Core Viewpoint - The article discusses the global consensus on gene therapy for hereditary hearing loss, marking a significant milestone in the field and providing a standardized framework for clinical applications [3][10][14]. Group 1: Consensus Development - The consensus was led by a team from Fudan University and involved 46 experts from various countries, taking over a year to develop [5][7]. - It was established using a modified Delphi method, resulting in 30 consensus statements covering key areas such as ethical review, patient selection, preoperative diagnosis, gene therapy delivery, postoperative follow-up, and auditory rehabilitation [7][14]. Group 2: Clinical Significance - According to WHO, over 430 million people globally suffer from disabling hearing loss, with genetic factors accounting for 60% of congenital hearing loss cases [10]. - The consensus aims to standardize clinical trials and patient management for gene therapy, particularly for OTOF-related hearing loss, and is expected to provide important references for clinicians, researchers, and regulatory bodies [15]. Group 3: Expert Opinions - Experts emphasized that this consensus represents a crucial step in establishing a unified framework for clinical trials in gene therapy for hearing loss, ensuring safety and scientific rigor [14]. - The consensus is seen as a potential game-changer in the treatment landscape for hereditary hearing loss, filling a significant gap in the guidance for gene therapy in this area [14][15].

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].

Core Viewpoint - The article discusses the significant advancements in gene therapy for hereditary hearing loss, particularly focusing on the OTOF gene and its implications for treatment effectiveness and safety [1][2][3]. Group 1: Gene Therapy Developments - Approximately 430 million people globally suffer from disabling hearing loss, with 26 million cases being congenital, 60% of which are linked to genetic susceptibility [1]. - Over 200 genes have been identified in relation to hereditary hearing loss, yet no approved drugs or therapies exist for treating genetic hearing loss [1]. - AAV-mediated gene replacement strategies and CRISPR-Cas gene editing technologies are the primary research directions in the field of gene therapy for hearing loss [1]. Group 2: Clinical Research Findings - In January 2024, a clinical study published in The Lancet demonstrated the safety and efficacy of AAV-mediated gene therapy in children with severe hearing impairment due to OTOF gene mutations [2]. - A subsequent study published in Nature Medicine in June 2024 confirmed the positive outcomes of bilateral gene therapy, reinforcing the initial findings [2]. - The physiological mechanisms involved in hearing recovery for DFNB9 patients include the restoration of inner ear hair cell synaptic vesicle release and the reorganization of central auditory pathways [2]. Group 3: Audiological Assessments - A study published in May 2025 analyzed audiological characteristics post-gene therapy in DFNB9 patients, providing critical data for evaluating treatment effectiveness [3]. - The assessment involved 10 patients, with evaluations using auditory brainstem response (ABR), auditory steady-state response (ASSR), pure tone audiometry (PTA), and distortion product otoacoustic emissions (DPOAE) [5]. - Results indicated significant improvements in hearing, with ABR showing clear V waves in all patients by 13 weeks post-treatment, and a notable reduction in V wave latency [6]. Group 4: Implications for Future Research - The study highlighted the correlation between PTA, ABR, and ASSR thresholds, validating their effectiveness as clinical assessment tools for hearing recovery [7]. - The findings suggest that while gene therapy restores inner ear hair cell function, it does not significantly impact outer hair cell function as measured by DPOAE [7]. - The combination of subjective (PTA) and objective (ABR, ASSR) assessment tools is recommended for comprehensive auditory evaluation, with further clinical validation needed to optimize treatment strategies and assess long-term effects [9].