Treatment of muscular dystrophies and related disorders

Abstract

The invention provides, among other aspects, compositions and methods for treating, preventing, and diagnosing diseases or conditions associated with an abnormal level or activity of biglycan; diseases or conditions associated with an abnormal level or activity of collagen VI; disorders associated with an unstable cytoplasmic membrane, due, e.g., to an unstable dystrophin associated protein complex (DAPC); and disorders associated with abnormal synapses or neuromuscular junctions, including those resulting from an abnormal MuSK activation or acetylcholine receptor (AChR) aggregation.

1 . A method for stabilizing collagen VI-deficient dystrophin-associated protein complexes (DAPCs) on the surface of a cell, comprising contacting the cell with an effective amount of a biglycan therapeutic, such that the collagen VI-deficient DAPCs are stabilized. 
     
     
         2 . The method of  claim 1 , wherein the biglycan therapeutic is a polypeptide including a biglycan amino acid sequence which is at least about 90% identical to SEQ ID No. 9, or a portion thereof. 
     
     
         3 . The method of  claim 2 , wherein the biglycan therapeutic binds to MuSK. 
     
     
         4 . The method of  claim 2 , wherein the biglycan therapeutic binds to a α-sarcoglycan and/or γ-sarcoglycan. 
     
     
         5 . The method of  claim 2 , wherein the biglycan therapeutic binds to a collagen VI polypeptide. 
     
     
         6 . The method of  claim 2 , wherein the biglycan therapeutic induces phosphorylation of sarcoglycans. 
     
     
         7 . The method of  claim 2 , wherein the biglycan therapeutic upregulates utrophin levels. 
     
     
         8 . The method of  claim 2 , wherein the biglycan amino acid sequence includes one or more LLRs of human biglycan having SEQ ID NO: 9. 
     
     
         9 . The method of  claim 2 , wherein the polypeptide is derivatized with one or more glycosaminoglycan (GAG) side chains. 
     
     
         10 . The method of  claim 2 , wherein the biglycan amino acid sequence is at least about 90% identical to amino acids 38-365 of SEQ ID NO: 9. 
     
     
         11 . The method of  claim 2 , wherein the biglycan amino acid sequence is at least about 95% identical to amino acids 38-365 of SEQ ID NO: 9. 
     
     
         12 . The method of  claim 2 , wherein the biglycan amino acid sequence is encoded by a nucleic acid which hybridizes to SEQ ID NO: 8. 
     
     
         13 . The method of  claim 1 , wherein the cell is a muscle cell. 
     
     
         14 . A method for treating or preventing a condition associated with a collagen VI deficiency, comprising administering to the subject a pharmaceutically effective amount of biglycan therapeutic. 
     
     
         15 - 21 . (canceled) 
     
     
         22 . A method for treating or preventing a condition associated with an abnormal dystrophin-associated complex (DAPC) in cells of a subject, comprising administering a pharmaceutically effective amount of a collagen VI therapeutic. 
     
     
         23 - 28 . (canceled)