METHODS FOR PREVENTING CARDIAC OR SKELETAL DEFECTS IN DISEASES INCLUDING MUCOPOLYSACCHARIDOSES
A method to prevent, inhibit the progression of, reduce the severity of, or treat cardiac, vascular or skeletal dysfunction or defect(s) in a human having lysosomal storage disorder, is provided.
1 . A method to prevent, inhibit the progression of, reduce the severity of, or treat cardiac, vascular
or skeletal dysfunction or defect(s) in a human having lysosomal storage disorder, comprising: administering to the human a first composition comprising an effective amount of a first recombinant adeno-associated virus (rAAV) vector comprising an open reading frame encoding a
first gene product and optionally a second composition comprising an amount of a second rAAV vector comprising an open reading frame encoding a second gene product, wherein if the first and second compositions are administered, they are administered via different routes.
2 . The method of claim 1 wherein the amount reduces cardiac valve dysfunction, coronary artery abnormalities, myocardial abnormalities, conduction system abnormalities, or aortic root dilation.
3 . The method of claim 1 wherein the amount decreases skeletal abnormalities.
4 . The method of claim 1 wherein the amount increases skull width, cross-sectional moment of inertia (MOM) or bone stiffness.
5 . The method of claim 1 wherein the first and the second compositions are administered.
6 . The method of claim 5 wherein the first and the second gene products are the same.
7 . The method of claim 5 wherein one of the routes is intravenous or intrathecal administration.
8 . (canceled)
9 . The method of claim 5 wherein the first and second compositions are concurrently administered.
10 . The method of claim 5 wherein the first composition is administered before the second composition or the first composition is administered after the second composition.
11 - 12 . (canceled)
13 . The method of claim 1 wherein the mammal is not immunotolerized prior to administration of at least one of the rAAVs.
14 . The method of claim 1 wherein the human is immunotolerized prior to administration of rAAV.
15 . The method of claim 1 wherein at least one of the rAAV vectors is a rAAV1, rAAV3, rAAV4, rAAV5, rAAVrh10, or rAAV9 vector.
16 . The method of claim 1 wherein the rAAV encodes alpha-L-iduronidase, iduronate-2-sulfatase, heparan sulfate sulfatase, N-acetyl-alpha-D-glucosaminidase, beta-hexosaminidase, alpha-galactosidase, betagalactosidase, beta-glucuronidase, or glucocerebrosidase
17 . The method of claim 1 wherein the human is less than 5 years old.
18 . The method of claim 1 wherein at least one of the rAAVs has an AAV9 or AAVrh10 capsid.
19 . The method of claim 1 wherein the first and the second rAAVs have different capsids.
20 . The method of claim 5 wherein the first composition is intravenously administered and the second composition is intrathecally administered
21 - 24 . (canceled)
25 . The method of claim 1 wherein the amount of rAAV administered is about 0.5×10 10 to 4×10 11 genome copies (GC)/g brain tissue for intrathecal administration.
26 . The method of claim 1 wherein the amount of rAAV administered is about 0.5×10 11 to 2×10 12 genome copies (GC)/kg of the human.