Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction.
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.
Carrillo-Carrasco
Nuria
N
Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, MD 20892, USA.
Chandler
Randy J
RJ
Chandrasekaran
Suma
S
Venditti
Charles P
CP
D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007267:Injections; D008099:Liver / Q000378:metabolism*; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D009928:Organ Specificity; D010641:Phenotype; D011995:Recombination, Genetic / Q000235:genetics*; D016019:Survival Analysis; D013975:Thyroxine-Binding Proteins / Q000378:metabolism; D013997:Time Factors
D013975:Thyroxine-Binding Proteins; D008765:Methylmalonyl-CoA Mutase