Efficacy and safety of OTOF-targeted gene therapy in patients with hereditary sensorineural hearing loss: a systematic review
DOI:
https://doi.org/10.70577/1sxb6220Keywords:
OTOF; DFNB9; gene therapy; sensorineural hearing loss; otoferlin.Abstract
Introduction: Hereditary sensorineural hearing loss associated with biallelic variants in the OTOF gene (DFNB9) impairs synaptic transmission in inner hair cells. Adeno-associated viral (AAV) gene therapy represents a targeted strategy to restore functional otoferlin expression. Objective: To evaluate the efficacy and safety of OTOF-targeted gene therapy in patients with DFNB9. Methods: A systematic review was conducted following PRISMA 2020. A total of 175 bibliographic records were identified in PubMed/MEDLINE, Europe PMC, and CENTRAL; after duplicate removal, 93 records underwent title and abstract screening. Eleven reports were assessed in full text and 10 met the inclusion criteria. Because of multiple publications and participant overlap, the reports were grouped into four independent interventional programs and one additional comparative investigation with possible participant overlap. Clinical and methodological heterogeneity precluded a global meta-analysis; therefore, narrative and tabular synthesis was performed. Results: The studies showed a consistent direction toward hearing recovery, with clinically relevant reductions in ABR and audiometric thresholds and improvements in speech perception and sound localization. Hearing benefits were maintained for up to 2.5 years in the longest available follow-up. ChiCTR2200063181, NCT05901480, and NCT05788536 were judged to have moderate risk of bias; NCT05821959 raised greater concerns because of the preliminary nature of the available evidence, whereas the comparative cohort had a serious risk of bias. The initial safety profile was favorable, although the number of exposed participants remains insufficient to characterize uncommon adverse events. Conclusions: OTOF-targeted gene therapy is associated with objective and functional hearing recovery in patients with DFNB9 and an initially favorable safety profile. However, interpretation of the evidence is limited by the small number of independent cohorts, the predominant absence of comparator groups, overlapping publications, and heterogeneous outcome reporting.
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