DMD基因治疗中AAV载体优化的研究进展

Advancements in AAV vector optimization for DMD gene therapy

杜氏肌营养不良症(Duchenne muscular dystrophy,DMD)是一种由抗肌萎缩蛋白(dystrophin)编码基因突变引起的进行性肌肉萎缩疾病,机体无法产生正常功能的dystrophin,最后由呼吸肌或心肌衰竭引发成年早期死亡。全身系统性基因治疗是最大程度治疗DMD的最有效方法。腺相关病毒(adeno-associated virus vector,AAV)是当前极具应用前景的基因治疗载体,在多种遗传性疾病的临床治疗中取得了前所未有的成功。然而,针对DMD的AAV载体基因治疗仍面临巨大挑战,包括无法容纳dystrophin全长编码序列,载体的肌肉靶向性不足且大量滞留在肝脏,AAV在体内大幅降解严重降低转导效率,机体对AAV衣壳蛋白产生免疫反应,AAV规模化制备的实施难度,以及安全性风险等。AAV载体优化旨在利用基因工程技术改变其相关特性以定制适用于DMD基因治疗的最佳载体。本文综述了AAV载体优化的方向及策略,以期跨越DMD基因治疗的障碍。

Duchenne muscular dystrophy(DMD)is a progressive muscle wasting disease caused by mutations in the gene encoding dystrophin,which prevents the body from producing functional dystrophin protein.Ultimately,respiratory or cardiac failure leads to early mortality in adulthood.Systemic gene therapy represents the most effective approach for treating DMD to the fullest extent.Adeno-associated virus(AAV)vectors are highly promising gene therapy vehicles and have achieved unprecedented clinical success in the treatment of various genetic disorders.However,AAV vector-based gene therapy for DMD still faces significant challenges,including the inability to accommodate the full-length dystrophin coding sequence,inadequate muscle targeting with substantial liver sequestration,substantial degradation and reduced transduction efficiency in vivo,immune responses against AAV capsid proteins,difficulties in large-scale AAV production,and safety concerns.Optimization of AAV vectors aims to utilize genetic engineering techniques to modify its relevant properties to tailor the optimal vector for DMD gene therapy.This review summarizes the directions and strategies for optimizing AAV vectors to overcome the barriers of DMD gene therapy.