Biglycan and related therapeutics and methods of use
The invention provides compositions and methods for treating, preventing, and diagnosing diseases or conditions associated with an abnormal level or activity of biglycan; disorders associated with an unstable cytoplasmic membrane, due, e.g., to an unstable dystrophin associated protein complex (DAPC); disorders associated with abnormal synapses or neuromuscular junctions, including those resulting from an abnormal MuSK activation or acetylcholine receptor (AChR) aggregation. Example of diseases include muscular dystrophies, such as Duchenne's Muscular Dystrophy, Becker's Muscular Dystrophy, neuromuscular disorders and neurological disorders.
1. A method for treating amyotrophic lateral sclerosis, denervation atrophy, cachexia, spinal muscular atrophy, or disuse atrophy in a subject, comprising administering to the subject a pharmaceutically effective amount of a polypeptide that comprises a sequence at least 90% identical to amino acids 38-368 of SEQ ID NO: 9 and has at least one biological activity of biglycan.
2. The method of claim 1 , which is a method for treating amyotrophic lateral sclerosis.
3. The method of claim 2 , wherein the polypeptide lacks glycosaminoglycan (GAG) side chains.
4. The method of claim 1 , which is a method for treating denervation atrophy.
5. The method of claim 4 , wherein the polypeptide lacks glycosaminoglycan (GAG) side chains.
6. The method of claim 1 , which is a method for treating cachexia.
7. The method of claim 6 , wherein the polypeptide lacks glycosaminoglycan (GAG) side chains.
8. The method of claim 1 , which is a method for treating spinal muscular atrophy.
9. The method of claim 8 , wherein the polypeptide lacks glycosaminoglycan (GAG) side chains.
10. The method of claim 1 , which is a method for treating disuse atrophy.
11. The method of claim 10 , wherein the polypeptide lacks glycosaminoglycan (GAG) side chains.
12. The method of claim 1 , wherein the polypeptide activates MuSK on the cell.
13. The method of claim 1 , wherein the polypeptide binds to MuSK.
14. The method of claim 1 , wherein the polypeptide upregulates utrophin levels.
15. The method of claim 1 , wherein the polypeptide binds to alpha-sarcoglycan and gamma-sarcoglycan.
16. The method of claim 1 , wherein the polypeptide induces phosphorylation of sarcoglycans.
17. The method of claim 1 , wherein the polypeptide comprises at least one repeat motif of 24 consecutive amino acids in the Leucine Rich Repeat (LRR) of SEQ ID NO: 9.
18. The method of claim 1 , wherein the polypeptide comprises a sequence at least 95% identical to amino acids 38-365 of SEQ ID NO: 9.
19. The method of claim 18 , wherein the polypeptide comprises an amino acid sequence that is identical to amino acids 38-365 of SEQ ID NO: 9.
20. The method of claim 18 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 9.
21. The method of claim 1 , wherein the polypeptide is encoded by a nucleic acid which hybridizes under stringent conditions of 6.0×sodium chloride/sodium citrate (SSC) at about 45° C. to a complementary strand of SEQ ID NO: 8.