Adeno-associated virus vector delivery of micro-dystrophin to treat muscular dystrophy

Abstract

The invention provide for recombinant AAV vectors comprising a miniaturized human micro-dystrophin gene and methods of using the recombinant vectors to reduce or prevent fibrosis in subjects suffering from muscular dystrophy.

What is claimed: 
     
         1 . A recombinant AAV vector comprising 
 a) a nucleotide sequence having at least 85% identity to the nucleotide sequence SEQ ID NO: 7 and encodes a functional micro-dystrophin protein,   b) the nucleotide sequence of SEQ ID NO: 7, or   c) the nucleotide sequence of SEQ ID NO: 9.   
     
     
         2 . The recombinant AAV vector of  claim 1  wherein the vector is the serotype AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAVrh74, AAV8, AAV9, AAV10, AAV11, AAV12 or AAV13. 
     
     
         3 . The recombinant AAV vector of  claim 1  or  2  wherein the polynucleotide sequence is operably linked to a muscle-specific control element. 
     
     
         4 . The recombinant AAV vector of  claim 3  wherein the muscle-specific control element is human skeletal actin gene element, cardiac actin gene element, myocytespecific enhancer binding factor mef, muscle creatine kinase (MCK), truncated MCK (tMCK), myosin heavy chain (MHC), C5-12, murine creatine kinase enhancer element, skeletal fast-twitch troponin c gene element, slow-twitch cardiac troponin c gene element, the slow-twitch troponin i gene element, hypoxia-inducible nuclear factors, steroid-inducible element or glucocorticoid response element (gre). 
     
     
         5 . The recombinant AAV vector of  claim 3  or  4  wherein the muscle-specific control element comprises the nucleotide sequence of SEQ ID NO: 10 or SEQ ID NO: 11. 
     
     
         6 . A composition comprising the recombinant AAV vector of any one of  claims 1-5 . 
     
     
         7 . A method of treating muscular dystrophy or dystrophinopathy comprising administering a therapeutically effective amount of the recombinant AAV vector of any one of  claims 1-5  or the composition of  claim 6 . 
     
     
         8 . A method of reducing or preventing fibrosis in a subject suffering from muscular dystrophy or dystrophinopathy comprising administering a therapeutically effective amount of the recombinant AAV vector of any one of  claims 1-5  or the composition of  claim 6 . 
     
     
         9 . A method of increasing muscular force or muscle mass in a subject suffering from muscular dystrophy or dystrophinopathy comprising administering a therapeutically effective amount of the recombinant AAV vector of any one of  claims 1-5  or the composition of  claim 6 . 
     
     
         10 . The method of any one of  claims 7-9  wherein the recombinant AAV vector or the composition is administered by intramuscular injection, intravenous injection, parental administration or systemic administration. 
     
     
         11 . The method of any one of  claims 7-10  wherein the recombinant AAV is administered before fibrosis is observed in the subject or before muscle force is reduced in the subject or before muscle mass is reduced in the subject. 
     
     
         12 . The method of any one of  claims 7-11  wherein the muscular dystrophy is Duchenne muscular dystrophy or Becker muscular dystrophy. 
     
     
         13 . A composition comprising the recombinant AAV vector of any one of  claims 1-5  for treatment of muscular dystrophy. 
     
     
         14 . A composition comprising the recombinant AAV vector of any one of  claims 1-5  for reducing or preventing fibrosis in a subject suffering from muscular dystrophy. 
     
     
         15 . A composition comprising the recombinant AAV vector of any one of  claims 1-5  for increasing muscular force in a subject suffering from muscular dystrophy. 
     
     
         16 . The composition of any one of  claims 13-15  wherein the composition is administered before fibrosis is observed in the subject or before muscle force is reduced in the subject or before muscle mass is reduced in the subject. 
     
     
         17 . The composition of any one of  claims 13-16  wherein the subject is suffering from Duchenne muscular dystrophy or Becker muscular dystrophy. 
     
     
         18 . Use of the recombinant AAV vector of any one of  claims 1-5  or the composition of  claim 6  for the preparation of a medicament for treatment of muscular dystrophy. 
     
     
         19 . Use of a recombinant AAV vector of any one of  claims 1-5  or the composition of  claim 6  for the preparation of a medicament for reducing or preventing fibrosis in a subject suffering from muscular dystrophy. 
     
     
         20 . Use of the recombinant AAV vector of any one of  claims 1-5  or the composition of  claim 6  for the preparation of a medicament for the increasing muscular strength or muscle mass in a subject suffering from muscular dystrophy. 
     
     
         21 . The use of any one of  claims 16-18  wherein the medicament is administered before fibrosis is observed in the subject or before muscle force is reduced in the subject or before muscle mass is reduced in the subject. 
     
     
         22 . The use of any one of  claims 18-21  wherein the subject is suffering from Duchenne muscular dystrophy or Becker muscular dystrophy. 
     
     
         23 . The composition or use of any one of  claims 13-22  wherein the composition or medicament is formulated for intramuscular administration, intravenous injection, parental administration or systemic administration. 
     
     
         24 . A method of producing a functional micro-dystrophin protein comprising infecting a host cell with a recombinant AAV vector of any one of  claims 1-5  and expressing a functional micro-dystrophin protein in the host cell.