Aug 2026· Current Opinion in Otolaryngology & Head and Neck Surgery· 0 citations· 28 references
Medicine
TL;DR
The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice.
Abstract
Purpose
OF REVIEW
Hereditary hearing loss has historically been approached as a diagnostic category rather than a therapeutically modifiable disease. Recent advances in molecular genetics, cochlear gene delivery, and first-in-human clinical trials are changing that. This review summarizes contemporary progress in the genetics of hearing loss, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice.
RECENT
Findings
Early clinical trials targeting OTOF-related DFNB9 deafness have demonstrated satisfactory safety profiles and meaningful auditory recovery, establishing the first proof-of-concept for cochlear gene therapy in humans, culminating in the April 2026 FDA approval of Otarmeni. Genetic diagnoses are increasingly informing prognosis, cochlear implant counseling, and therapeutic candidacy. Preclinical research continues to expand toward recessive, dominant, and syndromic hearing loss using gene replacement, antisense, RNA interference, and genome-editing strategies. Substantial challenges remain, including heterogeneous outcome measures, uncertain long-term efficacy, regulatory complexity, and inequitable global access.
SUMMARY
The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one. Widespread clinical impact will require advances in vector engineering, equitable implementation, multidisciplinary counseling, and integration with established rehabilitation pathways. For otolaryngologists, genetic literacy is becoming essential to contemporary hearing care.
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.
B. Pattnaik, Jose-Alein Sahel· Signal Transduction and Targ...· 0 citations
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.
J. Selvasingh, Justin R. Shinn· Otolaryngology Head & Neck S...· 0 citations
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.
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.
S. Suprianto, Y. Messe, Raehan AH. Hamzah et al.· Narra X· 0 citations
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.
Ali Naderi Malek, Amir Hossein Rasoli Jokar, Patricia Prelock· Neuropsychobiology· 0 citations
Recent advances in the molecular mechanisms, immune microenvironment involvement, and gene therapy strategies for hereditary hearing impairment are summarized, which delineates the research trajectory from gene discovery and mechanistic elucidation to therapeutic development, and discusses future translational research directions and clinical challenges.
X. Yang, Y. Q. Gao, L. Huang et al.· Zhonghua yu fang yi xue za z...· 0 citations
