Syndrome (SIDS) or with a combined cardiac and skeletal myopathy. Treatment of these disorders has consisted primarily of dietary manipulation and has been far less than optimal to this point. The recent development of recombinant adeno-associated virus (rAAV) vectors for highly efficient transduction of hepatocytes and myofibers present new tools for the study of FAO disorders. Specifically, our laboratory has produced rAAV vectors expressing FAO enzymes whose deficiency results in myopathy, such as short-chain acyl CoA dehydrogenase (SCAD) and long-chain acyl CoA dehydrogenase (LCAD). Human cell lines from patients deficient in these enzymes are available, and mutant mouse models exist for both of these disorders. We propose to utilize rAAV vectors expressing FAO enzymes in an attempt to unravel the pathobiology of FAO disorders and to better define endpoints for molecular or cell-based therapies of these disorders. This will be accomplished in three specific aims: (1) To assess the extent to which genetic correction of a limited percentage of SCAD deficient or LCAD deficient cells within a cell population or organ can affect biochemical correction of fatty acid oxidation. (2) To determine whether receptor binding and entry are limiting steps for stable transduction by rAAV in a intact mammalian liver or muscle bundle. (3) To test the hypothesis that the liver pathology observed in LCAD and VLCAD deficiencies are secondary to the accumulation of toxic metabolites as opposed to primary energy failure within hepatocytes. (4) To determine whether global phenotypic correction of FAO deficiency in mice is more effective after widespread vector delivery after intrauterine or neonatal IV injection. The information gained from these studies could also be used to guide the feasibility of other organ-directed therapies, potentially including stem cell transplantation.
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