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https://hdl.handle.net/2440/95183
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Type: | Journal article |
Title: | Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector |
Author: | Wong, E. McIntyre, C. Peters, H. Ranieri, E. Anson, D. Fletcher, J. |
Citation: | Human Gene Therapy, 2014; 25(6):529-538 |
Publisher: | Mary Ann Liebert |
Issue Date: | 2014 |
ISSN: | 1557-7422 1043-0342 |
Statement of Responsibility: | Edward S.Y. Wong, Chantelle McIntyre, Heidi L. Peters, Enzo Ranieri, Donald S. Anson, and Janice M. Fletcher |
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. |
Keywords: | Liver Animals Mice, Knockout Humans Lentivirus Amino Acid Metabolism, Inborn Errors Methylmalonic Acid Methylmalonyl-CoA Mutase Codon Genetic Engineering Gene Expression Genetic Vectors Female Male HEK293 Cells Genetic Therapy |
Rights: | © Mary Ann Liebert |
DOI: | 10.1089/hum.2013.111 |
Published version: | http://dx.doi.org/10.1089/hum.2013.111 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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