Adenovirus-Mediated Gene Delivery Rescues a Neonatal Lethal Murine Model of mut0 Methylmalonic Acidemia

摘要: Methylmalonic acidemia (MMA), an autosomal recessive metabolic disorder, is most often caused by mutations in methylmalonyl-CoA mutase (MUT). Severely affected patients typically present with crisis the early neonatal period and can perish despite intervention. Survivors follow unstable course require elective liver transplantation to prevent life-threatening decompensation. Therapeutic alternatives such as hepatocyte-directed gene cell therapies lack experimental validation. We have used a murine model of mut0 MMA assess efficacy virus-mediated therapy rescue lethality seen Mut(-/-) mice. Affected pups control littermates received either intramuscular or intrahepatic injections adenovirus carrying Mut expressed under cytomegalovirus promoter. All injected via route perished within first 48 hr birth. However, more than 50% that survived beyond weaning (day 15). The treated mutants mRNA protein, displayed decreased metabolite levels compared uninjected results demonstrate adenovirus-mediated, hepatic expression from mortality provide proof-of-principle evidence for liver-directed delivery methylmalonic acidemia.