ADENO-ASSOCIATED VIRUS MEDIATED GENE TRANSFER TO THE CENTRAL NERVOUS SYSTEM
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.
1 . A method to inhibit or treat one or more symptoms associated with a deficiency of glucocerebrosidase in a mammal, comprising:
administering to a cisterna magna of the mammal in need thereof a composition comprising an amount of a recombinant adeno-associated virus (rAAV) 9 or rAAVrh10 vector comprising 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 mammal has Gaucher disease.
3 . The method of claim 1 , wherein the mammal has Parkinson disease.
4 . The method of claim 1 , wherein the mammal is an immunocompetent adult.
5 . The method of claim 1 , wherein the mammal is a human.
6 . The method of any one of claims 1 , wherein prior to administration of the composition the mammal is immunotolerized to glucocerebrosidase.
7 . The method of claim 1 wherein rAAV9 vector is administered. The method of claim 1 , wherein rAAVrh10 vector is administered.
9 . The method of claim 1 , further comprising administering to the mammal in need thereof an immune suppressant.
10 . The method of claim 9 , 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 ecrosis factor-alpha) binding agent.
11 . The method of claim 9 , wherein the rAAV vector and the immune suppressant are co-administered or the immune suppressant is administered after the rAAV vector.
12 . The method of claim 9 , wherein the rAAV vector is a rAAV-9 vector.
13 . The method of claim 9 wherein the rAAV vector is rAAVrh10 vector.
14 . The method of claim 9 , wherein the immune suppressant is administered before: rAAV9 or rAAVh10 vector.
15 . The method of claim 9 , wherein the immune suppressant is systemically administered.
16 . The method of claim 9 , wherein the mammal is a human.