张子莲1 , 林坤章1 , 徐富强1 , 宋亚锋2,*
1中国科学院深圳先进技术研究院脑认知与脑疾病研究所,深圳市生物医药病毒载体重点实验室,国家 药品监督管理局细胞和基因治疗药物病毒载体技术研究与评价重点实验室,广东省药品监督管理局病毒治 疗制剂质控技术重点实验室,深圳 518055 2北京体育大学中国运动与健康研究院,北京 100084

摘 要:

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。

通讯作者:宋亚锋 ,

Advancements in AAV vector optimization for DMD gene therapy
ZHANG Zi-Lian1 , LIN Kun-Zhang1 , XU Fu-Qiang1 , SONG Ya-Feng2,*
1Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Key Laboratory of Cell and Gene Therapy Drug Viral Vector Technology Research and Evaluation, National Medical Products Administration, Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, Shenzhen- Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China 2China Institute of Exercise and Health, Beijing Sport University, Beijing 100084, China


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.

Communication Author:SONG Ya-Feng ,

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