Lysosomal storage diseases are progressive heritable disorders usually caused by deficiencies in lysosomal enzymes. We recently showed that systemic and tissue-directed delivery of recombinant adeno-associated virus (AAV) in neonatal mice with the lysosomal storage disease mucopolysaccharidosis type VII (MPS VII) results in persistent (16 week) beta-glucuronidase (GUSB) expression. The level of expression reduces lysosomal storage in multiple tissues including the central nervous system (CNS). We will now determine if neonatal gene therapy can result in improvements in auditory, visual, cognitive and immune functions. Since these diseases are progressive in nature, it is of interest to determine if in utero gene therapy for LSDs is more efficacious than neonatal therapy. Finally, it has yet to be determined if functional improvements can be achieved in a setting where lysosomal storage is well established, and the clinical defects are present. The goals of this proposal are to determine the consequences of neonatal, in utero and adult AAV-mediated gene transfer in the murine model of MPS VII. We will accomplish these goals with the following specific aims: 1. We will determine the long term clinical effects of systemic and liver-directed AAV-mediated gene transfer in neonatal MPS VII mice. 2. We will determine the effects of direct gene transfer to the brain and eye in young adult MPS VII mice with established disease. 3. We will characterize AAV-mediated in utero gene therapy. A) We will determine the efficacy of in utero gene therapy in the MPS VU mouse. B) We will determine whether in utero gene transfer reduces the immune response to repeated AAV injections in immunocompetent mice.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Medical Biochemistry Study Section (MEDB)
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Mckeon, Catherine T
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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