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Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, MD 20892, USA.
Human gene therapy (Impact Factor: 3.62). 09/2010; 21(9):1147-54. DOI: 10.1089/hum.2010.008
Source: PubMed

ABSTRACT Methylmalonic acidemia is a severe metabolic disorder caused by a deficiency of the ubiquitously expressed mitochondrial enzyme, methylmalonyl-CoA mutase (MUT). Liver transplantation has been used to treat a small number of patients with variable success, and whether liver-directed gene therapy might be employed in such a pleiotropic metabolic disorder is uncertain. In this study, we examined the therapeutic effects of hepatocyte-directed delivery of the Mut gene to mice with a severe form of methylmalonic acidemia. We show that a single intrahepatic injection of recombinant adeno-associated virus serotype 8 expressing the Mut gene under the control of the liver-specific thyroxine-binding globulin (TBG) promoter is sufficient to rescue Mut(-/-) mice from neonatal lethality and provide long-term phenotypic correction. Treated Mut(-/-) mice lived beyond 1 year of age, had improved growth, lower plasma methylmalonic acid levels, and an increased capacity to oxidize [1-(13)C]propionate in vivo. The older treated mice showed increased Mut transcription, presumably mediated by upregulation of the TBG promoter during senescence. The results indicate that the stable transduction of a small number of hepatocytes with the Mut gene can be efficacious in the phenotypic correction of an inborn error of organic acid metabolism and support the rapid translation of liver-directed gene therapy vectors already optimized for human subjects to patients with methylmalonic acidemia.

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Available from: Randy J. Chandler, Aug 19, 2015
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    • "Neither the elimination of transgene expression nor the impaired mitochondrial importation and processing of the human MUT protein is suggested by our studies. The fact that circulating metabolite concentrations and in vivo propionate oxidative capacity in the AAV treated Mut −/− mice is almost exactly what we previously observed in studies using AAVs that expressed the murine cDNA provide support for this claim [5] [6]. While the presence of antibodies against MUT was not directly investigated, the prolonged survival after treatment suggests the absence of an immune response. "
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    ABSTRACT: We demonstrate that human methylmalonyl-CoA mutase (MUT), delivered using an AAV serotype 8 vector, rescues the lethal phenotype displayed by mice with MMA and provides long-term phenotypic correction. In addition to defining a lower limit of effective dosing, our studies establish that neither a species barrier to mitochondrial processing nor an apparent immune response to MUT limits the murine model as an experimental platform to test the efficacy of human gene therapy vectors for MMA. Published by Elsevier Inc.
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    • "We have previously demonstrated rescue of a neonatal lethal murine model of methylmalonic acidemia (MMA) for over 18 months using AAV8 gene transfer (Carrillo-Carrasco et al., 2010; Chandler and Venditti, 2010). MMA is an organic acidemia caused by deficient activity of methylmalonyl-CoA mutase (MUT), an enzyme also needed for the conversion of propionyl-CoA to succinyl-CoA, and has a neonatal phenotype very similar to PA, in both patients and knock-out mice. "
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