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: Edward S Y Wong, Chantelle McIntyre, Heidi L Peters, Enzo Ranieri, Donald S Anson, Janice M Fletcher
• Journal: Human gene therapy (Hum Gene Ther) Vol. 25 Issue 6 Pg. 529-38 (Jun 2014) ISSN: 1557-7422 [Electronic] United States
• PMID: 24568291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon
• Methylmalonic Acid
• Methylmalonyl-CoA Mutase

Topics

• Amino Acid Metabolism, Inborn Errors (blood, therapy, urine)
• Animals
• Codon
• Female
• Gene Expression
• Genetic Engineering
• Genetic Therapy
• Genetic Vectors
• HEK293 Cells
• Humans
• Lentivirus (genetics)
• Liver (enzymology)
• Male
• Methylmalonic Acid (blood, urine)
• Methylmalonyl-CoA Mutase (biosynthesis, genetics)
• Mice, Knockout