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 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.