title: Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector.
abstract: Methylmalonic aciduria is a rare disorder of organic acid metabolism with limited therapeutic options, resulting in high morbidity and mortality. Positive results from combined liver/kidney transplantation suggest, however, that metabolic sink therapy may be efficacious. Gene therapy offers a more accessible approach for the treatment of methylmalonic aciduria than organ transplantation. Accordingly, we have evaluated a lentiviral vector-mediated gene transfer approach in an in vivo mouse model of methylmalonic aciduria. A mouse model of methylmalonic aciduria (Mut(-/-)MUT(h2)) was injected intravenously at 8 weeks of age with a lentiviral vector that expressed a codon-optimized human methylmalonyl coenzyme A mutase transgene, HIV-1SDmEF1αmurSigHutMCM. Untreated Mut(-/-)MUT(h2) and normal mice were used as controls. HIV-1SDmEF1αmurSigHutMCM-treated mice achieved near-normal weight for age, and Western blot analysis demonstrated significant methylmalonyl coenzyme A enzyme expression in their livers. Normalization of liver methylmalonyl coenzyme A enzyme activity in the treated group was associated with a reduction in plasma and urine methylmalonic acid levels, and a reduction in the hepatic methylmalonic acid concentration. Administration of the HIV-1SDmEF1αmurSigHutMCM vector provided significant, although incomplete, biochemical correction of methylmalonic aciduria in a mouse model, suggesting that gene therapy is a potential treatment for this disorder.
authors.affiliation: 1 Genetics and Molecular Pathology, Women's and Children's Hospital , North Adelaide, SA 5006, Australia .
authors.forename: Edward S Y
authors.initials: ES
authors.lastname: Wong
authors.forename: Chantelle
authors.initials: C
authors.lastname: McIntyre
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Peters
authors.forename: Enzo
authors.initials: E
authors.lastname: Ranieri
authors.forename: Donald S
authors.initials: DS
authors.lastname: Anson
authors.forename: Janice M
authors.initials: JM
authors.lastname: Fletcher
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000628:therapy* / Q000652:urine; D000818:Animals; D003062:Codon; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood / Q000652:urine; D008765:Methylmalonyl-CoA Mutase / Q000096:biosynthesis / Q000235:genetics*; D018345:Mice, Knockout
chemical_list: D003062:Codon; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase