Gene therapy for amyotrophic lateral sclerosis and other spinal cord disorders

Abstract

This disclosure provides methods and compositions for treating disorders or injuries that affect motor function and control in a subject. In one aspect, the invention a transgene product is delivered to a subject's spinal cord by administering a recombinant neurotrophic viral vector containing the transgene to the brain. The viral vector delivers the transgene to a region of the brain which is susceptible to infection by the virus and which expresses the encoded recombinant viral gene product. Also provided are compositions for delivery of a transgene product to a subject's spinal cord by administering a recombinant neurotrophic viral vector containing the transgene to the subject's brain.

1 . A method to deliver a transgene product to the spinal cord in a subject, comprising:
 administering a recombinant neurotrophic viral vector comprising said transgene to at least one ventricle of the brain, whereby said transgene is expressed and the expressed protein product is delivered to the spinal cord, wherein the transgene is IGF-1.   
     
     
         2 . The method of  claim 1  wherein the viral vector is an AAV vector. 
     
     
         3 . The method of  claim 1  wherein the viral vector is AAV4 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1  wherein the viral vector is administered by direct injection into a ventricle of the brain. 
     
     
         6 . The method of  claim 1  wherein the viral vector is administered by direct injection into a lateral ventricle of the brain. 
     
     
         7 . The method of  claim 1  wherein the viral vector is administered by direct injection into the fourth ventricle of the brain. 
     
     
         8 . The method of  claim 1  wherein the subject has amyotrophic lateral sclerosis. 
     
     
         9 . A method to deliver IGF-1 to the spinal cord in a subject having amyotrophic lateral scleroisis, comprising:
 administering a recombinant AAV4 viral vector comprising a transgene encoding IGF-1 to at least one ventricle of the brain selected from the group consisting of a lateral ventricle and the fourth ventricle, whereby said transgene is expressed and IGF-1 is delivered to the spinal cord.   
     
     
         10 . A method to treat a motor neuron disorder in a subject, comprising administering a recombinant neurotrophic viral vector comprising a therapeutic transgene to at least one ventricle of the brain, whereby said transgene is expressed in a therapeutically effective amount, wherein the transgene is IGF-1. 
     
     
         11 . The method of  claim 10  wherein the viral vector is an AAV vector. 
     
     
         12 . The method of  claim 10  wherein the viral vector is AAV4 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 10  wherein the viral vector is administered by direct injection into a ventricle of the brain. 
     
     
         15 . The method of  claim 10  wherein the viral vector is administered by direct injection into a lateral ventricle of the brain. 
     
     
         16 . The method of  claim 10  wherein the viral vector is administered by direct injection into the fourth ventricle of the brain. 
     
     
         17 . The method of  claim 10  wherein the subject has amyotrophic lateral sclerosis. 
     
     
         18 . A method to treat amyotrophic lateral sclerosis in a subject, comprising administering a recombinant AAV4 viral vector comprising an IGF-1 transgene to at least one ventricle of the brain selected from the group consisting of a lateral ventricle and the fourth ventricle, whereby said transgene is expressed in a therapeutically effective amount. 
     
     
         19 . The method of  claim 1  wherein said vector further encodes a protein selected from the group consisting of insulin growth factor-1 (IGF-1), calbindin D28, parvalbumin, HIF1-alpha, SIRT-2, VEGF, SMN-2, CNTF (Ciliary neurotrophic factor), sonic hedgehog (shh), erythropoietin EPO), lysyl oxidase (LOX), progranulin, prolactin, ghrelin, neuroserpin, angiogenin, and placenta lactogen. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1  wherein said subject is a mammal. 
     
     
         22 . The method of  claim 21 , wherein said mammal is selected from the group consisting of a rodent, a murine, a simian, and a human. 
     
     
         23 . The method of  claim 1 , wherein said subject is a human patient. 
     
     
         24 . The method of  claim 23 , wherein said human patient underexpresses an effective amount of a protein selected from the group consisting of insulin growth factor-1 (IGF-1), calbindin D28, parvalbumin, HIF1-alpha, sonic hedge hog (shh), erythropoietin (EPO), SIRT-2, VEGF, and CNTF (Ciliary neurotrophic factor). 
     
     
         25 . The method of  1 , wherein said transgene expresses a therapeutic amount of insulin growth factor-1 (IGF1). 
     
     
         26 - 30 . (canceled)