Methods and compositions for treating skeletal muscular dystrophy

Abstract

Some embodiments provide a method of treating skeletal muscular myopathy, e.g., Duchenne muscular dystrophy (DMD), with cardiosphere-derived cells (CDCs), wherein a therapeutically effective amount of CDCs is delivered to a targeted dystrophic skeletal muscle. Some embodiment enable delivery of a therapeutically effective amount of CDCs via intramuscular injection directly at a skeletal muscle or systemic administration, e.g., intravenous injection, in a single dose or multiple doses, to treat a targeted dystrophic skeletal muscle. Some embodiments provide a method for improving exercise capabilities in DMD patients. Additional embodiments relate to exosome mediated transfer of noncoding RNAs ameliorates Duchenne muscular dystrophy by restoring dystrophin in heart and skeletal muscle. Delivery of noncoding RNA species found in CDC-derived exosomes mimics the ability of CDCs and CDC-derived exosomes to increase dystrophin protein levels.

1 .- 136 . (canceled) 
     
     
         137 . A method of treating skeletal myopathy in a subject in need thereof, the method comprising administrating to the subject a therapeutically effective amount of cardiosphere-derived cells (CDCs) or CDC-derived exosomes (CDC-XOs) sufficient to maintain or restore skeletal muscle function of the subject. 
     
     
         138 . The method according to  claim 137 , wherein said skeletal muscle function is isometric force production. 
     
     
         139 . The method according to  claim 137 , wherein said subject in need has a dystrophinopathy. 
     
     
         140 . The method according to  claim 139 , wherein the dystrophinopathy involves skeletal muscle. 
     
     
         141 . The method according to  claim 140 , wherein the dystrophinopathy is Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). 
     
     
         142 . The method according to  claim 137 , wherein the skeletal muscle is a skeletal muscle of the diaphragm, the limbs, or the torso. 
     
     
         143 . The method according to  claim 142 , wherein the skeletal muscle is a skeletal muscle of the arms. 
     
     
         144 . The method according to  claim 137 , wherein said therapeutically effective amount of CDCs or CDC-XOs is administered to the subject systemically. 
     
     
         145 . The method according to  claim 144 , wherein said systemic administration of a therapeutically effective amount of CDCs or CDC-XOs is via intravenous injection. 
     
     
         146 . The method according to  claim 137 , wherein said administering of a therapeutically effective amount of CDCs or CDC-XOs is via two or more administrations. 
     
     
         147 . The method according to  claim 146 , wherein said two or more administrations of CDCs or CDC-XOs are given at intervals of about three months to deliver a therapeutically effective amount of CDCs or CDC-XOs at a targeted skeletal muscle. 
     
     
         148 . The method according to  claim 137 , wherein said therapeutically effective amount of CDCs is, or is at least, about 150×10 6  CDCs, at least about 300×10 6  CDCs, or at least about 450×10 6  CDCs. 
     
     
         149 . The method according to  claim 137 , wherein said therapeutically effective amount of CDC-XOs is 1×10 6  to 1×10 7 , 1×10 7  to 1×10 8 , 1×10 8  to 1×10 9 , 1×10 9  to 1×10 10 , 1×10 10  to 1×10 11 , 1×10 11  to 1×10 12 , or 1×10 12  or more. 
     
     
         150 . The method according to  claim 137 , wherein said CDCs are allogeneic human CDCs, and the subject is a human subject. 
     
     
         151 . The method according to  claim 137 , wherein said CDC-XOs are obtained from allogeneic human CDCs, and the subject is a human subject. 
     
     
         152 . A method of maintaining or restoring skeletal muscle isometric force production in a skeletal muscle of a subject with muscular dystrophy in need of treatment for skeletal muscle myopathy, the method comprising:
 administering to the subject a first dose of a composition comprising a therapeutically effective amount of cardiosphere-derived cells (CDCs) or CDC-derived exosomes (CDC-XOs),   wherein the therapeutically effective amount of the first dose ranges from about 1×10 7  to about 1×10 9  CDCs or a CDC equivalent dose of CDC-XOs;   waiting a first period of time after administration of said first dose,
 wherein said first period of time is between about 1 and 6 months; 
   administering to the subject a second dose of a composition comprising a therapeutically effective amount of CDCs or CDC-XOs,
 wherein the therapeutically effective amount of the second dose ranges from about 1×10 7  to about 1×10 9  CDCs or a CDC equivalent dose of CDC-XOs; 
   waiting a second period of time after administration of said second dose, wherein said second period of time is between about 1 and 6 months;   administering to the subject at least one additional dose of a composition comprising a therapeutically effective amount of CDCs or CDC-XOs,
 wherein the therapeutically effective amount of the at least one additional dose ranges from about 1×10 7  to about 1×10 9  CDCs or a CDC equivalent dose of CDC-XOs; 
   waiting at least one additional period of time after administration of said at least one additional dose,
 wherein said at least one additional period of time is between about 1 and 6 months; wherein said administrations result in a maintenance or a restoration of skeletal muscle isometric force, 
   wherein said CDCs or CDC-XOs are allogeneic with respect to said subject,   wherein said administrations do not induce a significant immune response in the subject, and   wherein said administrations comprise systemic administration.   
     
     
         153 . The method according to  claim 152 , wherein said systemic administration via intravenous injection. 
     
     
         154 . The method according to  claim 152 , wherein said administrations alter expression of one or more markers of T cell activation or proliferation. 
     
     
         155 . The method according to  claim 152 , wherein said skeletal muscular dystrophy is Duchenne muscular dystrophy (DMD) involving dystrophinopathy of a skeletal muscle. 
     
     
         156 . The method according to  claim 155 , wherein said dystrophic skeletal muscle is a skeletal muscle of the diaphragm, the arm, or the leg.