Wong Edward S Y, McIntyre Chantelle, Peters Heidi L, Ranieri Enzo, Anson Donald S, Fletcher Janice M
1 Genetics and Molecular Pathology, Women's and Children's Hospital , North Adelaide, SA 5006, Australia .
Hum Gene Ther. 2014 Jun;25(6):529-38. doi: 10.1089/hum.2013.111. Epub 2014 Apr 2.
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.
甲基丙二酸尿症是一种罕见的有机酸代谢紊乱疾病，治疗选择有限，导致高发病率和死亡率。然而，肝肾联合移植的阳性结果表明，代谢汇疗法可能有效。与器官移植相比，基因治疗为甲基丙二酸尿症的治疗提供了一种更易实现的方法。因此，我们在甲基丙二酸尿症的体内小鼠模型中评估了慢病毒载体介导的基因转移方法。在8周龄时，给甲基丙二酸尿症小鼠模型（Mut(-/-)MUT(h2)）静脉注射一种表达密码子优化的人甲基丙二酰辅酶A变位酶转基因的慢病毒载体HIV-1SDmEF1αmurSigHutMCM。未治疗的Mut(-/-)MUT(h2)小鼠和正常小鼠用作对照。经HIV-1SDmEF1αmurSigHutMCM治疗的小鼠体重接近同龄正常水平，蛋白质免疫印迹分析表明其肝脏中有显著的甲基丙二酰辅酶A酶表达。治疗组肝脏甲基丙二酰辅酶A酶活性的正常化与血浆和尿液中甲基丙二酸水平的降低以及肝脏中甲基丙二酸浓度的降低有关。给予HIV-1SDmEF1αmurSigHutMCM载体对小鼠模型中的甲基丙二酸尿症提供了显著的、尽管不完全的生化纠正，这表明基因治疗是这种疾病的一种潜在治疗方法。
