Gene Therapy for Hearing Loss: Which Genes Next?

Hearing loss is the most common sensory deficit in humans, and roughly half of childhood-onset sensorineural hearing loss is genetic. Advances in gene therapy techniques have led to the first clinical trials for OTOF-associated hearing loss DFNB9. Therapies for other hearing loss genes are in various stages of development, and therefore a comprehensive evaluation of potential candidate genes can help to prioritize and guide these efforts.

A list of 93 nonsyndromic hearing loss genes with consensus support was generated. Critical factors for evaluation were identified as 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. Each factor was addressed with gene-specific PubMed searches for applicable studies.

Each gene was evaluated according to the above factors, with favorable results indicating the most promising candidates for gene therapy. Genes that satisfied all the above conditions included TMPRSS3, PCDH15, and TMC1. Other genes, such as LOXHD1 and MYO6, had not yet had gene replacement attempts in a mouse model but otherwise satisfied all conditions and were likewise identified as promising candidates.

Based on this analysis, hearing loss genes vary widely in terms of their favorability for treatment by gene therapy approaches. Targeting development efforts to promising candidates will ensure the highest likelihood of clinical success. Several genes were identified as appealing next targets, signaling an increasing role of gene therapies in hearing loss care moving forward.