COMPOSITIONS AND METHODS OF TREATING MUSCLE ATROPHY AND MYOTONIC DYSTROPHY

1 . A method of treating muscle atrophy 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 mediates RNA interference against the Atrogin-1 mRNA preferentially in a muscle cell, thereby treating muscle atrophy in said subject.

2 . The method of claim 1 , wherein the polynucleotide is a single stranded antisense polynucleotide or a double stranded polynucleotide.

3 . The method 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.

4 . The method of claim 1 , wherein the mediation of RNA interference against the Atrogin-1 mRNA modulates muscle atrophy or myotonic dystrophy in said subject.

5 . The method of claim 1 , wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof binds to a transferrin receptor on the cell surface of the muscle cell.

6 . The method of claim 1 , wherein the muscle cell is a skeletal muscle cell or a cardiac muscle cell.

7 . The method of claim 1 , wherein the polynucleotide hybridizes to a target sequence of the Atrogin-1 mRNA and mediates RNA interference against the Atrogin-1 mRNA via RNase H activity in the muscle cell.

8 . The method of claim 1 , wherein the polynucleotide hybridizes to at least 8 contiguous bases of the target sequence of the Atrogin-1 mRNA.

9 . The method of claim 1 , wherein the polynucleotide is from about 8 to about 50 nucleotides in length or from about 10 to about 30 nucleotides in length.

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

11 . The method of claim 3 , 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), or 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide;

comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA); or

comprises a combination thereof.

12 . The method of claim 3 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

13 . The method of claim 3 , wherein the polynucleotide comprises 3 or more 2′ modified nucleotides selected from 2′-O-methyl and 2′-deoxy-2′-fluoro.

14 . The method of claim 1 , wherein the polynucleotide conjugate has a drug/polynucleotide to antibody ratio of from about 1 to about 4.

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

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

17 . The method of claim 4 , wherein the muscle atrophy is associated with myotonic dystrophy.

18 . The method of claim 4 , wherein the muscle atrophy is caused by disuse, starvation, cancer, diabetes, renal failure, or treatment with glucocorticoids.

19 . The method of claim 1 , wherein the polynucleotide conjugate is administered parenterally, orally, intranasally, buccally, rectally, or transdermally.

20 . A method of modulating muscle atrophy 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 mediates RNA interference against the Atrogin-1 mRNA preferentially in a muscle cell in said subject, thereby modulating muscle atrophy in said subject.

21 . A method of modulating Atrogin-1 mRNA in a muscle cell of a subject comprising administering to said subject a polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that mediates RNA interference against the Atrogin-1 mRNA in the muscle cell, thereby modulating Atrogin-1 mRNA in the muscle cell of said subject.

22 . A method of alleviating muscle atrophy in a subject suffering from a muscle disorder comprising administering to said subject a polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that mediates RNA interference against the Atrogin-1 mRNA preferentially in a muscle cell in said subject, thereby alleviating muscle atrophy in said subject.