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 . (canceled)
2 . A method to prevent, inhibit or treat one or more neurological symptoms in a human having a lysosomal storage disease, comprising administering to the human a composition comprising an effective amount of a recombinant adeno-associated virus (rAAV) vector comprising an open reading frame encoding a lysosomal storage enzyme, the expression of which in the human prevents, inhibits or treats the one or more symptoms, wherein the rAAV comprises an AAV-9 capsid or a rAAVrh10 capsid.
3 . The method of claim 2 wherein an immune suppressant is administered to the human.
4 . The method of claim 3 wherein the immune suppressant comprises cyclophosphamide.
5 . The method of claim 3 wherein the immune suppressant comprises a glucocorticoid, cytostatic agents including an alkylating agent, an anti-metabolite, a cytotoxic antibiotic, an antibody, or an agent active on immunophilin.
6 . The method of claim 3 wherein the immune suppressant comprises 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-P IFN-y, an opioid, or tumor necrosis factor-alpha binding agent.
7 . The method of claim 3 wherein the rAAV and the immune suppressant are co-administered or the immune suppressant is administered after the rAAV.
8 . The method of claim , wherein the immune suppressant s administered before the rAAV.
9 . The method of claim 3 wherein the immune suppressant is systemically, intrathecally or intracerebroventricularly administered.
10 . The method of claim 2 herein the rAAV comprises an AAV9 capsid.
11 . The method of claim 2 wherein the rAAV comprises an rhAAV10 capsid.
12 . The method of claim 2 wherein the rAAV is administered to the cisterna magna.
13 . The method of claim wherein the rAAV is systemically, endovascularly, intrathecally or intracerebroventricularlv administered.
14 . The method of claim 2 wherein neurodegeneration is prevented, inhibited or treated by the administration.
15 . The method of claim 2 wherein prior to administration the composition the human is immunotolerized to the enzyme.
16 . The method of claim 2 wherein the human has mucopolysaccharidosis type (I), mucopolysaccharidosis type (II), mucopolysaccharidosis type (III), Pompe Disease, Gaucher disease, Parkinson disease, or ceroid lipofuscinosis.
17 . The method of claim 2 wherein the enzyme is alpha-L-iduronidase, iduronate-2-sulfatase, heparan sulfate sulfatase, N-acetyl-alpha-D-glucosaminidase, beta-hexosaminidase, alpha-galactosidase, betagalactosidase, beta-glucuronidase, acid maltase or glucocerebrosidase.