Heparin-Associated Polypeptides and Uses Thereof

Abstract

Described herein are polypeptides comprising an IGF2 amino acid sequence and an amino acid sequence from a heterologous polypeptide useful for the treatment of soft-tissue and muscle diseases, disorders, and injuries. Mutations within the IGF2 amino acid sequence improved the stability of the molecule by reducing backbone cleavage. Also described herein are synergistic combinations of an Insulin-like Growth Factor 1 Receptor (IGF1R) agonist and a short chain fatty acid. Also described are methods of treating muscle and soft-tissue diseases comprising administering the polypeptides and/or synergistic compositions.

What is claimed is: 
     
         1 . A method of treating a muscle or soft-tissue disorder or condition in a subject comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an HSA-IGF2R61A. 
     
     
         2 . The method of  claim 1 , further comprising the step of administering a short chain fatty acid. 
     
     
         3 . The method of  claim 2 , wherein the short chain fatty acid is a butyrate. 
     
     
         4 . The method of  claim 1 , wherein the HSA-IGF2R61A comprises an amino acid sequence at least about 90%, 95%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 90. 
     
     
         5 . The method of  claim 4 , wherein the IGF2 sequence comprises at least one amino acid that is N-, C-, or O-linked glycosylated. 
     
     
         6 . The method of  claim 3 , further comprising the step of increasing a regenerative capability of a myoblast in the subject. 
     
     
         7 . The method of  claim 6 , wherein the regenerative capability is a proliferation, a degree of differentiation, or a cellular survival. 
     
     
         8 . The method of  claim 7 , wherein increasing a proliferation of the myoblast produces an increase in new myofibers. 
     
     
         9 . The method of  claim 7 , wherein the subject has an increase in a muscle regeneration. 
     
     
         10 . The method of  claim 7 , wherein a grip strength of the subject is increased. 
     
     
         11 . The method of  claim 7 , wherein a weight of muscle in the subject is increased. 
     
     
         12 . The method of  claim 7 , wherein a forelimb force in the subject is increased. 
     
     
         13 . The method of  claim 7 , wherein a lean body mass of the subject is increased. 
     
     
         14 . The method of  claim 7 , wherein an appendicular skeletal muscle index of the subject is increased. 
     
     
         15 . The method of  claim 1 , wherein the disorder or condition is a muscle-wasting condition. 
     
     
         16 . The method of  claim 15 , wherein the muscle-wasting condition is a sarcopenia. 
     
     
         17 . The method of  claim 15 , wherein the muscle-wasting condition is a muscular dystrophy. 
     
     
         18 . The method of  claim 15 , wherein the muscle-wasting condition is a result of an obesity, a disease progression, a metabolic disorder, a therapeutic treatment, or a combination thereof. 
     
     
         19 . The method of  claim 15 , wherein the muscle-wasting condition is a cachexia. 
     
     
         20 . The method of  claim 18 , wherein the metabolic disorder is a diabetes.