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 a 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.
5 . The method of claim 2 wherein the human about 4 months to about 5 years old.
6 . The method of claim 2 wherein the human is less than 2.5 years old.
7 . The method of claim 1 any one of claims 2 to 6 wherein the human has received a bone marrow transplant or enzyme rep
8 . The method of claim 1 wherein the mammal has or is at risk if 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 9 wherein the amount reduces GAG levels in the brain or prevents or reduces hydroencephaly.
11 . The method of claim 1 wherein the amount decreases or prevents skeletal dysplasia or spinal cord compression, decreases hepatosplenomegaly or cardiopulmonary obstructions.
12 - 19 . (canceled)
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 . The method of claim 9 further comprising administering an rAAV encoding sulfatase modifying factor 1 in conjunction with the rAAV encoding iduronate-2-sulfatase.
23 - 24 . (canceled)
25 . The method of claim 1 wherein the rAAV is rAAV9 or rAAVrh10.
26 . The method of claim 1 wherein the rAAV is intrathecally, intracerebrovascularly or intravenously administered.
27 . (canceled)
28 . The method of claim 1 wherein the mammal is administered an immune suppressant optionally comprising 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, all 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.
30 . The method of claim 1 wherein the amount of rAAV administered is about 1×10 13 to 5.6×10 13 GC (flat dose per mammal).
31 . The method of claim 1 wherein the amount of rAAV administered is about 1×10 12 to about 5.6×10—GC (flat dose per mammal).
32 . (canceled)