Adeno-associated virus-mediated delivery of GDNF to skeletal muscles

Abstract

Compositions and methods for delivering GDNF to skeletal muscles to result in a therapeutic effect are disclosed. The compositions and methods use adeno-associated virus (AAV)-based gene delivery systems. The methods are useful for treating motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).

1 . A method of delivering a recombinant adeno-associated virus (AAV) virion to a muscle cell or muscle tissue of a mammalian subject with a motoneuron disorder, said method comprising: 
 (a) providing a recombinant AAV virion which comprises a polynucleotide encoding a glial cell line-derived neurotrophic factor (GDNF) operably linked to control elements capable of directing the in vivo transcription and translation of said GDNF; and    (b) delivering said recombinant AAV virion directly into said muscle cell or muscle tissue of said subject, whereby said GDNF is expressed at a level which provides a therapeutic effect in said mammalian subject.    
     
     
         2 . The method of  claim 1 , wherein said muscle cell or tissue is derived from skeletal muscle.  
     
     
         3 . The method of  claim 1 , wherein said recombinant AAV virion is introduced into said muscle cell in vivo.  
     
     
         4 . The method of  claim 3 , wherein said recombinant AAV virion is introduced by intramuscular injection.  
     
     
         5 . The method of  claim 1 , wherein said recombinant AAV virion is introduced into said muscle cell in vitro.  
     
     
         6 . A method of treating a mammalian subject with a motoneuron disorder comprising administering intramuscularly to said subject recombinant adeno-associated virus (AAV) virions comprising a polynucleotide encoding a glial cell line-derived neurotrophic factor (GDNF) polypeptide operably linked to expression control elements capable of directing the in vivo transcription and translation of said GDNF to provide a therapeutic effect.  
     
     
         7 . The method of  claim 6 , wherein the subject is human and the polynucleotide encodes a human GDNF.  
     
     
         8 . The method of  claim 7 , wherein the polynucleotide encodes human pre-pro-GDNF.  
     
     
         9 . The method of  claim 6 , wherein the control elements comprise a viral promoter.  
     
     
         10 . The method of  claim 9 , wherein the promoter is an MLP, CMV, or RSV LTR promoter.  
     
     
         11 . The method of  claim 6 , wherein muscle cells are transduced in vivo.  
     
     
         12 . The method of  claim 11 , wherein the recombinant AAV virions are administered into skeletal muscle of said subject.