Cell系列综述：舒易来团队等系统总结耳聋治疗的范式转变——临床基因治疗恢复听力

Core Viewpoint - The article discusses the groundbreaking advancements in gene therapy for hereditary hearing loss, particularly focusing on the OTOF gene mutation and its clinical trials, marking a significant paradigm shift in treatment approaches [5][8][54]. Group 1: Gene Therapy Developments - Adeno-associated virus (AAV)-based gene therapy strategies have shown effectiveness in animal models for over 20 genetic mutations causing hereditary deafness [5]. - In 2022, Fudan University completed the world's first clinical trial for genetic therapy of hereditary deafness in Shanghai, establishing a clinical framework for treating congenital hearing loss [5][10]. - As of 2023-2025, seven additional clinical trials targeting OTOF gene mutations have been registered across eight countries, with five trials reporting successful hearing restoration through dual AAV delivery strategies [5][8]. Group 2: Clinical Trial Insights - Eight clinical trials for autosomal recessive deafness type 9 (DFNB9) have been registered in 51 centers across eight countries, accelerating the development of auditory gene therapy [8][10]. - The first DFNB9 gene therapy case was reported in December 2022, with subsequent trials confirming hearing improvement in various patient demographics [13][33]. - The trials face challenges such as precise surgical delivery methods and the establishment of standardized patient selection criteria [14][56]. Group 3: Technical Aspects of Gene Delivery - AAVs are preferred for inner ear gene delivery due to their efficient cochlear transduction and low immunogenicity [16]. - Various AAV serotypes have been tested for their ability to transduce inner hair cells effectively, with non-human primate studies showing promising results [16][17]. - The gene therapy strategies include both gene replacement and gene editing approaches, with ongoing research into optimizing delivery methods and ensuring safety [18][20]. Group 4: Clinical Trial Challenges and Future Directions - The clinical trials for DFNB9 gene therapy face significant challenges, including the anatomical complexity of the inner ear and the need for rigorous safety and efficacy assessments [14][30]. - Future strategies must address the optimization of treatment protocols, including patient age and severity of hearing loss, to maximize therapeutic benefits [55][56]. - The article emphasizes the importance of establishing standardized follow-up protocols to monitor long-term outcomes and potential risks associated with gene therapy [52][56].