Hearing Loss Genes Evaluated as Candidates for Therapy

Clinical Question

What does an evaluation of 93 nonsyndromic hearing loss genes show about their comparative favorability for treatment by gene therapy approaches?

Bottom Line

Hearing loss genes vary widely in treatment favorability; thus, targeting development efforts to promising candidates will ensure the highest likelihood of clinical success. Several genes were identified as appealing targets.

Background: Roughly half of childhood-onset sensorineural hearing loss is genetic, caused by mutations in many different genes that affect a variety of molecular pathways. Advances in gene therapy techniques have led to the first clinical trials for OTOF-associated hearing loss DFNB9, and therapies for other hearing loss genes are in development.

Study design: Systematic review

Setting: Departments of Genome Sciences and Medicine, University of Washington, Seattle

Synopsis: Noting the recent effectiveness of clinical trials using dual-vector adeno-associated virus-based gene replacement techniques in treating OTOF-associated hearing loss DFNB9, researchers set out to help prioritize and guide efforts in developing more gene therapies for hearing loss. They compiled a list of 93 nonsyndromic hearing loss genes. Each gene was evaluated according to the following factors: gene size, timing of cochlear degradation, cell type(s) of primary expression, availability of mouse models and efficacy of adeno-associated virus experiments in those mice, and human hearing loss severity, onset, and prevalence. Favorable results indicated the most promising candidates for gene therapy. Genes that satisfied all the conditions included TMPRSS3, PCDH15, and TMC1, which have all been identified by the field and undergone gene replacement attempts. Other genes, which included LOXHD1 and MYO6, also satisfied all conditions and were identified as promising candidates, but had not yet been used in gene replacement attempts in a mouse model. Authors emphasize the genetic heterogeneity behind human hearing loss and thus the need for all four approaches in gene therapy currently in preclinical use: gene replacement, gene silencing, splicing alteration, and gene editing.

Citation: Carlson RJ, et al. Gene therapy for hearing loss: which genes next? Otol Neurotol. 2025;46:239-247. doi:10.1097/MAO.0000000000004423.

Comment: Readers may be interested in an update on where we stand with gene therapy for hearing loss. There’s some exciting preliminary data surrounding the otoferlin clinical trial. This review paper examines 93 nonsyndromic hearing loss genes and the rationale for the next potential target genes. Ana H. Kim, MD