PDF(Pubmed)
Abstract：
Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disorder caused by a deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), with accumulation of neurotoxic metabolites, resulting in a complex movement disorder, irreversible brain damage, and premature death in untreated individuals. While early diagnosis and a lysine restricted diet can extend survival, they do not prevent neurological damage in approximately one-third of treated patients, and more effective therapies are required. Here we report the efficacy of adeno-associated virus 9 (AAV9)-mediated systemic delivery of human GCDH at preventing a high lysine diet (HLD)-induced phenotype in Gcdh -/- mice. Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. This treatment protects the mice from HLD-aggressive phenotype with all mice surviving this exposure; in stark contrast, a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. Magnetic resonance imaging findings show protection against striatal injury. Altogether, these results provide preclinical evidence to support AAV-GCDH gene therapy for GA1.
摘要：
1型戊二酸尿症（GA1）是一种罕见的遗传性代谢紊乱，由戊二酰辅酶A脱氢酶（GCDH）缺乏引起，随着神经毒性代谢物的积累，导致复杂的运动障碍，不可逆的脑损伤,以及未经治疗的个体过早死亡。虽然早期诊断和赖氨酸限制饮食可以延长生存期，它们不能防止大约三分之一接受治疗的患者的神经损伤，需要更有效的治疗方法。在这里，我们报道了腺相关病毒9（AAV9）介导的人GCDH全身递送在预防高赖氨酸饮食（HLD）诱导的Gcdh-/-小鼠表型中的功效。使用AAV-GCDH的新生儿治疗可恢复肝脏和纹状体中的GCDH表达和酶活性。这种治疗可以保护小鼠免受HLD侵袭性表型的影响，所有小鼠都能在这种暴露中幸存下来；与之形成鲜明对比的是，缺乏对HLD的治疗会引发非常高的戊二酸积累，3-羟基戊二酸,和组织中的戊二酰肉碱，大约60%的死亡是由于大脑中积累了有毒的赖氨酸代谢物。AAV-GCDH显着改善纹状体神经病理学，减少神经元功能障碍，胶质增生,和髓鞘形成的改变。磁共振成像发现显示对纹状体损伤的保护作用。总之,这些结果为支持AAV-GCDH基因治疗GA1提供了临床前证据.
