357. A Mouse Model of Cobalamin A (cblA) Class Isolated Methymalonic Academy (MMA) Provides Unique Platform for Testing Gene and Cell Therapies

作者：Madeline Epping, Irini Manoli, Cindy Wang, Pat Zerfas, Victoria Hoffmann, Gene Elliott, Lingli Li, Chuck Venditti · 发表于：Molecular Therapy · 年份：2016 · DOI：10.1016/s1525-0016(16)33166-5 · 研究领域：Metabolism and Genetic Disorders、Folate and B Vitamins Research、RNA modifications and cancer

Isolated Methylmalonic Acidemia (MMA) comprises a relatively common and heterogeneous group of inborn errors of metabolism. Most affected individuals display severe multisystemic disease with episodes of metabolic instability, chronic renal disease, and neurological complications. The most severe clinical presentations are typically associated with complete loss of methylmalonyl-CoA mutase (MUT) enzymatic activity. MUT converts methylmalonyl-CoA to succinyl-CoA within mitochondria but defects in the transport or synthesis of its cobalamin co-factor also variably impair MUT activity. Previous mouse models of Mut MMA generated by our group have been critical to developing gene therapy for MMA but have either displayed neonatal lethality or required concomitant transgenesis for viability. Thus, the need for ameliorated models to further investigate disease-associated pathophysiology and facilitate gene therapy studies exists. We have therefore constructed a mouse model of an attenuated form of isolated MMA, the cblA subtype, by using homologous recombination to create a deletion allele of Mmaa, the enzyme that performs the gated transfer of adenosylcobalamin to Mut and protects Mut from oxidative inactivation. Patients with the cblA subtype of MMA can have variable presentations, spanning the full spectrum of MMA associated symptoms and pathology, yet always harbor an element of clinical and biochemical responsiveness to injectable B12. Mmaa-/- mice were born in mendelian propor...