The central theme of this program (revised application) is the development of innovative gene therapy strategies, especially for metabolic disorders causing mental retardation. The program is highly focused on identifying and resolving the barriers to clinical gene therapy. In the re-organized program, three projects aim to exploit recent innovations that will enhance gene delivery and expression. Lentiviral gene therapy for mucopolysaccharidosis type I (Whitley) builds upon characterization of a """"""""true"""""""" murine knockout model of Hurler syndrome in which newborn treatment virtually """"""""cures"""""""" the pathologic features. Gene therapy for cerebellar ataxia (Mclvor) explores methods to inactivate a detrimental mutant gene in the brain. Sleeping Beauty transposon for gene therapy (Hackett) will evaluate a new, non-viral method of integrating therapeutic genes into mammalian chromosomes in vivo, aiming to optimize efficiency and safety. Institutional support for this program includes co-localization of project investigators in new, state-of-the-art laboratory facilities. These projects utilize a number of models of human metabolic disorders causing brain disease, notably, rodent models of mucopolysaccharidosis, ornithine transcarbamylase deficiency, and spinocerebellar ataxia. The program shares core facilities for administration (Whitley), microchemical synthesis and analysis (Brown), real-time quantitative PCR (Pan), hematopoietic stem cell processing (Miller), animal resources (Gillett), viral vector production (Mclvor), and neurological procedures and analysis (Low).
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