Gene Therapy Using Recombinant Adeno-Associated Virus for Leber Congenital Amaurosis Induced by RPE65 Mutation

Iman Owliaee,1 Ali Teimoori,1 Mohammad Shoushtari,2 Ali Shojaeian3 1Department of Medical Virology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; 2Department of Virology, Pasteur Institute of Iran, Tehran, Iran; 3Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, IranCorrespondence: Ali Shojaeian, Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran, Tel +989397533875, Email ali.shojaeian65@gmail.com Mohammad Shoushtari, Department of Virology, Pasteur Institute of Iran, Tehran, Iran, Tel +98-21-66953311 Ext. No.2251, Email mb.shoushtari@gmail.comAbstract: Gene therapy using recombinant adeno-associated virus (AAV) vectors has emerged as a promising approach for treating genetic disorders, including Leber congenital amaurosis 2 (LCA-2) induced by RPE65 mutation, a severe form of inherited retinal dystrophies (IRDs). This review provides recent advancements, methodological strategies, and therapeutic aims related to AAV vector-mediated retinal gene therapy for LCA-2 induced by RPE65 mutation. The literature search was performed using the PubMed, Scopus, and Web of Science databases, focusing on studies that examine gene therapy as a potential therapeutic strategy for LCA-2 by introducing functional copies of the RPE65 gene into affected cells. Due to their ability to efficiently deliver therapeutic genes without significant immune responses or mutagenesis events, AAV vectors have shown efficacy in restoring retinal and visual functions in animal models of LCA-2. Advancements in molecular biology and retinal surgery have enabled clinical studies and trials for gene therapy in LCA-2, providing a foundation for further research and improving treatment outcomes. While there is currently no known cure for IRDs, treatments such as vitamin supplementation, gene therapy, and assistive devices can help manage symptoms and slow disease progression. Ongoing clinical trials are investigating novel therapies, including stem cell therapy and gene editing technologies, to expand treatment options for IRDs. The favorable safety profile and proven efficacy of AAV vectors, combined with their capacity for sustained transgene expression, position them as ideal vehicles for ocular gene therapy applications. However, immune responses and off-target effects must be addressed carefully.Keywords: RPE65, AAV, IRDs, gene therapy, gene editing