Adeno-associated virus mediated gene transfer to the central nervous system

Abstract

A method to prevent, inhibit or treat one or more symptoms associated with a disease of the central nervous system by intrathecally, intracerebroventricularly or endovascularly administering a rAAV encoding a gene product associated with the disease, e.g., a mammal in which the gene product is absent or present at a reduced level relative to a mammal without the disease.

What is claimed is: 
     
         1 . A method to inhibit or treat one or more symptoms associated with a deficiency of glucocerebrosidase in a human in need thereof, consisting of:
 administering to the cisterna magna of the human an amount of a recombinant adeno-associated virus (rAAV) vector having an AAV9 or AAVrh10 capsid encapsidating a rAAV genome having an open reading frame encoding glucocerebrosidase effective to inhibit or treat the one or more symptoms associated with the deficiency.   
     
     
         2 . The method of  claim 1  wherein the human has Gaucher disease. 
     
     
         3 . The method of  claim 1  wherein the human has Parkinson disease. 
     
     
         4 . The method of  claim 1  wherein the human is an immunocompetent adult. 
     
     
         5 . The method of  claim 1  wherein the human is immunotolerized to glucocerebrosidase. 
     
     
         6 . The method of  claim 1  wherein the vector having the AAV9 capsid is administered. 
     
     
         7 . The method of  claim 1  wherein the vector having AAVrh10 capsid is administered. 
     
     
         8 . The method of  claim 1  wherein the human was administered an immune suppressant. 
     
     
         9 . The method of  claim 1  wherein multiple doses of the rAAV vector are administered. 
     
     
         10 . A method to inhibit or treat one or more symptoms associated with a deficiency of glucocerebrosidase in a human in need thereof, consisting of:
 administering to the human an effective amount of an immune suppressant and to the cisterna magna of the human an amount of a recombinant adeno-associated virus (rAAV) vector having an AAV9 or AAVrh10 capsid encapsidating a rAAV genome having an open reading frame encoding glucocerbrosidase that is effective to inhibit or treat the one or more symptoms associated with a deficiency of glucocerebrosidase in the human.   
     
     
         11 . The method of  claim 10  wherein the immune suppressant comprises cyclophosphamide, a glucocorticoid, cytostatic agents including an alkylating agent, an anti-metabolite, a cytotoxic antibiotic, an antibody, an agent active on immunophilin, a nitrogen mustard, nitrosourea, platinum compound, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, an anthracycline, mitomycin C, bleomycin, mithramycin, IL-2 receptor-(CD25-) or CD3-directed antibodies, anti-IL-2 antibodies, ciclosporin, tacrolimus, sirolimus, IFN-beta, IFN-gamma, an opioid, or a TNF-alpha (tumor cecrosis factor-alpha) binding agent. 
     
     
         12 . The method of  claim 10  wherein the rAAV vector and the immune suppressant are co-administered. 
     
     
         13 . The method of  claim 10  wherein the immune suppressant is administered after the rAAV vector. 
     
     
         14 . The method of  claim 10  wherein the rAAV vector is a rAAV-9 vector. 
     
     
         15 . The method of  claim 10  wherein the rAAV vector is rAAVrh10 vector. 
     
     
         16 . The method of  claim 10  wherein the immune suppressant is administered before the rAAV vector. 
     
     
         17 . The method of  claim 10  wherein the immune suppressant is systemically administered. 
     
     
         18 . A method to inhibit or treat one or more symptoms associated with a deficiency in glucocerebrosidase in a human, consisting of: providing a human with a deficiency in glucocerebrosidase that is immunotolerized to glucocerebrosidase; and administering to the cisterna magna of the human an amount of a rAAV vector comprising an AAV9 or AAVrh10 capsid encapsidating a rAAV genome having an open reading frame encoding glucocerebrosidase effective to inhibit or treat the one or more symptoms associated with the deficiency in glucocerebrosidase in the human. 
     
     
         19 . The method of  claim 18  wherein multiple doses of the rAAV vector are administered. 
     
     
         20 . The method of  claim 18  wherein the vector having the AAV9 capsid is administered. 
     
     
         21 . The method of  claim 18  wherein the vector having the AAVrh10 capsid is administered.