A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

Reprogramming translation for rare disease therapy: challenges posed by large genes

A recent study published in Nature by Jiang et al. delineates a breakthrough in the treatment of inherited hearing loss through gene therapy. 1 This study offers the most compelling clinical evidence so far that gene replacement therapy can safely restore signi fi cant hearing in children with OTOF-related deafness, with bene fi ts lasting up to 2.5 years, setting a new standard for treating inherited sensory disorders. The bespoke cell and gene therapy approach is revolutionizing precision medicine for genetically diverse diseases. The OTOF gene encodes otoferlin, a transmembrane protein involved in signal transduction that functions as a calcium sensor for synaptic vesicle fusion within the inner hair cells of the cochlea. This gene was linked to hereditary deafness in 1999 by Christine Petit ’ s group. 2 Here, in pediatric patients with autosomal recessive deafness caused by OTOF mutations, dual adeno-associated virus (AAV) – mediated delivery of the OTOF transgene was developed. 3 As the OTOF gene ’ s coding sequence exceeds the packaging capacity of a single AAV vector, the study employed a dual-AAV1 vector strategy to reconstitute the full-length OTOF coding sequence under the control of a Myo15 promoter in vivo following cochlear delivery. 3 In the earlier reported clinical trial, about 75% of children met both behavioral pure-tone audiometry (PTA) and auditory brainstem response (ABR) criteria. 3 Across multiple clinical centers, treated children demonstrated substantial and durable improvements in auditory function, including the restoration of ABRs, enhanced speech perception, and signi fi cant gains in sound detection and communication skills. Importantly, therapeutic bene fi ts were observed relatively quickly after treatment and persisted during extended follow-up periods, indicating stable transgene expression and enduring cochlear rescue. 1 Younger patients generally exhibited the most pronounced outcomes, underscoring the

Restoration, Not Bypass: Otoferlin Gene Therapy and a New Era in Hearing Loss Treatment.

The FDA approval of Otarmeni, an AAV-based gene therapy for biallelic OTOF-associated sensorineural hearing loss, represents a conceptual shift in otology: from bypassing defective auditory physiology to restoring it. Unlike cochlear implantation, which circumvents damaged sensory structures, OTOF gene replacement targets a synaptic deficit in a structurally intact cochlea. Early clinical trial data are encouraging, with 75% of evaluable participants-children with molecularly confirmed biallelic OTOF variants enrolled in early-phase trials-achieving the primary hearing endpoint at 24 weeks. However, critical questions remain regarding long-term durability, the feasibility of redosing, and the surgical and logistical infrastructure required for intracochlear delivery. This commentary argues that otoferlin gene therapy initiates a new treatment hierarchy rather than rendering cochlear implantation obsolete: restore when biology permits, bypass when it does not. Realizing this potential will require advances in newborn genetic screening, workforce training, and equitable access to gene delivery.

Inner-Ear Gene Therapy for Hereditary Hearing Loss: A PubMed-Based Scoping Review of Published Human Studies and the Clinical Trial Registry Landscape

Gene therapy for hereditary hearing loss has entered early clinical translation, but human evidence remains limited. This scoping review mapped published human evidence and situated it within the broader clinical trial landscape. Following PRISMA-ScR, PubMed was searched on April 17, 2026, for peer-reviewed human studies of therapeutic gene transfer for hereditary hearing loss published from 2015 to 2026. Restriction to one bibliographic database is acknowledged, and the review is framed as a PubMed-based scoping review rather than a comprehensive multi-database synthesis. ClinicalTrials.gov, ICTRP, ChiCTR, and CTIS were also searched. Records were manually screened and deduplicated across registries. A primary reviewer screened titles and abstracts, and a second reviewer verified all full-text and registry inclusion decisions. PubMed yielded 129 records, of which six studies from three independent clinical programs were included. All targeted OTOF-related deafness using intracochlear dual-vector AAV systems. Three publications represented 11 unique participants from ChiCTR2200063181; two Otovia publications (NCT05901480) reported overlapping cohorts; and one publication reported the DB-OTO trial (NCT05788536). Overall, the evidence represented approximately 33 unique participants, not the publication-level total of 46. Auditory outcomes generally improved, but reporting was heterogeneous and follow-up was short. Registry searches yielded 632 raw records and nine unique interventional trials after screening and deduplication. Eight targeted OTOF, one targeted GJB2, and none targeted TMC1. Published evidence remains confined to early-phase studies of a single genetic subtype, whereas registry data indicate a broader, evolving landscape. Generalizability, target imbalance, and long-term safety remain unresolved.

Gene therapy for rare diseases marks a new era in precision medicine: Insights from clinical trials

Gene therapy represents an important advance in the treatment of rare diseases, offering precise and transformative therapeutic strategies. As many rare diseases are associated with well-defined genetic variants, they represent ideal candidates for targeted genetic interventions. The substantial unmet medical need associated with rare diseases has driven growing interest in gene therapy, with more than 300 clinical trials reported to date. The aim of this study was to evaluate the current evidence on gene therapy for rare diseases by examining therapeutic strategies, target diseases, clinical progress, clinical outcomes, and emerging research trends. Several approved therapies, including those for hemophilia B, spinal muscular atrophy, metachromatic leukodystrophy, and Wiskott–Aldrich syndrome, have demonstrated the clinical potential of gene therapy. Clinical evidence suggests that gene-based therapies in the management of rare diseases can achieve sustained functional benefits, reduce disease-related complications, and lessen dependence on long-term replacement or supportive treatments. However, challenges in ethical considerations, regulatory requirements, manufacturing complexity, treatment costs, and limited patient access remain. Continued clinical evaluation is essential to further establish long-term safety and effectiveness. Advances in gene therapy technologies and clinical applications continue to expand therapeutic opportunities for rare diseases while supporting the broader development of precision medicine.

Gene Therapy for Autism Spectrum Disorder: Preclinical Advances, Translational Barriers, and Ethical Dimensions - A Scoping Review.

BACKGROUND Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role. METHODS A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations. RESULTS Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials. CONCLUSIONS Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. Standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.

[Advances in research on the molecular mechanisms and gene therapy of hereditary hearing impairment].