POLYNUCLEOTIDE CONJUGATES COMPRISING PLN-TARGETING POLYNUCLEOTIDES AND ANTI-TRANSFERRIN RECEPTOR ANTIBODIES AND METHOD OF USE THEREOF TO TREAT PLN-ASSOCIATED CARDIOMYOPATHIES

1 . A polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that hybridizes to a target sequence of PLN mRNA and mediates downregulation of the PLN mRNA in a cardiac muscle cell, wherein the polynucleotide hybridizes to a nucleic acid sequence at positions selected from the group consisting of 195-213, 242-379, 449-546, 780-811, 967-1002, 1072-1099, 1119-1138, and 1234-1253 of the PLN mRNA (NM_002667.5).

2 . The polynucleotide conjugate of claim 1 , wherein the target sequence of the PLN mRNA is a genetic PLN variant having a genetic mutation selected from the group consisting of Arg14del (R14del), Arg9Cys (R9C), and Arg25Cys (R25C).

3 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide is an antisense oligonucleotide (ASO) or a double-stranded small interfering RNA (siRNA) comprising a guide strand and a passenger strand.

4 . The polynucleotide conjugate of claim 3 , wherein the ASO comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 265-276.

5 . The polynucleotide conjugate of claim 3 , wherein the ASO comprises a nucleic acid sequence having at least 14, 15, 16, 17, or 18 consecutive nucleotides from a sequence selected from the group consisting of SEQ ID NOs: 265-276.

6 . The polynucleotide conjugate of claim 3 , wherein the passenger strand comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 144, 152, 155, 158-160, 162-166, 168-170, 172-177, 181, 187-188, 191-192, 196, 198, 200, 203, 206, 210-216, 225-228, 230, 232, 235-238, 241, 245-247, and 254-255.

7 . The polynucleotide conjugate of claim 3 , wherein the guide strand comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 12, 20, 23, 26-28, 30-34, 36-38, 40-45, 49, 55-56, 59-60, 64, 66, 68, 71, 74, 78-84, 93-96, 98, 100, 103-106, 109, 113-115, and 122-123.

8 . The polynucleotide conjugate of claim 3 , wherein the passenger strand comprises a nucleic acid sequence having at least 16, 17, 18, 19, 20, or 21 consecutive nucleotides from a sequence selected from the group consisting of SEQ ID NOs: 144, 152, 155, 158-160, 162-166, 168-170, 172-177, 181, 187-188, 191-192, 196, 198, 200, 203, 206, 210-216, 225-228, 230, 232, 235-238, 241, 245-247, and 254-255.

9 . The polynucleotide conjugate of claim 3 , wherein the guide strand comprises a nucleic acid sequence having at least 16, 17, 18, 19, 20, or 21 consecutive nucleotides from a sequence selected from the group consisting of SEQ ID NOs: 12, 20, 23, 26-28, 30-34, 36-38, 40-45, 49, 55-56, 59-60, 64, 66, 68, 71, 74, 78-84, 93-96, 98, 100, 103-106, 109, 113-115, and 122-123.

10 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide comprises at least one 2′-modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety.

11 . The polynucleotide conjugate of claim 10 , wherein the at least one 2′-modified nucleotide comprises:

2′-O-methyl, 2′-O-methoxyethyl(2′—O-MOE), 2′-O-aminopropyl, 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-aminopropyl(2′—O-AP), 2′-O-dimethylaminoethyl(2′—O-DMAOE), 2′-O-dimethylaminopropyl(2′—O-DMAP), 2′-O-dimethylaminoethyloxyethyl(2′—O-DMAEOE), 2′—O—N-methylacetamido (2′-O-NMA) modified nucleotide, locked nucleic acid (LNA), or ethylene nucleic acid (ENA), or a combination thereof.

12 . The polynucleotide conjugate of claim 10 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

13 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide comprises a 5′-terminal vinylphosphonate-modified nucleotide.

14 . The polynucleotide conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof comprises a non-human antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a monoclonal antibody or antigen-binding fragment thereof, a monovalent Fab′, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or antigen-binding fragment thereof.

15 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen-binding fragment thereof to the polynucleotide.

16 . A method of treating a cardiomyopathy associated with PLN in a subject in need thereof comprising administering to said subject a polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that hybridizes to a target sequence of PLN mRNA, thereby treating the cardiomyopathy in said subject, wherein the polynucleotide hybridizes to a nucleic acid sequence at positions selected from the group consisting of 195-213, 242-379, 449-546, 780-811, 967-1002, 1072-1099, 1119-1138 and 1234-1253 of the PLN mRNA (NM_002667.5).

17 . The method of claim 16 , wherein the cardiomyopathy associated with PLN is a genetic cardiomyopathy associated with a genetic PLN variant comprising a genetic mutation selected from the group consisting of Arg14del (R14del), Arg9Cys (R9C), and Arg25Cys (R25C).

18 . The method of claim 16 , wherein the cardiomyopathy associated with PLN is a dilated cardiomyopathy or a hypertrophic cardiomyopathy.

19 . The method of claim 18 , wherein the dilated cardiomyopathy is a genetic dilated cardiomyopathy associated with TTN, LMNA, RI3M20, SCN5A, MYH7, TNNT2, or TPMI mutations.

20 . The method of claim 18 , wherein the hypertrophic cardiomyopathy is associated with MYH7, MYBPC3, TNNT2, TNNC, or TPMI mutations.