Biglycan mutants and related therapeutics and methods of use

Abstract

The present disclosure provides compositions and methods for treating diseases or conditions associated with an abnormal level or activity of biglycan; disorders associated with an unstable cytoplasmic membrane, for example, due 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. Examples of diseases include muscular dystrophies, such as Duchenne's Muscular Dystrophy, Becker's Muscular Dystrophy, neuromuscular disorders and neurological disorders.

1 - 29 . (canceled) 
     
     
         30 . A method of predicting a patient's response to biglycan therapy, comprising determining whether the patient has a decreased utrophin protein level or activity compared to a reference level, wherein a utrophin protein level or activity that is not decreased relative to the reference level indicates that the patient will likely respond to biglycan therapy. 
     
     
         31 . A method of monitoring an effect of biglycan therapy, comprising measuring the amount of membrane-associated utrophin in a patient receiving biglycan therapy, wherein an increased level of membrane-associated utrophin indicates that the biglycan therapy is effective. 
     
     
         32 . The method of  claim 30  or  31 , wherein the biglycan therapy comprises administration of a polypeptide comprising an amino acid sequence which is at least 90% identical to SEQ ID NO: 9, or a fragment thereof. 
     
     
         33 . The method of  claim 30  or  31 , wherein the biglycan therapy comprises administration of a polypeptide comprising the amino acid sequence of SEQ ID NO: 9. 
     
     
         34 . The method of  claim 30  or  31 , wherein the biglycan therapy comprises administration of a polypeptide comprising an amino acid sequence which is at least 90% identical to SEQ ID NO: 10, or a fragment thereof. 
     
     
         35 . The method of  claim 30  or  31 , wherein the biglycan therapy comprises administration of a polypeptide comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
         36 . The method of  claim 30  or  31 , wherein the biglycan therapy comprises administration of a polypeptide comprising an amino acid sequence which is at least 90% identical to SEQ ID NO: 11, or a fragment thereof. 
     
     
         37 . The method of  claim 30  or  31 , wherein the biglycan therapy comprises administration of a polypeptide comprising the amino acid sequence of SEQ ID NO: 11. 
     
     
         38 . A method of measuring the activity of a biglycan polypeptide, comprising administering the biglycan polypeptide to a test cell that expresses utrophin and comparing an amount of membrane-associated utrophin in the test cell with an amount of membrane-associated utrophin in a control cell that did not receive biglycan polypeptide, wherein an increased amount of membrane-associated utrophin in the test cell is indicative of biglycan activity. 
     
     
         39 . The method of  claim 38 , wherein the biglycan polypeptide comprises an amino acid sequence which is at least 90% identical to SEQ ID NO: 9, or a fragment thereof. 
     
     
         40 . The method of  claim 38 , wherein the biglycan polypeptide comprises the amino acid sequence of SEQ ID NO: 9. 
     
     
         41 . The method of  claim 38 , wherein the biglycan polypeptide comprises an amino acid sequence which is at least 90% identical to SEQ ID NO: 10, or a fragment thereof. 
     
     
         42 . The method of  claim 38 , wherein the biglycan polypeptide comprises the amino acid sequence of SEQ ID NO: 10. 
     
     
         43 . The method of  claim 38 , wherein the biglycan polypeptide comprises an amino acid sequence which is at least 90% identical to SEQ ID NO: 11, or a fragment thereof. 
     
     
         44 . The method of  claim 38 , wherein the biglycan polypeptide comprises the amino acid sequence of SEQ ID NO: 11. 
     
     
         45 . A method of identifying a therapeutic for a biglycan-related condition, comprising administering a test compound to a test cell that expresses utrophin and comparing an amount of membrane-associated utrophin in the test cell with an amount of membrane-associated utrophin in a control cell that did not receive the test compound, wherein an increased amount of membrane-associated utrophin in the test cell indicates that the compound is a therapeutic for a biglycan-related condition. 
     
     
         46 . The method of  claim 45 , wherein the biglycan-related condition is muscular dystrophy, a neuromuscular disease, a neurological disease, or a condition characterized by an abnormal neuromuscular junction or synapse. 
     
     
         47 . The method of  claim 45 , wherein the muscular dystrophy is Duchenne's Muscular Dystrophy, Becker's Muscular Dystrophy, Congenital Muscular Dystrophy, Limb-girdle Muscular Dystrophy, or mytonic dystrophy. 
     
     
         48 . The method of  claim 45 , wherein the test cell is a muscle cell.