RGD Reference Report - Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy. - Rat Genome Database

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Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy.

Authors: Chandler, Randy J  Venditti, Charles P 
Citation: Chandler RJ and Venditti CP, Mol Ther. 2010 Jan;18(1):11-6. doi: 10.1038/mt.2009.247. Epub 2009 Oct 27.
RGD ID: 13208535
Pubmed: PMID:19861951   (View Abstract at PubMed)
PMCID: PMC2839224   (View Article at PubMed Central)
DOI: DOI:10.1038/mt.2009.247   (Journal Full-text)

Methylmalonic acidemia (MMA) is an organic acidemia caused by deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). This disorder is associated with lethal metabolic instability and carries a poor prognosis for long-term survival. A murine model of MMA that replicates a severe clinical phenotype was used to examine the efficacy of recombinant adeno-associated virus (rAAV) serotype 8 gene therapy as a treatment for MMA. Lifespan extension, body weight, circulating metabolites, transgene expression, and whole animal propionate oxidation were examined as outcome parameters after gene therapy. One-hundred percent of the untreated Mut(-/-) mice (n = 58) died by day of life (DOL) 72, whereas >95% of the adeno-associated virus-treated Mut(-/-) mice (n = 27) have survived for > or = 1 year. Despite a gradual loss of transgene expression and elevated circulating metabolites in the treated Mut(-/-) mice, the animals are indistinguishable from unaffected control littermates in size and activity levels. These experiments provide the first definitive evidence that gene therapy will have clinical utility in the treatment of MMA and support the development of gene therapy for other organic acidemias.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Mmut  (methylmalonyl-CoA mutase)

Genes (Mus musculus)
Mmut  (methylmalonyl-Coenzyme A mutase)

Genes (Homo sapiens)
MMUT  (methylmalonyl-CoA mutase)


Additional Information