Adeno-associated viruses (AAV) are being developed as vectors for human gene therapy. Although promising, important questions remain regarding the characteristics of recombinant AAV in authentic animal models of human diseases. One major question is whether AAV will function similarly in newborn compared to adult animals. Currently, little or no data have been generated in neonatal animals. For many genetic metabolic diseases, the highest degree of efficacy may be achieved early in development when irreversible damage could be avoided. It is also not clear whether AAV can be readministered, what the in vivo distribution is following intravenous administration to newborn animals or whether the levels of expression can impact on a disease. We have developed several novel AAV vectors for use in the lysosomal storage disease mucopolysaccharidosis type VII (MPS VII, beta-glucuronidase deficiency). These vectors efficiently transduce beta- glucuronidase deficient fibroblasts in vitro, and result in persistent, high-level expression in muscle and brain in intact mice with MPS VII. We have also developed techniques to manipulate and analyze neonatal MPS VII mice, and have developed assays to measure functional improvements following therapeutic interventions. The goals of this proposal are to determine the biochemical, clinical and immunologic consequences of AAV administration in neonatal MPS VII mice. We will accomplish these goals with the following specific aims: 1) We will determine the distribution, level and persistence and beta- glucuronidase expression following intravenous injection of AAV into newborn MPS VII mice. 2) We will determine the effects of lysosomal storage in neurons of the brain and on higher mental functions following intracranial injections of AAV in newborns MPS VII mice. 3) We will determine the effects of AAV injections in newborn MPS VII mice on the production of antibodies to beta-glucuronidase and on the readministration of the virus.
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