METHOD FOR IMPROVING NEUROLOGICAL FUNCTION IN MPSI AND MPSII AND OTHER NEUROLOGICAL DISORDERS
A method to prevent, inhibit or treat one or more neurological symptoms associated with a central nervous system disorder, e.g. MPSI or MPSII by, for example, intrathecally, intracerebroventricularly or intravenously administering a rAAV encoding gene product associated with the disease, e.g., administering to an adult mammal in which the gene product is absent, defective or present at a reduced level relative to a mammal without the disease.
1 . A method to prevent or inhibit neurocognitive deterioration, to enhance neurocognition, or recover neurologic function in a mammal manifesting or at risk of having a disorder of the central nervous system, comprising: administering to the central nervous system of the mammal a composition comprising an amount of a recombinant adeno-associated virus (rAAV) vector comprising an open reading frame encoding a gene product effective to prevent or inhibit neurocognitive deterioration, enhance neurocognition, or recover neurologic function.
2 . The method of claim 1 wherein the mammal is a human.
3 . The method of claim 1 wherein the mammal is not an adult.
4 . The method of claim 2 wherein the human is about 6 to about 13 years old, about 4 months to about 5 years old or is less than 2.5 years old.
5 - 6 . (canceled)
7 . The method of claim 2 wherein the human has received a bone marrow transplant or enzyme replacement therapy.
8 . The method of claim 1 wherein the mammal has or is at risk of having mucopolysaccharoidosis type I (MPSI), mucopolysaccharoidosis type II (MPSII), spinal cord muscular atrophy, or Batten disease.
9 . The method of claim 1 wherein the open reading frame encodes IDUA, iduronate-2-sulfatase (IDS), survivor motor neuron-1 (SMN-1) or ceroid lipidfucinosis protein (CLN).
10 . The method of claim 1 wherein the amount reduces GAG levels in the brain or prevents or reduces hydroencephaly, decreases or prevents skeletal dysplasia or spinal cord compression, decreases hepatosplenomegaly or decreases cardiopulmonary obstruction.
11 - 14 . (canceled)
15 . The method of claim 1 wherein the mammal is treated with an immunosuppressant.
16 . The method of claim 15 wherein the rAAV and the immune suppressant are co-administered or the immune suppressant is administered after the rAAV.
17 . The method of claim 1 wherein the mammal is not immunotolerized prior to administration of rAAV.
18 . The method of claim 1 wherein the mammal is immunotolerized prior to administration of rAAV.
19 . The method of claim 1 wherein the mammal is immunocompetent.
20 . The method of claim 1 wherein the rAAV vector is a rAAV1, rAAV3, rAAV4, rAAV5, rAAVrh10, or rAAV9 vector.
21 . The method of claim 9 wherein the rAAV encoding iduronate-2-sulfatase further encodes sulfatase modifying factor 1.
22 - 25 . (canceled)
26 . The method of claim 1 wherein the rAAV is intrathecally, intracerebrovascularly or intravenously administered.
27 . The method of claim 1 wherein the rAAV is administered to the cisterna magna.
28 . The method of claim 15 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-β, IFN-γ, an opioid, or TNF-α (tumor necrosis factor-alpha) binding agent.
29 . The method of claim 1 wherein the amount of rAAV administered is about 1.3×10 10 GC/g brain mass to about 6.5×10 10 GC/g brain mass, about 1×10 13 to 5.6×10 13 GC (flat dose per mammal) or about 1×10 12 to about 5.6×10 13 GC (flat dose per mammal.
30 - 31 . (canceled)
32 . The method of claim 29 wherein the rAAV is intrathecally administered.