Compositions and methods of treating muscle atrophy and myotonic dystrophy

1. A method of reducing muscle weight loss in a subject in need thereof comprising administering to said subject a short interfering RNA (siRNA)-antibody conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to an siRNA having a guide strand comprising a sequence selected from SEQ ID NO: 592-702 that hybridizes to a target sequence of Murf1 mRNA and mediates RNA interference against the Murf1 mRNA preferentially in a muscle cell, thereby reducing muscle weight loss in said subject.

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

3. The method of claim 1 , wherein said subject has muscle atrophy or myotonic dystrophy.

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

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

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

7. The method of claim 2 , 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.

8. The method of claim 2 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

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

10. The method of claim 1 , wherein the siRNA-antibody conjugate has an siRNA to antibody ratio of from 1 to 4.

11. The method of claim 1 , wherein the siRNA of the siRNA-antibody conjugate comprises a 5′-vinylphosphonate modified nucleotide.

12. The method of claim 3 , wherein the muscle atrophy is associated with myotonic dystrophy.

13. The method of claim 3 , wherein the muscle atrophy is caused by disuse, starvation, cancer, diabetes, renal failure, or treatment with glucocorticoids.

14. The method of claim 1 , wherein the siRNA-antibody conjugate is administered parenterally.