRNA as compared to vehicle-treated control cells. IC50 values were calculated using the GraphPad Prism 4-parameter nonlinear fit model.Example 7: In vivo knockdown of human ACVR2A andor ACVR2B mRNA in human TfR transgenic mice with TfR-binding protein conjugated ACVR2A or ACVR2B dsRNAs[000166] The activity of TfR-binding protein conjugated ACVR2A orACVR2B dsRNAs were tested in hTfR transgenic mice. Six- to eight-week-old female hTfR transgenic mice were divided into groups of 6 mice each. Each mouse received a single dose of TfR-binding protein conjugated ACVR2A or ACVR2B dsRNAs at 8.3, 33 or 132 nmole / kg by subcutaneous administration. A group of 6 mice received PBS as negative control. The mice were sacrificed fourteen days post-treatment and tibialis anterior muscle tissue was collected for real-time quantitative polymerase chain reaction (qPCR). Total RNA was isolated using Trizol™ (Invitrogen) reagent followed by purification of RNA using Purelink™ RNA mini kit (Invitrogen). cDNA was synthesized from muscle tissue RNA using ABI High-Capacity cDNA Archive Kit (ThermoFisher Scientific) using the following steps in a thermocycler: 25 °C for 10 minutes, 37 °C for 2 hours, and 4 °C hold. cDNA samples were used immediately or stored frozen, and qPCR was performed using TaqMan Fast Advanced Master Mix, to measure the amount of ACVR2A or ACVR2B mRNA using the mouse primer probe sets (ACVR2a Mm00725448_sl, ACVR2b Mm00431664_ml). The following cycle temperatures and times were used: 50 °C for 2 minutes, 95 °C for 20 seconds, 40 cycles of 95 °C for 1 second and 60 °C for 20 seconds. Results are presented as percent knockdown of ACVR2A or ACVR2B mRNA relative to PBS control, normalized to mouse RplpO (primer probe set Mm00725448_sl)Table 27. In vivo knockdown of human ACVR2A or ACVR2B mRNA with TfR-binding protein conjugated ACVR2A or ACVR2B dsRNAs in tibialis anterior muscle of hTfR transgenic miceND- knockdown not detected.Example 8: In vivo knockdown of human ACVR2A and ACVR2B mRNA in human TfR transgenic mice co-dosed with TfR-binding protein conjugated ACVR2A and ACVR2B dsRNAs up to 84 days[000167] The activity of TfR-binding protein-conjugated ACVR2A and ACVR2B dsRNAs were tested in hTfR transgenic mice. Six- to eight-week-old female hTfR transgenic mice were divided into 3 groups of 30 mice each. Each mouse was co-administered with a single dose of TfR-binding protein conjugated with each of ACVR2A and ACVR2B dsRNAs at 132 or 396 nmole / kg of each conjugate, by subcutaneous administration. Each siRNA-TBP conjugate was synthesized with linker 2. A group of 30 mice received PBS as negative control. Groups of mice were sacrificed at 6 hours and at days 1, 2, 7, 14, 30, 60 and 84 posttreatment, and tibialis anterior muscle tissue was collected for real-time quantitative polymerase chain reaction (qPCR). Total RNA was isolated using Trizol™ (Invitrogen) reagent followed by purification of RNA using Purelink™ RNA mini kit (Invitrogen). cDNA was synthesized from muscle tissue RNA using ABI High-Capacity cDNA Archive Kit (ThermoFisher Scientific) using the following steps in a thermocycler: 25°C for 10 minutes, 37°C for 2 hours, and 4°C hold. cDNA samples were used immediately or stored frozen, and qPCR was performed using TaqMan Fast Advanced Master Mix to measure the amount of ACVR2A or ACVR2B mRNA using the mouse primer probe sets (ACVR2a Mm00725448_sl, ACVR2b Mm00431664_ml). The following cycle temperatures and times were used: 50°C for 2 minutes, 95°C for 20 seconds, 40 cycles of 95 °C for 1 second and 60°C for 20 seconds.[000168] Results are presented in Table 28 as percent knockdown of ACVR2A or ACVR2B mRNA relative to PBS control, normalized to mouse RplpO (primer probe set Mm00725448_sl).Table 28. In vivo knockdown of human ACVR2A and ACVR2B mRNA upon coadministration of TfR-binding protein conjugated ACVR2A and ACVR2B dsRNAs in tibialismuscle of hTfR transgenic miceND-knockdown not detectedExample 9: In vivo exposure of human ACVR2A and ACVR2B mRNA in human TfR transgenic mice co-dosed with TfR-binding protein conjugated ACVR2A and ACVR2B dsRNAs up to 84 days.[000169] Total siRNA concentrations were determined by a non-GLP hybridization ELISA assay in tibialis of hTfR transgenic mice. In this assay, standards, controls, and samples were diluted 20-fold in a solution containing a biotinylated capture probe complimentary to the 3 ’-end of either ACVR2A and ACVR2B dsRNAs antisense strand, and a digoxigenin-labeled detection probe complimentary to the 5 ’-end of either ACVR2A and ACVR2B dsRNAs antisense strand (probes custom ordered from BioSynthesis).[000170] The diluted standards, controls, and samples were then incubated in a thermocycler (Cole-Parmer PCRMax Thermocycler) set to 90 °C for 5 minutes then 20 °C for 30 minutes followed by a hold at 4 °C. During this incubation, the siRNA strand was denatured, and the antisense strand was annealed to the capture and detection probes. The antisense-probe compound was then added to a blocked streptavidin-coated mesoscale discovery (MSD) plate (MSD #L15SA-1) and incubated for ~1 hour at room temperature with shaking. After washing, ruthenium-labeled anti-digoxigenin antibody (Invitrogen #PA1 -85378, ruthenium- labeled in-house) was added to the plate and incubated for ~1 hour, protected from light, at room temperature with shaking. The plate was washed again and 2X Read Buffer T (MSD #R92TC-1) was added before reading the plate on an MSD QuickPlex SQ 120MM.[000171] Concentrations were determined from calibrators using a 4-parameter logistic regression model (Watson LIMS, version 7.7.1) with 1 / Y weighting. The quantifiable curve range for both ACVR2A and ACVR2B dsRNAs in tibialis was 0.229-500 ng / mL.[000172] Run acceptance criteria were as follows: a minimum of 6 non-zero standards had a mean back calculated concentration equal to or within ±30% of the nominal value (%Relative Error, RE) and a coefficient of variation (CV) equal to or less than 30%.Table 29. Tibialis exposure ofACVR2A and ACVR2B dsRNAs after co-administration of TfR-binding protein conjugated ACVR2A and ACVR2B dsRNAs in tibialis anterior muscle of hTfR transgenic miceExample 10: In vivo knockdown of human ACVR2A mRNA in human TfR transgenic mice dosed with TfR-binding peptide conjugated ACVR2A dsRNAs after 14 days[000173] C57BL / 6NTac-Tfrctm7330.1_B-F1 l(TFRC*)Tac (hTfR) female mice were dosed with a single subcutaneous administration of transferrin targeting siRNA conjugates at either 132 / 396 nmol / kg diluted in lx PBS or vehicle control. Terminal gastrocnemius muscle tissues were then collected 14 days after test article administration. Gastrocnemius RNA was extracted using MagMAX™ mirVana™ Total RNA Isolation Kit following manufacturing protocol. Levels of mouse Acvr2a mRNA (using ThermoFisher probe Mm01331097_ml) and Acvr2b mRNA(using ThermoFisher probe Mm00431664_ml) were quantified by RT- qPCR, using High Capacity cDNA Reverse Transcription Kit (Applied Biosy stems™ # 4368813 ), TbermoFisher Quantstudio 7Pro RT-PCR system, and TaqMan™ Gene Expression Master Mix (Applied Biosystems™ #4369016). Target mRNA reduction was normalized to HPRT mRNA (Thermosteric probe Mm03024075_.ml) for each sample and reported as relative reduction (AACT method) compared to control animals treated with PBS alone. All siRNA-TBP conjugates in this study used linker 17.Table 30. In vivo knockdown of human ACVR2A mRNA upon administration of TfR- binding peptide conjugated ACVR2A dsRNAs in tibialis anterior muscle of hTfR transgenic mice[000174] The present invention is encompassed or described by the following numbered embodiments.EmbodimentsEmbodiment 1. An AC VR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:3 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:33; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:4 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:34; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:5 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:35; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:6 and the second nucleic acid sequence has at least 95% sequence identity to SQ ID NO:36; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:7 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:37; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:8 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:38; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:9 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:39; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 10 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:40; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 11 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:41; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 12 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:42; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 13 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:43;l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 14 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:44; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 15 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:45; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 16 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:46; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 17 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:47; p. the first nucleic acid sequence has least 95% sequence identity to SEQ ID NO: 18 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:48; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 19 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:49; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:20 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:50; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:21 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:51; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:22 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:52; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:23 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:53; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:24 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:54; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:25 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:55; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:26 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:56; y. the first nucleic acid sequence has least 95% sequence identity to SEQ ID NO:27 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:57;z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:28 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:58; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:29 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:59; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:30 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:60; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:31 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID N0:61; and dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:32 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:62.Embodiment 2. The ACVR2A RNAi agent of Embodiment 1 comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO:3 and the second nucleic acid sequence comprises SEQ ID NO: 33; b. the first nucleic acid sequence comprises SEQ ID NO:4 and the second nucleic acid sequence comprises SEQ ID NO:34; c. the first nucleic acid sequence comprises SEQ ID NO:5 and the second nucleic acid sequence comprises SEQ ID NO: 35; d. the first nucleic acid sequence comprises SEQ ID NO:6 and the second nucleic acid sequence comprises SQ ID NO: 36; e. the first nucleic acid sequence comprises SEQ ID NO:7 and the second nucleic acid sequence comprises SEQ ID NO:37; f. the first nucleic acid sequence comprises SEQ ID NO:8 and the second nucleic acid sequence comprises SEQ ID NO:38;g. the first nucleic acid sequence comprises SEQ ID NO:9 and the second nucleic acid sequence comprises SEQ ID NO:39; h. the first nucleic acid sequence comprises SEQ ID NO: 10 and the second nucleic acid sequence comprises SEQ ID NO:40; i. the first nucleic acid sequence comprises SEQ ID NO: 11 and the second nucleic acid sequence comprises SEQ ID NO:41 ; j. the first nucleic acid sequence comprises SEQ ID NO: 12 and the second nucleic acid sequence comprises SEQ ID NO:42; k. the first nucleic acid sequence comprises SEQ ID NO: 13 and the second nucleic acid sequence comprises SEQ ID NO:43; l. the first nucleic acid sequence comprises SEQ ID NO: 14 and the second nucleic acid sequence comprises SEQ ID NO:44; m. the first nucleic acid sequence comprises SEQ ID NO: 15 and the second nucleic acid sequence comprises SEQ ID NO:45; n. the first nucleic acid sequence comprises SEQ ID NO: 16 and the second nucleic acid sequence comprises SEQ ID NO:46; o. the first nucleic acid sequence comprises SEQ ID NO: 17 and the second nucleic acid sequence comprises SEQ ID NO:47; p. the first nucleic acid sequence comprises SEQ ID NO: 18 and the second nucleic acid sequence comprises SEQ ID NO:48; q. the first nucleic acid sequence comprises SEQ ID NO: 19 and the second nucleic acid sequence comprises SEQ ID NO:49; r. the first nucleic acid sequence comprises SEQ ID NO:20 and the second nucleic acid sequence comprises SEQ ID NO:50; s. the first nucleic acid sequence comprises SEQ ID NO:21 and the second nucleic acid sequence comprises SEQ ID NO: 51 ; t. the first nucleic acid sequence comprises SEQ ID NO:22 and the second nucleic acid sequence comprises SEQ ID NO:52;u. the first nucleic acid sequence comprises SEQ ID NO:23 and the second nucleic acid sequence comprises SEQ ID NO: 53; v. the first nucleic acid sequence comprises SEQ ID NO:24 and the second nucleic acid sequence comprises SEQ ID NO:54; w. the first nucleic acid sequence comprises SEQ ID NO:25 and the second nucleic acid sequence comprises SEQ ID NO: 55; x. the first nucleic acid sequence comprises SEQ ID NO:26 and the second nucleic acid sequence comprises SEQ ID NO:56; y. the first nucleic acid sequence comprises SEQ ID NO:27 and the second nucleic acid sequence comprises SEQ ID NO:57; z. the first nucleic acid sequence comprises SEQ ID NO:28 and the second nucleic acid sequence comprises SEQ ID NO:58; aa. the first nucleic acid sequence comprises SEQ ID NO:29 and the second nucleic acid sequence comprises SEQ ID NO:59; bb. the first nucleic acid sequence comprises SEQ ID NO:30 and the second nucleic acid sequence comprises SEQ ID NO:60; cc. the first nucleic acid sequence comprises SEQ ID NO:31 and the second nucleic acid sequence comprises SEQ ID NO:61 ; and dd. the first nucleic acid sequence comprises SEQ ID NO:32 and the second nucleic acid sequence comprises SEQ ID NO: 62.Embodiment 3. The ACVR2A RNAi agent of Embodiment 1 or 2 wherein the antisense strand comprises a 3’ overhang of two nucleotides.Embodiment 4. The ACVR2A RNAi agent of any one of Embodiments 1-3 wherein the sense and antisense strands each comprise one or more modified nucleotides.Embodiment 5. The ACVR2A RNAi agent of Embodiment 4 wherein one or more modified nucleotides is a 2’fluoro modified nucleotide or a 2’ O-methyl modified nucleotide.Embodiment 6. The ACVR2A RNAi agent of any one of Embodiments 1-5 wherein the sense and antisense strands each comprise one or more modified intemucleotide linkages.Embodiment 7. The ACVR2A RNAi agent of Embodiment 6 wherein one or more modified intemucleotide linkages are phosphorothioate linkages.Embodiment 8. The ACVR2A RNAi agent of any one of Embodiments 1-7, wherein the sense strand or antisense strand further comprises an abasic moiety or an inverted abasic moiety.Embodiment 9. The ACVR2A RNAi agent of Embodiment 8 wherein the antisense strand further comprises an inverted abasic moiety.Embodiment 10. The ACVR2A RNAi agent of any one of Embodiments 1-9, wherein the antisense strand is between 15 and 50 nucleotides in length.Embodiment 11. The ACVR2A RNAi agent of any one of Embodiments 1-10, wherein the sense strand is between 15 and 50 nucleotides in length.Embodiment 12. The ACVR2A RNAi agent of any one of Embodiments 1-11, wherein the antisense strand is between 18 and 23 nucleotides in length.Embodiment 13. The ACVR2A RNAi agent of any one of Embodiments 1-12, wherein the sense strand is between 18 and 21 nucleotides in length.Embodiment 14. The ACVR2A RNAi agent of any one of Embodiments 1 -13, wherein the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length.Embodiment 15. The ACVR2A RNAi agent of any one of Embodiments 1-14, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 125 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 126; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 127 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 128; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 129 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 130; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 131 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 132; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 133 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 134; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 135 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 136; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 137 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 138; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 139 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 140;i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 141 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 142; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 143 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 144; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 145 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 146; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 147 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 148; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 149 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 150; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 151 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 152; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 153 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 154; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 155 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 156; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 157 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:158;r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 159 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 160; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 161 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 162; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 163 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 164; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 165 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 166; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 167 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:168; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 169 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 170; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 171 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 172; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 173 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 174; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 175 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 176;aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 177 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 178; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 179 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 180; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 181 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 182; and dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 183 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 184.Embodiment 16. The ACVR2A RNAi agent of any one of Embodiments 1-15, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid comprises SEQ ID NO: 125 and the second nucleic acid sequence comprises SEQ ID NO: 126; b. the first nucleic acid comprises SEQ ID NO: 127 and the second nucleic acid sequence comprises SEQ ID NO: 128; c. the first nucleic acid comprises SEQ ID NO: 129 and the second nucleic acid sequence comprises SEQ ID NO: 130; d. the first nucleic acid comprises SEQ ID NO: 131 and the second nucleic acid sequence comprises SEQ ID NO: 132; e. the first nucleic acid comprises SEQ ID NO: 133 and the second nucleic acid sequence comprises SEQ ID NO: 134; f. the first nucleic acid comprises SEQ ID NO: 135 and the second nucleic acid sequence comprises SEQ ID NO: 136;g. the first nucleic acid comprises SEQ ID NO:137 and the second nucleic acid sequence comprises SEQ ID NO: 138; h. the first nucleic acid comprises SEQ ID NO: 139 and the second nucleic acid sequence comprises SEQ ID NO: 140; i. the first nucleic acid comprises SEQ ID NO:141 and the second nucleic acid sequence comprises SEQ ID NO: 142; j. the first nucleic acid comprises SEQ ID NO: 143 and the second nucleic acid sequence comprises SEQ ID NO: 144; k. the first nucleic acid comprises SEQ ID NO: 145 and the second nucleic acid sequence comprises SEQ ID NO: 146; l. the first nucleic acid comprises SEQ ID NO: 147 and the second nucleic acid sequence comprises SEQ ID NO: 148; m. the first nucleic acid comprises SEQ ID NO: 149 and the second nucleic acid sequence comprises SEQ ID NO: 150; n. the first nucleic acid comprises SEQ ID NO: 151 and the second nucleic acid sequence comprises SEQ ID NO: 152; o. the first nucleic acid comprises SEQ ID NO: 153 and the second nucleic acid sequence comprises SEQ ID NO: 154; p. the first nucleic acid comprises SEQ ID NO: 155 and the second nucleic acid sequence comprises SEQ ID NO: 156; q. the first nucleic acid comprises SEQ ID NO: 157 and the second nucleic acid sequence comprises SEQ ID NO: 158; r. the first nucleic acid comprises SEQ ID NO:159 and the second nucleic acid sequence comprises SEQ ID NO: 160; s. the first nucleic acid comprises SEQ ID NO: 161 and the second nucleic acid sequence comprises SEQ ID NO: 162; t. the first nucleic acid comprises SEQ ID NO:163 and the second nucleic acid sequence comprises SEQ ID NO: 164;u. the first nucleic acid comprises SEQ ID NO:165 and the second nucleic acid sequence comprises SEQ ID NO: 166; v. the first nucleic acid comprises SEQ ID NO: 167 and the second nucleic acid sequence comprises SEQ ID NO: 168; w. the first nucleic acid comprises SEQ ID NO:169 and the second nucleic acid sequence comprises SEQ ID NO: 170; x. the first nucleic acid comprises SEQ ID NO: 171 and the second nucleic acid sequence comprises SEQ ID NO: 172; y. the first nucleic acid comprises SEQ ID NO: 173 and the second nucleic acid sequence comprises SEQ ID NO: 174; z. the first nucleic acid comprises SEQ ID NO: 175 and the second nucleic acid sequence comprises SEQ ID NO: 176; aa. the first nucleic acid comprises SEQ ID NO: 177 and the second nucleic acid sequence comprises SEQ ID NO: 178; bb. the first nucleic acid comprises SEQ ID NO: 179 and the second nucleic acid sequence comprises SEQ ID NO: 180; cc. the first nucleic acid comprises SEQ ID NO: 181 and the second nucleic acid sequence comprises SEQ ID NO: 182; and dd. the first nucleic acid comprises SEQ ID NO: 183 and the second nucleic acid sequence comprises SEQ ID NO: 184.Embodiment 17. The ACVR2A RNAi agent of any one of Embodiment 1-16 wherein the 5’ terminal nucleotide of the antisense strand comprises a phosphate group, a vinyl phosphonate, a phosphate analog, or a hydroxyl group.Embodiment 18. The ACVR2A RNAi agent of Embodiment 17 wherein the phosphate analog is vinyl phosphonate.Embodiment 19. The ACVR2A RNAi agent of any one of Embodiments 1-18, wherein the RNAi agent decreases the expression of the ACVR2A gene in a muscle cell, as compared to a control RNAi agent.Embodiment 20. An ACVR2A RNAi agent of the Formula: R-L-TBP, wherein R is the RNAi agent of any one of Embodiments 1-19, L is a linker or a direct bond, and TBP is a transferrin receptor binding protein.Embodiment 21. The ACVR2A RNAi agent of Embodiment 20 comprising one of the following formulas:Embodiment 22. The ACVR2A RNAi agent of Embodiment 20 wherein the linker is:Embodiment 23. The ACVR2A RNAi agent of Embodiment 21 wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP wherein the TBP is selected from the group consisting of a Fab, a VHH, or a one-arm heteromab.Embodiment 24. The ACVR2A RNAi agent of Embodiment 22 wherein the linker connects the 3 ’end of the sense strand of the RNAi agent to a TBP wherein the TBP is a peptide.Embodiment 25. The ACVR2A RNAi agent of Embodiment 23 wherein the TBP is a Fab.Embodiment 26. The ACVR2A RNAi agent of Embodiment 25 wherein the TBP is a Fab which further comprises a VHH that binds to human serum albumin (HSA).Embodiment 27. The ACVR2A RNAi agent of Embodiment 25 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ IDNO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDCR2 comprises SEQ ID NO:251, LCDR3 comprises SEQ ID NO:252.Embodiment 28. The ACVR2A RNAi agent of Embodiment 27 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254.Embodiment 29. The AC VR2A RNAi agent of Embodiment 28 wherein the TBP comprises a heavy chain (HC) and light chain (LC), wherein the HC comprises SEQ ID NO:291 and the LC comprises SEQ ID NO:256.Embodiment 30. The AC VR2A RNAi agent of Embodiment 26 wherein the TBP is a Fab- albVHH.Embodiment 31. The ACVR2A RNAi agent of Embodiment 30 wherein the TBP comprises a heavy chain variables region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDCR2 comprises SEQ ID NO:251, LCDR3 comprises SEQ ID NO:252.Embodiment 32. The ACVR2A RNAi agent of Embodiment 31 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254.Embodiment 33. The ACVR2A RNAi agent of Embodiment 32 wherein the TBP comprises a heavy chain (HC) and light chain (LC), wherein the HC comprises SEQ ID NO:255 and the LC comprises SEQ ID NO:256.Embodiment 34. The ACVR2A RNAi agent of Embodiment 23 wherein the TBP is a one- arm heteromab.Embodiment 35. The RNAi agent of Embodiment 34 wherein the TBP comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDCR2, and LCDCR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDR2 comprises SEQ ID NO:251, and LCDCR3 comprises SEQ ID NO:252.Embodiment 36. The ACVR2A RNAi agent of Embodiment 35 wherein the TBP comprises a VH and VL, wherein the VH comprises SEQ ID NO:252 and the VL comprises SEQ ID NO:254.Embodiment 37. The ACVR2A RNAi agent of Embodiment 36 wherein the TBP comprises two heavy chains (HC1) and (HC2) and one light chain (LC), wherein HC1 comprises SEQ ID NO:263, HC2 comprises SEQ ID NO:264, and the LC comprises SEQ ID NO:256.Embodiment 38. The ACVR2A RNAi agent of Embodiment 23 wherein the TBP is a VHH.Embodiment 39. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:265, CDR2 comprising SEQ ID NO:266, and CDR3 comprising SEQ ID NO:267.Embodiment 40. The ACVR2A RNAi agent of Embodiment 39 wherein the TBP comprises SEQ ID NO:268.Embodiment 41. The ACVR2A RNAi agent of Embodiment 39 wherein the VHH further comprises a VHH that binds human serum albumin (HSA).Embodiment 42. The ACVR2A RNAi agent of Embodiment 41 wherein the TBP comprises SEQ ID NO:269.Embodiment 43. The ACVR2A RNAi agent of Embodiment 41 wherein the TBP comprises SEQ ID NO:270.Embodiment 44. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:273.Embodiment 45. The ACVR2A RNAi agent of Embodiment 44 wherein the TBP comprises SEQ ID NO:274.Embodiment 46. The AC VR2A RNAi agent of Embodiment 44 wherein the VHH further comprises a VHH that binds human serum albumin (HSA).Embodiment 47. The ACVR2A RNAi agent of Embodiment 46 wherein the TBP comprises SEQ ID NO:275.Embodiment 48. The ACVR2A RNAi agent of Embodiment 46 wherein the TBP comprises SEQ ID NO:276.Embodiment 49. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:279, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:277.Embodiment 50. The ACVR2A RNAi agent of Embodiment 49 wherein the TBP comprises SEQ ID NO:280.Embodiment 51. The AC VR2A RNAi agent of Embodiment 49 wherein the VHH further comprises a VHH that binds human serum albumin (HSA).Embodiment 52. The AC VR2A RNAi agent of Embodiment 51 wherein the TBP comprises SEQ ID NO:292.Embodiment 53. The ACVR2A RNAi agent of Embodiment 51 wherein the TBP comprises SEQ ID NO:293.Embodiment 54. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:281, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:277.Embodiment 55. The ACVR2A RNAi agent of Embodiment 54 wherein the TBP comprises SEQ ID NO:282.Embodiment 56. The ACVR2A RNAi agent of Embodiment 54 wherein the VHH further comprises a VHH that binds human serum albumin (HSA).Embodiment 57. The ACVR2A RNAi agent of Embodiment 56 wherein the TBP comprises SEQ ID NO:294.Embodiment 58. The ACVR2A RNAi agent of Embodiment 56 wherein the TBP comprises SEQ ID NO:295.Embodiment 59. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:283, and CDR3 comprising SEQ ID NO:277.Embodiment 60. The ACVR2A RNAi agent of Embodiment 59 wherein the TBP comprises SEQ ID NO:284.Embodiment 61. The ACVR2A RNAi agent of Embodiment 59 wherein the VHH further comprises a VHH that binds human serum albumin (HSA).Embodiment 62. The ACVR2A RNAi agent of Embodiment 61 wherein the TBP comprises SEQ ID NO:296.Embodiment 63. The ACVR2A RNAi agent of Embodiment 61 wherein the TBP comprises SEQ ID NO:297.Embodiment 64. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:285, and CDR3 comprising SEQ ID NO:277.Embodiment 65. The ACVR2A RNAi agent of Embodiment 64 wherein the TBP comprises SEQ ID NO:286.Embodiment 66. The ACVR2A RNAi agent of Embodiment 64 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 67. The ACVR2A RNAi agent of Embodiment 66 wherein the TBP comprises SEQ ID NO:298.Embodiment 68. The ACVR2A RNAi agent of Embodiment 66 wherein the TBP comprises SEQ ID NO:299.Embodiment 69. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:287, and CDR3 comprising SEQ ID NO:277.Embodiment 70. The AC VR2A RNAi agent of Embodiment 69 wherein the TBP comprises SEQ ID NO:288.Embodiment 71. The AC VR2A RNAi agent of Embodiment 69 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 72. The ACVR2A RNAi agent of Embodiment 71 wherein the TBP comprises SEQ ID NO:300.Embodiment 73. The ACVR2A RNAi agent of Embodiment 71 wherein the TBP comprises SEQ ID NO:301.Embodiment 74. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:289, and CDR3 comprising SEQ ID NO:277.Embodiment 75. The ACVR2A RNAi agent of Embodiment 74 wherein the TBP comprises SEQ ID NO:290.Embodiment 76. The ACVR2A RNAi agent of Embodiment 74 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 77. The ACVR2A RNAi agent of Embodiment 76 wherein the TBP comprises SEQ ID NO:302.Embodiment 78. The ACVR2A RNAi agent of Embodiment 76 wherein the TBP comprises SEQ ID NO:303.Embodiment 79. The ACVR2A RNAi agent of Embodiment 38 wherein the TBP comprises a CDR1 comprising SEQ ID NO:304, CDR2 comprising SEQ ID NQ:3O5, and CDR3 comprising SEQ ID NO:277.Embodiment 80. The ACVR2A RNAi agent of Embodiment 79 wherein the TBP comprises SEQ ID NO:306.Embodiment 81. The ACVR2A RNAi agent of Embodiment 24 wherein the TBP comprises SEQ ID NO:307.Embodiment 82. The AC VR2A RNAi agent of Embodiment 24 wherein the TBP comprises SEQ ID NO:308.Embodiment 83. The ACVR2A RNAi agent of Embodiment 24 wherein the TBP comprises SEQ ID NQ:309.Embodiment 84. The ACVR2A RNAi agent of Embodiment 24 wherein the TBP comprises SEQ ID NO:310.Embodiment 85. A pharmaceutical composition comprising the ACVR2A RNAi agent of any one of Embodiments 1-84.Embodiment 86. A method of treating a subject having a disease associated with an elevated level ACVR2A gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2A RNAi agent of any one of Embodiments 1- 84.Embodiment 87. A method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2A, the method comprising administering to the subject a therapeutically effective amount of the ACVR2A RNAi agent of any one of Embodiments 1-84.Embodiment 88. The ACVR2A RNAi agent of any one of Embodiments 1-84 or the pharmaceutical composition of Embodiment 85 for use in the treatment of a disease associated with ACVR2A gene expression.Embodiment 89. The ACVR2A RNAi agent for use of Embodiment 88, wherein the disease associated with ACVR2A gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.Embodiment 90. An ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 63 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:94; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 64 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:95;c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 65 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:96; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 66 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:97; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 67 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:98; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 68 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:99; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 69 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 100; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 70 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 101 ; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:71 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 102; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 72 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 103; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:73 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 104;l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 74 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 105; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 75 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 106; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 76 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:107; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:77 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 108; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:78 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 109; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 79 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:110; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 80 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:111 ; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 81 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 112; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:82 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:113;u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 83 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 114; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 84 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:115; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 85 and the second nucleic sequence has at least 95% sequence identity to SEQ ID NO: 116; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 86 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 117; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 87 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:118; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 88 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:119; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 89 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 120; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 90 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 121; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:91 and the second nucleic acid sequence has at least 95% sequence identity to EQ ID NO: 122;dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 92 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 123; and ee. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 93 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 124.Embodiment 91. The ACVR2B RNAi agent of Embodiment 90 comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO:63 and the second nucleic acid sequence comprises SEQ ID NO:94; b. the first nucleic acid sequence comprises SEQ ID NO:64 and the second nucleic acid sequence comprises SEQ ID NO:95; c. the first nucleic acid sequence comprises SEQ ID NO:65 and the second nucleic acid sequence comprises SEQ ID NO:96; d. the first nucleic acid sequence comprises SEQ ID NO:66 and the second nucleic acid sequence comprises SEQ ID NO:97; e. the first nucleic acid sequence comprises SEQ ID NO:67 and the second nucleic acid sequence comprises SEQ ID NO:98; f. the first nucleic acid sequence comprises SEQ ID NO:68 and the second nucleic acid sequence comprises SEQ ID NO:99; g. the first nucleic acid sequence comprises SEQ ID NO:69 and the second nucleic acid sequence comprises SEQ ID NO: 100; h. the first nucleic acid sequence comprises SEQ ID NQ:70 and the second nucleic acid sequence comprises SEQ ID NO: 101 ;i. the first nucleic acid sequence comprises SEQ ID NO:71 and the second nucleic acid sequence comprises SEQ ID NO: 102; j. the first nucleic acid sequence comprises SEQ ID NO:72 and the second nucleic acid sequence comprises SEQ ID NO: 103; k. the first nucleic acid sequence comprises SEQ ID NO:73 and the second nucleic acid sequence comprises SEQ ID NO: 104; l. the first nucleic acid sequence comprises SEQ ID NO:74 and the second nucleic acid sequence comprises SEQ ID NO: 105; m. the first nucleic acid sequence comprises SEQ ID NO:75 and the second nucleic acid sequence comprises SEQ ID NO: 106; n. the first nucleic acid sequence comprises SEQ ID NO:76 and the second nucleic acid sequence comprises SEQ ID NO: 107; o. the first nucleic acid sequence comprises SEQ ID NO:77 and the second nucleic acid sequence comprises SEQ ID NO: 108; p. the first nucleic acid sequence comprises SEQ ID NO:78 and the second nucleic acid sequence comprises SEQ ID NO: 109; q. the first nucleic acid sequence comprises SEQ ID NO:79 and the second nucleic acid sequence comprises SEQ ID NO: 110; r. the first nucleic acid sequence comprises SEQ ID NO:80 and the second nucleic acid sequence comprises SEQ ID NO: 111 ; s. the first nucleic acid sequence comprises SEQ ID NO:81 and the second nucleic acid sequence comprises SEQ ID NO: 112; t. the first nucleic acid sequence comprises SEQ ID NO:82 and the second nucleic acid sequence comprises SEQ ID NO: 113; u. the first nucleic acid sequence comprises SEQ ID NO:83 and the second nucleic acid sequence comprises SEQ ID NO:114; v. the first nucleic acid sequence comprises SEQ ID NO:84 and the second nucleic acid sequence comprises SEQ ID NO: 115;w. the first nucleic acid sequence comprises SEQ ID NO:85 and the second nucleic sequence comprises SEQ ID NO: 116; x. the first nucleic acid sequence comprises SEQ ID NO:86 and the second nucleic acid sequence comprises SEQ ID NO: 117; y. the first nucleic acid sequence comprises SEQ ID NO:87 and the second nucleic acid sequence comprises SEQ ID NO: 118; z. the first nucleic acid sequence comprises SEQ ID NO:88 and the second nucleic acid sequence comprises SEQ ID NO: 119; aa. the first nucleic acid sequence comprises SEQ ID NO:89 and the second nucleic acid sequence comprises SEQ ID NO: 120; bb. the first nucleic acid sequence comprises SEQ ID NO:90 and the second nucleic acid sequence comprises SEQ ID NO: 121 ; cc. the first nucleic acid sequence comprises SEQ ID NO:91 and the second nucleic acid sequence comprises SEQ ID NO: 122; dd. the first nucleic acid sequence comprises SEQ ID NO:92 and the second nucleic acid sequence comprises SEQ ID NO: 123; and ee. the first nucleic acid sequence comprises SEQ ID NO:93 and the second nucleic acid sequence comprises SEQ ID NO: 124.Embodiment 92. The ACVR2B RNAi agent of Embodiment 90 or 91 wherein the antisense strand comprises a 3’ overhang of two nucleotides.Embodiment 93. The ACVR2B RNAi agent of any one of Embodiments 90-92 wherein the sense and antisense strands each comprise one or more modified nucleotides.Embodiment 94. The ACVR2B RNAi agent of Embodiment 93 wherein one or more modified nucleotides is a 2’ fluoro modified nucleotide or a 2’0-methyl modified nucleotide.Embodiment 95. The ACVR2B RNAi agent of any one of Embodiments 90-94 wherein the sense and antisense strands each comprise one or more modified internucleotide linkages.Embodiment 96. The ACVR2B RNAi agent of Embodiment 95 wherein the one or more modified intemucleotide linkages are phosphorothioate linkages.Embodiment 97. The ACVR2B RNAi agent of any one of Embodiments 90-96, wherein the sense strand or antisense strand further comprises an abasic moiety or an inverted abasic moiety.Embodiment 98. The ACVR2B RNAi agent of Embodiment 97 wherein the antisense strand further comprises an inverted abasic moiety.Embodiment 99. The ACVR2B RNAi agent of any one of Embodiments 90-98, wherein the antisense strand is between 15 and 50 nucleotides in length.Embodiment 100. The ACVR2B RNAi agent of any one of Embodiments 90-99, wherein the sense strand is between 15 and 50 nucleotides in length.Embodiment 101. The ACVR2B RNAi agent of any one of Embodiments 90-100, wherein the antisense strand is between 18 and 23 nucleotides in length.Embodiment 102. The ACVR2B RNAi agent of any one of Embodiments 90-101, wherein the sense strand is between 18 and 21 nucleotides in length.Embodiment 103. The ACVR2B RNAi agent of any one of Embodiments 90-102, wherein the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length.Embodiment 104. The ACVR2B RNAi agent of any one of Embodiments 90-103, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 185 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 186; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 187 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 188; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 189 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 190; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 191 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 192; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 193 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 194; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 195 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 196; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 197 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 198; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 199 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:200;i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:201 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 202; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:203 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:204; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:205 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:206; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:207 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:208; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:209 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:210; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:211 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:212; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:213 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:214; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:215 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:216; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:217 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:218;r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:219 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 220; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:221 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:222; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:223 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:224; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:225 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:226; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:227 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:228; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:229 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:230; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:231 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:232; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:233 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:234; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:235 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:236;aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:237 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 238; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:239 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:240; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:241 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:242; dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:243 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:244; and ee. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:245 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:246.Embodiment 105. The ACVR2B RNAi agent of any one of Embodiments 90-104, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO: 185 and the second nucleic acid sequence comprises SEQ ID NO: 186; b. the first nucleic acid sequence comprises SEQ ID NO: 187 and the second nucleic acid sequence comprises SEQ ID NO: 188; c. the first nucleic acid sequence comprises SEQ ID NO: 189 and the second nucleic acid sequence comprises SEQ ID NO: 190; d. the first nucleic acid sequence comprises SEQ ID NO: 191 and the second nucleic acid sequence comprises SEQ ID NO: 192;e. the first nucleic acid sequence comprises SEQ ID NO: 193 and the second nucleic acid sequence comprises SEQ ID NO: 194; f. the first nucleic acid sequence comprises SEQ ID NO: 195 and the second nucleic acid sequence comprises SEQ ID NO: 196; g. the first nucleic acid sequence comprises SEQ ID NO:197 and the second nucleic acid sequence comprises SEQ ID NO: 198; h. the first nucleic acid sequence comprises SEQ ID NO: 199 and the second nucleic acid sequence comprises SEQ ID NQ:200; i. the first nucleic acid sequence comprises SEQ ID NO:201 and the second nucleic acid sequence comprises SEQ ID NO:202; j. the first nucleic acid sequence comprises SEQ ID NO: 203 and the second nucleic acid sequence comprises SEQ ID NO:204; k. the first nucleic acid sequence comprises SEQ ID NO:205 and the second nucleic acid sequence comprises SEQ ID NO:206; l. the first nucleic acid sequence comprises SEQ ID NO:207 and the second nucleic acid sequence comprises SEQ ID NO:208; m. the first nucleic acid sequence comprises SEQ ID NO:209 and the second nucleic acid sequence comprises SEQ ID NO:210; n. the first nucleic acid sequence comprises SEQ ID NO:211 and the second nucleic acid sequence comprises SEQ ID NO:212; o. the first nucleic acid sequence comprises SEQ ID NO:213 and the second nucleic acid sequence comprises SEQ ID NO:214; p. the first nucleic acid sequence comprises SEQ ID NO:215 and the second nucleic acid sequence comprises SEQ ID NO:216; q. the first nucleic acid sequence comprises SEQ ID NO:217 and the second nucleic acid sequence comprises SEQ ID NO:218; r. the first nucleic acid sequence comprises SEQ ID NO :219 and the second nucleic acid sequence comprises SEQ ID NO:220;s. the first nucleic acid sequence comprises SEQ ID NO: 221 and the second nucleic acid sequence comprises SEQ ID NO:222; t. the first nucleic acid sequence comprises SEQ ID NO:223 and the second nucleic acid sequence comprises SEQ ID NO:224; u. the first nucleic acid sequence comprises SEQ ID NO:225 and the second nucleic acid sequence comprises SEQ ID NO:226; v. the first nucleic acid sequence comprises SEQ ID NO:227 and the second nucleic acid sequence comprises SEQ ID NO:228; w. the first nucleic acid sequence comprises SEQ ID NO:229 and the second nucleic acid sequence comprises SEQ ID NO:230; x. the first nucleic acid sequence comprises SEQ ID NO:231 and the second nucleic acid sequence comprises SEQ ID NO:232; y. the first nucleic acid sequence comprises SEQ ID NO:233 and the second nucleic acid sequence comprises SEQ ID NO:234; z. the first nucleic acid sequence comprises SEQ ID NO:235 and the second nucleic acid sequence comprises SEQ ID NO:236; aa. the first nucleic acid sequence comprises SEQ ID NO:237 and the second nucleic acid sequence comprises SEQ ID NO:238; bb. the first nucleic acid sequence comprises SEQ ID NO:239 and the second nucleic acid sequence comprises SEQ ID NO:240; cc. the first nucleic acid sequence comprises SEQ ID NO:241 and the second nucleic acid sequence comprises SEQ ID NO:242; dd. the first nucleic acid sequence comprises SEQ ID NO:243 and the second nucleic acid sequence comprises SEQ ID NO:244; and ee. the first nucleic acid sequence comprises SEQ ID NO:245 and the second nucleic acid sequence comprises SEQ ID NO:246.Embodiment 106. The ACVR2B RNAi agent of any one of Embodiment 90-105 wherein the 5’ terminal nucleotide of the antisense strand comprises a phosphate group, a vinyl phosphonate, a phosphate analog, or a hydroxyl group.Embodiment 107. The ACVR2B RNAi agent of Embodiment 106 wherein the phosphate analog is vinyl phosphonate.Embodiment 108. The ACVR2B RNAi agent of any one of Embodiments 90-107, wherein the RNAi agent decreases the expression of the ACVR2B gene in a muscle cell, as compared to control.Embodiment 109. An ACVR2B RNAi agent of the Formula: R-L-TBP, wherein R is the RNAi agent of any one of Embodiments 90-108, L is a linker or a direct bond, and TBP is a transferrin receptor binding protein.Embodiment 110. The AVR2B RNAi agent of Embodiment 109 comprising one of the following formulas:Embodiment 111. The ACVR2B RNAi agent of Embodiment 109 wherein the linker is:Embodiment 112. The ACVR2B RNAi agent of Embodiment 104 wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP wherein the TBP is selected from the group consisting of a Fab, a VHH, and a one-arm heteromab,Embodiment 113. The ACVR2B RNAi agent of Embodiment 111 wherein the linker connects the 3’end of the sense strand of the RNAi agent to a TBP wherein the TBP is a peptide.Embodiment 114. The ACVR2B RNAi agent of Embodiment 112 wherein the TBP is a Fab.Embodiment 115. The ACVR2B RNAi agent of Embodiment 114 wherein the TBP is a Fab which further comprises a VHH that binds to human serum albumin (HSA).Embodiment 116. The ACVR2B RNAi agent of Embodiment 114 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDCR2 comprises SEQ ID NO:251, LCDR3 comprises SEQ ID NO:252.Embodiment 117. The ACVR2B RNAi agent of Embodiment 116 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254.Embodiment 118. The ACVR2B RNAi agent of Embodiment 117 wherein the TBP comprises a heavy chain (HC) and light chain (LC), wherein the HC comprises SEQ ID NO:291 and the LC comprises SEQ ID NO:256.Embodiment 119. The ACVR2B RNAi agent of Embodiment 115 wherein the TBP is a Fab- albVHH.Embodiment 120. The ACVR2B RNAi agent of Embodiment 119 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1 , LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDCR2 comprises SEQ ID NO:251, LCDR3 comprises SEQ ID NO:252.Embodiment 121. The ACVR2B RNAi agent of Embodiment 120 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254.Embodiment 122. The ACVR2B RNAi agent of Embodiment 121 wherein the TBP comprises a heavy chain (HC) and light chain (LC), wherein the HC comprises SEQ ID NO:255 and the LC comprises SEQ ID NO:256.Embodiment 123. The ACVR2B RNAi agent of Embodiment 112 wherein the TBP is a one- arm heteromab.Embodiment 124. The ACVR2B RNAi agent of Embodiment 123 wherein the TBP comprises a VH and a VL, wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDCR2, and LCDCR3, and wherein HCDR1 comprises SEQ ID NO:247, HCDR2 comprises SEQ ID NO:248, HCDR3 comprises SEQ ID NO:249, LCDR1 comprises SEQ ID NO:250, LCDR2 comprises SEQ ID NO:251, and LCDCR3 comprises SEQ ID NO:252.Embodiment 125. The ACVR2B RNAi agent of Embodiment 124 wherein the TBP comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO:253 and the VL comprises SEQ ID NO:254.Embodiment 126. The ACVR2B RNAi agent of Embodiment 125 wherein the TBP comprises two heavy chains, (HC1) and (HC2), and one light chain (LC), wherein HC1 comprises SEQ ID NO:263, HC2 comprises SEQ ID NO:264, and the LC comprises SEQ ID NO:256.Embodiment 127. The ACVR2B RNAi agent of Embodiment 112 wherein the TBP is a VHH.Embodiment 128. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:265, CDR2 comprising SEQ ID NO:266, and CDR3 comprising SEQ ID NO:267.Embodiment 129. The ACVR2B RNAi agent of Embodiment 128 wherein the TBP comprises SEQ ID NO:268.Embodiment 130. The ACVR2B RNAi agent of Embodiment 128 wherein the VHH further comprises a VHH that binds human serum albumin (HSA).Embodiment 131. The ACVR2B RNAi agent of Embodiment 130 wherein the TBP comprises SEQ ID NO:269.Embodiment 132. The ACVR2B RNAi agent of Embodiment 130 wherein the TBP comprises SEQ ID NO:270.Embodiment 133. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:273.Embodiment 134. The ACVR2B RNAi agent of Embodiment 133 wherein the TBP comprises SEQ ID NO:274.Embodiment 135. The ACVR2B RNAi agent of Embodiment 133 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 136. The ACVR2B RNAi agent of Embodiment 135 wherein the TBP comprises SEQ ID NO:275.Embodiment 137. The ACVR2B RNAi agent of Embodiment 135 wherein the TBP comprises SEQ ID NO:276.Embodiment 138. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:279, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:277.Embodiment 139. The ACVR2B RNAi agent of Embodiment 138 wherein the TBP comprises SEQ ID NO:280.Embodiment 140. The ACVR2B RNAi agent of Embodiment 138 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 141. The ACVR2B RNAi agent of Embodiment 140 wherein the TBP comprises SEQ ID NO:292.Embodiment 142. The ACVR2B RNAi agent of Embodiment 140 wherein the TBP comprises SEQ ID NO:293.Embodiment 143. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:281, CDR2 comprising SEQ ID NO:272, and CDR3 comprising SEQ ID NO:277.Embodiment 144. The ACVR2B RNAi agent of Embodiment 143 wherein the TBP comprises SEQ ID NO:282.Embodiment 145. The ACVR2B RNAi agent of Embodiment 143 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 146. The ACVR2B RNAi agent of Embodiment 145 wherein the TBP comprises SEQ ID NO:294.Embodiment 147. The ACVR2B RNAi agent of Embodiment 145 wherein the TBP comprises SEQ ID NO:295.Embodiment 148. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:283, and CDR3 comprising SEQ ID NO:277.Embodiment 149. The ACVR2B RNAi agent of Embodiment 148 wherein the TBP comprises SEQ ID NO:284.Embodiment 150. The ACVR2B RNAi agent of Embodiment 148 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 151. The ACVR2B RNAi agent of Embodiment 150 wherein the TBP comprises SEQ ID NO:296.Embodiment 152. The ACVR2B RNAi agent of Embodiment 150 wherein the TBP comprises SEQ ID NO:297.Embodiment 153. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:285, and CDR3 comprising SEQ ID NO:277.Embodiment 154. The ACVR2B RNAi agent of Embodiment 153 wherein the TBP comprises SEQ ID NO:286.Embodiment 155. The ACVR2B RNAi agent of Embodiment 153 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 156. The ACVR2B RNAi agent of Embodiment 155 wherein the TBP comprises SEQ ID NO:298.Embodiment 157. The ACVR2B RNAi agent of Embodiment 155 wherein the TBP comprises SEQ ID NO:299.Embodiment 158. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:287, and CDR3 comprising SEQ ID NO:277.Embodiment 159. The ACVR2B RNAi agent of Embodiment 158 wherein the TBP comprises SEQ ID NO:288.Embodiment 160. The ACVR2B RNAi agent of Embodiment 158 wherein the VHH further comprises a VHH that bind to human serum albumin (HSA).Embodiment 161. The ACVR2B RNAi agent of Embodiment 160 wherein the TBP comprises SEQ ID NO:300.Embodiment 162. The ACVR2B RNAi agent of Embodiment 160 wherein the TBP comprises SEQ ID NO:301.Embodiment 163. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:271, CDR2 comprising SEQ ID NO:289, and CDR3 comprising SEQ ID NO:277.Embodiment 164. The ACVR2B RNAi agent of Embodiment 163 wherein the TBP comprises SEQ ID NO:290.Embodiment 165. The ACVR2B RNAi agent of Embodiment 163 wherein the VHH further comprises a VHH that binds to human serum albumin (HSA).Embodiment 166. The ACVR2B RNAi agent of Embodiment 165 wherein the TBP comprises SEQ ID NO:302. Embodiment 167. The ACVR2B RNAi agent of Embodiment 165 wherein the TBP comprises SEQ ID NQ:303.Embodiment 168. The ACVR2B RNAi agent of Embodiment 127 wherein the TBP comprises a CDR1 comprising SEQ ID NO:304, CDR2 comprising SEQ ID NO:305, and a CDR3 comprising SEQ ID NO:277.Embodiment 169. The ACVR2B RNAi agent of Embodiment 168 wherein the TBP comprises SEQ ID NO:306.Embodiment 170. The ACVR2B RNAi agent of Embodiment 113 wherein the TBP comprises SEQ ID NO:307.Embodiment 171. The ACVR2B RNAi agent of Embodiment 113 wherein the TBP comprises SEQ ID NO:308.Embodiment 172. The ACVR2B RNAi agent of Embodiment 113 wherein the TBP comprises SEQ ID NQ:309.Embodiment 173. The ACVR2B RNAi agent of Embodiment 113 wherein the TBP comprises SEQ ID NO:310.Embodiment 174. A pharmaceutical composition comprising the ACVR2B RNAi agent of any one of Embodiments 90-173.Embodiment 175. A method of treating a subject having a disease associated with an elevated level of ACVR2B gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2B RNAi agent of anyone Embodiments 90- 173.Embodiment 176. A method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2B, the method comprising administering to the subject a therapeutically effective amount of the ACVR2B RNAi agent of any one of Embodiments 90-173.Embodiment 177. The ACVR2B RNAi agent of any one of Embodiments 90-173 or the pharmaceutical composition of Embodiment 174 for use in the treatment of a disease associated with ACVR2B gene expression.Embodiment 178. The ACVR2B RNAi agent for use of any one of Embodiments 90-173 or the pharmaceutical composition of Embodiment 174 wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.Embodiment 179. The ACVR2B RNAi agent for use of Embodiment 178, wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD,MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.Embodiment 180. A pharmaceutical composition comprising: i. an ACVR2A RNAi agent of any one of Embodiments 1-84, and ii. an ACVR2B RNAi agent of any one of Embodiments 90-173.Embodiment 181. A method of treating a subject having a disease associated with an elevated level of ACVR2 and ACVR2B gene expression, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of Embodiment 180.Embodiment 182. A method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2 and ACVR2B, the method comprising to the subject a therapeutically effective amount of the pharmaceutical composition of Embodiment 180.Embodiment 183. The ACVR2A RNAi agent of any one of Embodiments 1-84 or the pharmaceutical composition of Embodiment 85 for use in simultaneous, separate or sequential combination with the ACVR2B RNAi agent of any one of Embodiments 90-173 or the pharmaceutical composition of Embodiment 174 for use in the treatment of a disease associated with ACVR2A and ACVR2B gene expression.Embodiment 184. A method of treating a subject having a disease associated with an elevated level of ACVR2A and ACVR2B gene expression, the method comprising administering to the subject a first AC VR2A RNAi agent of any one of Embodiments 1 -84 and a second ACVR2B RNAi agent of any one of Embodiments 90-173.Embodiment 185. The method of any one of Embodiments 181, 182, or 184, wherein the disease associated with ACVR2A and ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.Embodiment 186. An ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein each strand of the dsRNA has at least 95% sequence identity to the sequences of one of the strands of one of Duplex No. 123 -181.Embodiment 187. The AC VR2A RNAi agent of Embodiment 186, wherein the first nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 313- 371, and the second nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 372-430; or the ACVR2A RNAi agent of this embodiment, wherein the first nucleic acid sequence comprises any one of SEQ ID NOs: 313-371, and the second nucleic acid sequence comprises any one of SEQ ID NOs: 372-430.Embodiment 188. The ACVR2A RNAi agent of Embodiment 186 or Embodiment 187, wherein the dsRNA is selected from Duplex No. 305 -363.Embodiment 189. The ACVR2A RNAi agent of any one of Embodiments 186-188, wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP, wherein the TBP is selected from the group consisting of a Fab, a VHH, a one-arm heteromab, and a peptide.Embodiment 190. The ACVR2A RNAi agent of Embodiment 189, wherein the TBP is a VHH.Embodiment 191. The ACVR2A RNAi agent of Embodiment 190, wherein the VHH has a CDR1 selected from the group consisting of SEQ ID NO: 265, SEQ ID NO: 271, SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 304; a CDR2 selected from the group consisting of SEQ ID NO: 266, SEQ ID NO: 272, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, and SEQ ID NO: 305; and a CDR3 selected from the group consisting of SEQ ID NO: 267, SEQ ID NO: 273, and SEQ ID NO: 277.Embodiment 192. A pharmaceutical composition comprising the ACVR2A RNAi agent of any one of claims Embodiments 186-191.Embodiment 193. A method of treating a subject having a disease associated with an elevated level ACVR2A gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2A RNAi agent of any one of Embodiments 186-191, or the pharamaceutical composition of Embodiment 192.Embodiment 194. The ACVR2A RNAi agent of any one of Embodiments 186-191, or the pharamaceutical composition of Embodiment 192 for use in the treatment of a disease associated with ACVR2A gene expression.Embodiment 195. The ACVR2A RNAi agent for use of Embodiment 194, wherein the disease associated with ACVR2A gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.Embodiment 196. An ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein each strand of the dsRNA has at least 95% sequence identity to the sequences of one of the strands of one of Duplex No. 182 -304.Embodiment 197. The ACVR2B RNAi agent of Embodiment 196, wherein each strand of the dsRNA is an antisense strand and a sense strand of one of Duplex No. 182-304.Embodiment 198. The ACVR2B RNAi agent of Embodiment 196 or Embodiment 197, wherein the dsRNA is selected from Duplex No. 364 -486.Embodiment 199. The ACVR2B RNAi agent of any one of Embodiments 196-198, wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP, wherein the TBP is selected from the group consisting of a Fab, a VHH, a one-arm heteromab, and a peptide.Embodiment 200. The ACVR2B RNAi agent of Embodiment 199, wherein the TBP is a VHH.Embodiment 201. The ACVR2B RNAi agent of Embodiment 200, wherein the VHH has a CDR1 selected from the group consisting of SEQ ID NO: 265, SEQ ID NO: 271, SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 304; a CDR2 selected from the group consisting of SEQ ID NO: 266, SEQ ID NO: 272, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, and SEQ ID NO: 305; and a CDR3 selected from the group consisting of SEQ ID NO: 267, SEQ ID NO: 273, and SEQ ID NO: 277.Embodiment 202. A pharmaceutical composition comprising the ACVR2B RNAi agent of any one of Embodiments 196-201.Embodiment 203. A method of treating a subject having a disease associated with an elevated level ACVR2B gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2B RNAi agent of any one of claims Embodiments 196-201, or the pharamaceutical composition of Embodiment 202.Embodiment 204. The ACVR2B RNAi agent of any one of Embodiments 196-201 or the pharmaceutical composition of Embodiment 202 for use in the treatment of a disease associated with ACVR2B gene expression.Embodiment 205. The ACVR2B RNAi agent for use of Embodiment 204, wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

Claims

CLAIMSWhat is claimed is:

1. An ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:3 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:33; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:4 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 34; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 5 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:35; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 6 and the second nucleic acid sequence has at least 95% sequence identity to SQ ID NO:36; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:7 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 37; f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 8 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:38; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:9 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 39;h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 10 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:40; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 11 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:41; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 12 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:42; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 13 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:43; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 14 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:44; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 15 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:45; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 16 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:46; o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 17 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:47; p. the first nucleic acid sequence has least 95% sequence identity to SEQ ID NO:18 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:48;q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 19 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:49; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 20 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:50; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:21 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:51 ; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 22 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:52; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 23 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:53; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 24 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:54; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 25 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:55; x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 26 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:56; y. the first nucleic acid sequence has least 95% sequence identity to SEQ ID NO:27 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:57;z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:28 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:58; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 29 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:59; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 30 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:60; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:31 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:61; and dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:32 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:62.

2. The ACVR2A RNAi agent of claim 1, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO: 3 and the second nucleic acid sequence comprises SEQ ID NO:33; b. the first nucleic acid sequence comprises SEQ ID NO:4 and the second nucleic acid sequence comprises SEQ ID NO:34; c. the first nucleic acid sequence comprises SEQ ID NO:5 and the second nucleic acid sequence comprises SEQ ID NO: 35; d. the first nucleic acid sequence comprises SEQ ID NO:6 and the second nucleic acid sequence comprises SQ ID NO:36; e. the first nucleic acid sequence comprises SEQ ID NO:7 and the second nucleic acid sequence comprises SEQ ID NO:37;f. the first nucleic acid sequence comprises SEQ ID NO: 8 and the second nucleic acid sequence comprises SEQ ID NO:38; g. the first nucleic acid sequence comprises SEQ ID NO:9 and the second nucleic acid sequence comprises SEQ ID NO:39; h. the first nucleic acid sequence comprises SEQ ID NO:10 and the second nucleic acid sequence comprises SEQ ID NO:40; i. the first nucleic acid sequence comprises SEQ ID NO:11 and the second nucleic acid sequence comprises SEQ ID NO:41 ; j. the first nucleic acid sequence comprises SEQ ID NO:12 and the second nucleic acid sequence comprises SEQ ID NO:42; k. the first nucleic acid sequence comprises SEQ ID NO: 13 and the second nucleic acid sequence comprises SEQ ID NO:43; l. the first nucleic acid sequence comprises SEQ ID NO:14 and the second nucleic acid sequence comprises SEQ ID NO:44; m. the first nucleic acid sequence comprises SEQ ID NO: 15 and the second nucleic acid sequence comprises SEQ ID NO:45; n. the first nucleic acid sequence comprises SEQ ID NO: 16 and the second nucleic acid sequence comprises SEQ ID NO:46; o. the first nucleic acid sequence comprises SEQ ID NO:17 and the second nucleic acid sequence comprises SEQ ID NO:47; p. the first nucleic acid sequence comprises SEQ ID NO: 18 and the second nucleic acid sequence comprises SEQ ID NO:48; q. the first nucleic acid sequence comprises SEQ ID NO:19 and the second nucleic acid sequence comprises SEQ ID NO:49; r. the first nucleic acid sequence comprises SEQ ID NO:2Q and the second nucleic acid sequence comprises SEQ ID NO:50; s. the first nucleic acid sequence comprises SEQ ID NO:21 and the second nucleic acid sequence comprises SEQ ID NO:51;t. the first nucleic acid sequence comprises SEQ ID NO:22 and the second nucleic acid sequence comprises SEQ ID NO:52; u. the first nucleic acid sequence comprises SEQ ID NO:23 and the second nucleic acid sequence comprises SEQ ID NO:53; v. the first nucleic acid sequence comprises SEQ ID NO:24 and the second nucleic acid sequence comprises SEQ ID NO:54; w. the first nucleic acid sequence comprises SEQ ID NO:25 and the second nucleic acid sequence comprises SEQ ID NO:55; x. the first nucleic acid sequence comprises SEQ ID NO:26 and the second nucleic acid sequence comprises SEQ ID NO:56; y. the first nucleic acid sequence comprises SEQ ID NO:27 and the second nucleic acid sequence comprises SEQ ID NO:57; z. the first nucleic acid sequence comprises SEQ ID NO:28 and the second nucleic acid sequence comprises SEQ ID NO:58; aa. the first nucleic acid sequence comprises SEQ ID NO:29 and the second nucleic acid sequence comprises SEQ ID NO:59; bb. the first nucleic acid sequence comprises SEQ ID NO:30 and the second nucleic acid sequence comprises SEQ ID NO:60; cc. the first nucleic acid sequence comprises SEQ ID NO:31 and the second nucleic acid sequence comprises SEQ ID NO:61; and dd. the first nucleic acid sequence comprises SEQ ID NO:32 and the second nucleic acid sequence comprises SEQ ID NO:62.

3. The ACVR2A RNAi agent of claim 1 or claim 2, wherein the sense strand and antisense strand each comprise one or more modified nucleotides.

4. The ACVR2A RNAi agent of any one of claims 1 -3, wherein the sense strand and antisense strand each comprise one or more modified internucleotide linkages.

5. The ACVR2A RNAi agent of any one of claims 1-4, wherein the antisense strand and the sense strand are each between 15 and 50 nucleotides in length.

6. The ACVR2A RNAi agent of any one of claims 1-5, wherein the antisense strand is between 18 and 23 nucleotides in length, and the sense strand is between 18 and 21 nucleotides in length.

7. The ACVR2A RNAi agent of any one of claims 1-6, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid comprises SEQ ID NO: 125 and the second nucleic acid sequence comprises SEQ ID NO: 126; b. the first nucleic acid comprises SEQ ID NO: 127 and the second nucleic acid sequence comprises SEQ ID NO: 128; c. the first nucleic acid comprises SEQ ID NO: 129 and the second nucleic acid sequence comprises SEQ ID NO: 130; d. the first nucleic acid comprises SEQ ID NO: 131 and the second nucleic acid sequence comprises SEQ ID NO: 132; e. the first nucleic acid comprises SEQ ID NO: 133 and the second nucleic acid sequence comprises SEQ ID NO: 134; f. the first nucleic acid comprises SEQ ID NO: 135 and the second nucleic acid sequence comprises SEQ ID NO: 136; g. the first nucleic acid comprises SEQ ID NO: 137 and the second nucleic acid sequence comprises SEQ ID NO: 138; h. the first nucleic acid comprises SEQ ID NO: 139 and the second nucleic acid sequence comprises SEQ ID NO: 140; i. the first nucleic acid comprises SEQ ID NO:141 and the second nucleic acid sequence comprises SEQ ID NO: 142; j. the first nucleic acid comprises SEQ ID NO: 143 and the second nucleic acid sequence comprises SEQ ID NO: 144; k. the first nucleic acid comprises SEQ ID NO: 145 and the second nucleic acid sequence comprises SEQ ID NO: 146;l. the first nucleic acid comprises SEQ ID NO: 147 and the second nucleic acid sequence comprises SEQ ID NO: 148; m. the first nucleic acid comprises SEQ ID NO: 149 and the second nucleic acid sequence comprises SEQ ID NO: 150; n. the first nucleic acid comprises SEQ ID NO:151 and the second nucleic acid sequence comprises SEQ ID NO: 152; o. the first nucleic acid comprises SEQ ID NO: 153 and the second nucleic acid sequence comprises SEQ ID NO: 154; p. the first nucleic acid comprises SEQ ID NO:155 and the second nucleic acid sequence comprises SEQ ID NO: 156; q. the first nucleic acid comprises SEQ ID NO: 157 and the second nucleic acid sequence comprises SEQ ID NO: 158; r. the first nucleic acid comprises SEQ ID NO: 159 and the second nucleic acid sequence comprises SEQ ID NO: 160; s. the first nucleic acid comprises SEQ ID NO: 161 and the second nucleic acid sequence comprises SEQ ID NO: 162; t. the first nucleic acid comprises SEQ ID NO: 163 and the second nucleic acid sequence comprises SEQ ID NO: 164; u. the first nucleic acid comprises SEQ ID NO: 165 and the second nucleic acid sequence comprises SEQ ID NO: 166; v. the first nucleic acid comprises SEQ ID NO: 167 and the second nucleic acid sequence comprises SEQ ID NO: 168; w. the first nucleic acid comprises SEQ ID NO:169 and the second nucleic acid sequence comprises SEQ ID NO: 170; x. the first nucleic acid comprises SEQ ID NO: 171 and the second nucleic acid sequence comprises SEQ ID NO: 172; y. the first nucleic acid comprises SEQ ID NO: 173 and the second nucleic acid sequence comprises SEQ ID NO: 174;z. the first nucleic acid comprises SEQ ID NO:175 and the second nucleic acid sequence comprises SEQ ID NO: 176; aa. the first nucleic acid comprises SEQ ID NO: 177 and the second nucleic acid sequence comprises SEQ ID NO: 178; bb. the first nucleic acid comprises SEQ ID NO: 179 and the second nucleic acid sequence comprises SEQ ID NO: 180; cc. the first nucleic acid comprises SEQ ID NO: 181 and the second nucleic acid sequence comprises SEQ ID NO: 182; and dd. the first nucleic acid comprises SEQ ID NO: 183 and the second nucleic acid sequence comprises SEQ ID NO: 184.

8. An ACVR2A RNAi agent of the Formula: R-L-TBP, wherein R is the RNAi agent of any one of claims 1-7, L is a linker or a direct bond, and TBP is a transferrin receptor binding protein.

9. The ACVR2A RNAi agent of claim 8, comprising one of the following formulas:

10. The ACVR2A RNAi agent of claim 8 or claim 9, wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP, wherein the TBP is selected from the group consisting of a Fab, a VHH, a one-arm heteromab, and a peptide.

11. The ACVR2A RNAi agent of claim 10, wherein the TBP is a VHH.

12. The ACVR2A RNAi agent of claim 11, wherein the VHH comprises a CDR1 comprising a sequence selected from the group consisting of SEQ ID NO: 265, SEQ ID NO: 271, SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 304; a CDR2 comprising a sequence selected from the group consisting of SEQ ID NO: 266, SEQ ID NO: 272, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, and SEQ ID NO: 305; and a CDR3 comprising a sequence selected from the group consisting of SEQ ID NO: 267, SEQ ID NO: 273, and SEQ ID NO: 277.

13. A pharmaceutical composition comprising the ACVR2A RNAi agent of any one of claims 1-12.

14. A method of treating a subject having a disease associated with an elevated levelACVR2A gene expression, the method comprising administering to the subject atherapeutically effective amount of the ACVR2A RNAi agent of any one of claims 1- 12, or the pharmaceutical composition of claim 13.

15. The ACVR2A RNAi agent of any one of claims 1-12 or the pharmaceutical composition of claim 13 for use in the treatment of a disease associated with ACVR2A gene expression.

16. The ACVR2A RNAi agent for use of claim 15, wherein the disease associated with ACVR2A gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

17. An ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 63 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 94; b. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 64 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:95; c. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 65 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:96; d. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 66 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:97; e. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 67 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:98;f. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:68 and the second nucleic acid sequence has least 95% sequence identity to SEQ ID NO:99; g. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 69 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 100; h. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 70 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 101 ; i. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:71 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 102; j. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 72 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:103; k. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 73 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 104; l. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 74 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 105; m. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 75 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 106; n. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:76 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NQ:107;o. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:77 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 108; p. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:78 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 109; q. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 79 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:110; r. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 80 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 111 ; s. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 81 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 112; t. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 82 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:113; u. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 83 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 114; v. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 84 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 115; w. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:85 and the second nucleic sequence has at least 95% sequence identity to SEQ ID NO: 116;x. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 86 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 117; y. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 87 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:118; z. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 88 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:119; aa. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 89 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 120; bb. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 90 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 121; cc. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO:91 and the second nucleic acid sequence has at least 95% sequence identity to EQ ID NO: 122; dd. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 92 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 123; and ee. the first nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 93 and the second nucleic acid sequence has at least 95% sequence identity to SEQ ID NO: 124.

18. The ACVR2B RNAi agent of claim 17, wherein the first nucleic acid sequence and second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO:63 and the second nucleic acid sequence comprises SEQ ID NO:94;b. the first nucleic acid sequence comprises SEQ ID NO:64 and the second nucleic acid sequence comprises SEQ ID NO:95; c. the first nucleic acid sequence comprises SEQ ID NO:65 and the second nucleic acid sequence comprises SEQ ID NO:96; d. the first nucleic acid sequence comprises SEQ ID NO:66 and the second nucleic acid sequence comprises SEQ ID NO:97; e. the first nucleic acid sequence comprises SEQ ID NO:67 and the second nucleic acid sequence comprises SEQ ID NO:98; f. the first nucleic acid sequence comprises SEQ ID NO:68 and the second nucleic acid sequence comprises SEQ ID NO:99; g. the first nucleic acid sequence comprises SEQ ID NO:69 and the second nucleic acid sequence comprises SEQ ID NO: 100; h. the first nucleic acid sequence comprises SEQ ID NO:70 and the second nucleic acid sequence comprises SEQ ID NO: 101 ; i. the first nucleic acid sequence comprises SEQ ID NO:71 and the second nucleic acid sequence comprises SEQ ID NO: 102; j. the first nucleic acid sequence comprises SEQ ID NO:72 and the second nucleic acid sequence comprises SEQ ID NO: 103; k. the first nucleic acid sequence comprises SEQ ID NO:73 and the second nucleic acid sequence comprises SEQ ID NO: 104; l. the first nucleic acid sequence comprises SEQ ID NO:74 and the second nucleic acid sequence comprises SEQ ID NO: 105; m. the first nucleic acid sequence comprises SEQ ID NO:75 and the second nucleic acid sequence comprises SEQ ID NO: 106; n. the first nucleic acid sequence comprises SEQ ID NO:76 and the second nucleic acid sequence comprises SEQ ID NO: 107; o. the first nucleic acid sequence comprises SEQ ID NO:77 and the second nucleic acid sequence comprises SEQ ID NO: 108;p. the first nucleic acid sequence comprises SEQ ID NO:78 and the second nucleic acid sequence comprises SEQ ID NO: 109; q. the first nucleic acid sequence comprises SEQ ID NO:79 and the second nucleic acid sequence comprises SEQ ID NO: 110; r. the first nucleic acid sequence comprises SEQ ID NO:80 and the second nucleic acid sequence comprises SEQ ID NO: 111 ; s. the first nucleic acid sequence comprises SEQ ID NO:81 and the second nucleic acid sequence comprises SEQ ID NO: 112; t. the first nucleic acid sequence comprises SEQ ID NO:82 and the second nucleic acid sequence comprises SEQ ID NO:113; u. the first nucleic acid sequence comprises SEQ ID NO:83 and the second nucleic acid sequence comprises SEQ ID NO: 114; v. the first nucleic acid sequence comprises SEQ ID NO:84 and the second nucleic acid sequence comprises SEQ ID NO:115; w. the first nucleic acid sequence comprises SEQ ID NO:85 and the second nucleic sequence comprises SEQ ID NO: 116; x. the first nucleic acid sequence comprises SEQ ID NO:86 and the second nucleic acid sequence comprises SEQ ID NO: 117; y. the first nucleic acid sequence comprises SEQ ID NO:87 and the second nucleic acid sequence comprises SEQ ID NO: 118; z. the first nucleic acid sequence comprises SEQ ID NO:88 and the second nucleic acid sequence comprises SEQ ID NO: 119; aa. the first nucleic acid sequence comprises SEQ ID NO:89 and the second nucleic acid sequence comprises SEQ ID NO: 120; bb. the first nucleic acid sequence comprises SEQ ID NO:90 and the second nucleic acid sequence comprises SEQ ID NO:121 ; cc. the first nucleic acid sequence comprises SEQ ID NO:91 and the second nucleic acid sequence comprises SEQ ID NO: 122;dd. the first nucleic acid sequence comprises SEQ ID NO:92 and the second nucleic acid sequence comprises SEQ ID NO: 123; and ee. the first nucleic acid sequence comprises SEQ ID NO:93 and the second nucleic acid sequence comprises SEQ ID NO: 124.

19. The ACVR2B RNAi agent of claim 17 or claim 18, wherein the sense strand and antisense strand each comprise one or more modified nucleotides.

20. The ACVR2B RNAi agent of any one of claims 17-19, wherein the sense strand and antisense strands each comprise one or more modified intemucleotide linkages.

21. The ACVR2B RNAi agent of any one of claims 17-20, wherein the antisense strand and the sense strand are each between 15 and 50 nucleotides in length.

22. The ACVR2B RNAi agent of any one of claims 17-21, wherein the antisense strand is between 18 and 23 nucleotides in length, and the sense strand is between 18 and 21 nucleotides in length.

23. The ACVR2B RNAi agent of any one of claims 17-22, wherein the first nucleic acid sequence and the second nucleic acid sequence are selected from the group consisting of: a. the first nucleic acid sequence comprises SEQ ID NO: 185 and the second nucleic acid sequence comprises SEQ ID NO: 186; b. the first nucleic acid sequence comprises SEQ ID NO: 187 and the second nucleic acid sequence comprises SEQ ID NO: 188; c. the first nucleic acid sequence comprises SEQ ID NO: 189 and the second nucleic acid sequence comprises SEQ ID NO: 190; d. the first nucleic acid sequence comprises SEQ ID NO: 191 and the second nucleic acid sequence comprises SEQ ID NO: 192; e. the first nucleic acid sequence comprises SEQ ID NO: 193 and the second nucleic acid sequence comprises SEQ ID NO: 194; f. the first nucleic acid sequence comprises SEQ ID NO: 195 and the second nucleic acid sequence comprises SEQ ID NO: 196;g. the first nucleic acid sequence comprises SEQ ID NO:197 and the second nucleic acid sequence comprises SEQ ID NO: 198; h. the first nucleic acid sequence comprises SEQ ID NO: 199 and the second nucleic acid sequence comprises SEQ ID NO:200; i. the first nucleic acid sequence comprises SEQ ID NO:201 and the second nucleic acid sequence comprises SEQ ID NO:202; j. the first nucleic acid sequence comprises SEQ ID NO:2Q3 and the second nucleic acid sequence comprises SEQ ID NQ:204; k. the first nucleic acid sequence comprises SEQ ID NO:205 and the second nucleic acid sequence comprises SEQ ID NO:206; l. the first nucleic acid sequence comprises SEQ ID NO:2Q7 and the second nucleic acid sequence comprises SEQ ID NO:208; m. the first nucleic acid sequence comprises SEQ ID NO:209 and the second nucleic acid sequence comprises SEQ ID NO:210; n. the first nucleic acid sequence comprises SEQ ID NO:211 and the second nucleic acid sequence comprises SEQ ID NO:212; o. the first nucleic acid sequence comprises SEQ ID NO:213 and the second nucleic acid sequence comprises SEQ ID NO:214; p. the first nucleic acid sequence comprises SEQ ID NO:215 and the second nucleic acid sequence comprises SEQ ID NO:216; q. the first nucleic acid sequence comprises SEQ ID NO:217 and the second nucleic acid sequence comprises SEQ ID NO:218; r. the first nucleic acid sequence comprises SEQ ID NO :219 and the second nucleic acid sequence comprises SEQ ID NO:220; s. the first nucleic acid sequence comprises SEQ ID NO:221 and the second nucleic acid sequence comprises SEQ ID NO:222; t. the first nucleic acid sequence comprises SEQ ID NO: 223 and the second nucleic acid sequence comprises SEQ ID NO:224;u. the first nucleic acid sequence comprises SEQ ID NO:225 and the second nucleic acid sequence comprises SEQ ID NO:226; v. the first nucleic acid sequence comprises SEQ ID NO:227 and the second nucleic acid sequence comprises SEQ ID NO:228; w. the first nucleic acid sequence comprises SEQ ID NO:229 and the second nucleic acid sequence comprises SEQ ID NO:230; x. the first nucleic acid sequence comprises SEQ ID NO:231 and the second nucleic acid sequence comprises SEQ ID NO:232; y. the first nucleic acid sequence comprises SEQ ID NO:233 and the second nucleic acid sequence comprises SEQ ID NO:234; z. the first nucleic acid sequence comprises SEQ ID NO:235 and the second nucleic acid sequence comprises SEQ ID NO:236; aa. the first nucleic acid sequence comprises SEQ ID NO:237 and the second nucleic acid sequence comprises SEQ ID NO:238; bb. the first nucleic acid sequence comprises SEQ ID NO:239 and the second nucleic acid sequence comprises SEQ ID NO:240; cc. the first nucleic acid sequence comprises SEQ ID NO:241 and the second nucleic acid sequence comprises SEQ ID NO:242; dd. the first nucleic acid sequence comprises SEQ ID NO:243 and the second nucleic acid sequence comprises SEQ ID NO:244; and ee. the first nucleic acid sequence comprises SEQ ID NO:245 and the second nucleic acid sequence comprises SEQ ID NO:246.

24. An ACVR2B RNAi agent of the Formula: R-L-TBP, wherein R is the RNAi agent of any one of claims 17-23, L is a linker or a direct bond, and TBP is a transferrin receptor binding protein.

25. The AVR2B RNAi agent of claim 24 comprising one of the following formulas:

26. The ACVR2B RNAi agent of claim 24 or claim 25, wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP, wherein the TBP is selected from the group consisting of a Fab, a VHH, a one-arm heteromab, and a peptide.

27. The ACVR2B RNAi agent of claim 26, wherein the TBP is a VHH.

28. The ACVR2B RNAi agent of claim 27, wherein the VHH comprises a CDR1 comprising a sequence selected from the group consisting of SEQ ID NO: 265, SEQ ID NO: 271, SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 304; a CDR2 comprising a sequence selected from the group consisting of SEQ ID NO: 266, SEQ ID NO: 272, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, and SEQ ID NO: 305; and a CDR3 comprising a sequence selected from the group consisting of SEQ ID NO: 267, SEQ ID NO: 273, and SEQ ID NO: 277.

29. A pharmaceutical composition comprising the ACVR2B RNAi agent of any one of claims 17-28.

30. A method of treating a subject having a disease associated with an elevated level of ACVR2B gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2B RNAi agent of anyone claims 17-28.

31. The ACVR2B RNAi agent of any one of claims 17-28 or the pharmaceutical composition of claim 29 for use in the treatment of a disease associated with ACVR2B gene expression.

32. The ACVR2B RNAi agent for use of any one of claims 17-28 or the pharmaceutical composition of claim 29 wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

33. The ACVR2B RNAi agent for use of claim 32, wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

34. A pharmaceutical composition comprising: i. an ACVR2A RNAi agent of any one of claims 1 -12, and ii. an ACVR2B RNAi agent of any one of claims 17-28.

35. A method of treating a subject having a disease associated with an elevated level of ACVR2 and ACVR2B gene expression, the method comprising administering to thesubject a therapeutically effective amount of the pharmaceutical composition of claim 34.

36. A method of treating a subject having a disease associated with elevated levels of ligands that signal through ACVR2 and ACVR2B, the method comprising to the subject a therapeutically effective amount of the pharmaceutical composition of claim 34.

37. The ACVR2A RNAi agent of any one of claims 1-12 or the pharmaceutical composition of claim 13 for use in simultaneous, separate or sequential combination with the ACVR2B RNAi agent of any one of claims 17-28 or the pharmaceutical composition of claim 29 for use in the treatment of a disease associated with ACVR2A and ACVR2B gene expression.

38. A method of treating a subject having a disease associated with an elevated level of ACVR2A and ACVR2B gene expression, the method comprising administering to the subject a first ACVR2A RNAi agent of any one of claims 1-12 and a second ACVR2B RNAi agent of any one of claims 17-28.

39. The method of any one of claims 35, 36, or 38, wherein the disease associated with ACVR2A and ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

40. An ACVR2A RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence has at least 95% sequence identity to any one of SEQ TD NOs: 313-371 , and the second nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 372-430.

41. The ACVR2A RNAi agent of claim 40, wherein the first nucleic acid sequence comprises any one of SEQ ID NOs: 313-371, and the second nucleic acid sequence comprises any one of SEQ ID NOs: 372-430.

42. The ACVR2A RNAi agent of claim 40 or claim 41, wherein the dsRNA is selected from any one of dsRNA Duplex No. 305-363.

43. The ACVR2A RNAi agent of any one of claims 40-42, wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP, wherein the TBP is selected from the group consisting of a Fab, a VHH, a one-arm heteromab, and a peptide.

44. The ACVR2A RNAi agent of claim 43, wherein the TBP is a VHH.

45. The ACVR2A RNAi agent of claim 44, wherein the VHH comprises a CDR1 comprising a sequence selected from the group consisting of SEQ ID NO: 265, SEQ ID NO: 271, SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 304; a CDR2 comprising a sequence selected from the group consisting of SEQ ID NO: 266, SEQ ID NO: 272, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, and SEQ ID NO: 305; and a CDR3 comprising a sequence selected from the group consisting of SEQ ID NO: 267, SEQ ID NO: 273, and SEQ ID NO: 277.

46. A pharmaceutical composition comprising the ACVR2A RNAi agent of any one of claims 40-45.

47. A method of treating a subject having a disease associated with an elevated level ACVR2A gene expression, the method comprising administering to the subject a therapeutically effective amount of the ACVR2A RNAi agent of any one of claims 40-45, or the pharmaceutical composition of claim 46.

48. The ACVR2A RNAi agent of any one of claims 40-45 or the pharmaceutical composition of claim 46 for use in the treatment of a disease associated with ACVR2A gene expression.

49. The ACVR2A RNAi agent for use of claim 48, wherein the disease associated with ACVR2A gene expression is T2DM, obesity, overweight, NAFLD, MASH,dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

50. An ACVR2B RNAi agent comprising a double stranded RNA (dsRNA) comprising an antisense strand and a sense strand forming a duplex region, wherein the sense strand comprises a first nucleic acid sequence and the antisense strand comprises a second nucleic acid sequence, wherein the first nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 431-553, and the second nucleic acid sequence has at least 95% sequence identity to any one of SEQ ID NOs: 554-676.

51. The ACVR2B RNAi agent of claim 50, wherein the first nucleic acid sequence comprises any one of SEQ ID NOs: 431-553, and the second nucleic acid sequence comprises any one of SEQ ID NOs: 554-676.

52. The ACVR2B RNAi agent of claim 50 or claim 51, wherein the dsRNA is selected from any one of dsRNA Duplex No. 364-486.

53. The ACVR2B RNAi agent of any one of claims 50-52, wherein the linker connects the 3’ end of the sense strand of the RNAi agent to a TBP, wherein the TBP is selected from the group consisting of a Fab, a VHH, a one-arm heteromab, and a peptide.

54. The ACVR2B RNAi agent of claim 53, wherein the TBP is a VHH.

55. The ACVR2B RNAi agent of claim 54, wherein the VHH comprises a CDR1 comprising a sequence selected from the group consisting of SEQ ID NO: 265, SEQ ID NO: 271, SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 304; a CDR2 comprising a sequence selected from the group consisting of SEQ ID NO: 266, SEQ ID NO: 272, SEQ ID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, and SEQ ID NO: 305; and a CDR3 comprising a sequence selected from the group consisting of SEQ ID NO: 267, SEQ ID NO: 273, and SEQ ID NO: 277.

56. A pharmaceutical composition comprising the ACVR2B RNAi agent of any one of claims 50-55.

57. A method of treating a subject having a disease associated with an elevated level ACVR2B gene expression, the method comprising administering to the subject atherapeutically effective amount of the ACVR2B RNAi agent of any one of claims 50-55, or the pharmaceutical composition of claim 56.

58. The ACVR2B RNAi agent of any one of claims 50-55 or the pharmaceutical composition of claim 56 for use in the treatment of a disease associated with ACVR2B gene expression.

59. The ACVR2B RNAi agent for use of claim 58, wherein the disease associated with ACVR2B gene expression is T2DM, obesity, overweight, NAFLD, MASH, dyslipidemia, metabolic syndrome, CKD, OA, OSA, sarcopenia, cachexia, SO, or PCOS.

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