Wang Jiang-Hui, Zhan Wei, Gallagher Thomas L, Gao Guangping
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC 3002, Australia.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mol Ther. 2024 Dec 4;32(12):4185-4207. doi: 10.1016/j.ymthe.2024.10.017. Epub 2024 Oct 28.
Adeno-associated virus (AAV) has emerged as a leading platform for in vivo gene therapy, particularly in ocular diseases. AAV-based therapies are characterized by low pathogenicity and broad tissue tropism and have demonstrated clinical success, as exemplified by voretigene neparvovec-rzyl (Luxturna) being the first gene therapy to be approved by the U.S. Food and Drug Administration to treat RPE65-associated Leber congenital amaurosis (LCA). However, several challenges remain in the development of AAV-based gene therapies, including immune responses, limited cargo capacity, and the need for enhanced transduction efficiency, especially for intravitreal delivery to photoreceptors and retinal pigment epithelium cells. This review explores the biology of AAVs in the context of gene therapy, innovations in capsid engineering, and clinical advancements in AAV-based ocular gene therapy. We highlight ongoing clinical trials targeting inherited retinal diseases and acquired conditions, discuss immune-related limitations, and examine novel strategies for enhancing AAV vector performance to address current barriers.
腺相关病毒（AAV）已成为体内基因治疗的主要平台，尤其是在眼科疾病治疗方面。基于AAV的疗法具有低致病性和广泛的组织嗜性等特点，并已取得临床成功，例如voretigene neparvovec-rzyl（Luxturna）成为美国食品药品监督管理局批准的首个用于治疗RPE65相关的Leber先天性黑蒙（LCA）的基因疗法。然而，基于AAV的基因疗法的开发仍面临一些挑战，包括免疫反应、有限的载量能力，以及提高转导效率的需求，特别是对于玻璃体内递送至光感受器和视网膜色素上皮细胞而言。本综述探讨了基因治疗背景下AAV的生物学特性、衣壳工程的创新以及基于AAV的眼部基因治疗的临床进展。我们重点介绍了针对遗传性视网膜疾病和后天性疾病的正在进行的临床试验，讨论了免疫相关的局限性，并研究了增强AAV载体性能以克服当前障碍的新策略。
