Otoferlin Gene Therapy: Narrative Review for Ear and Hearing Special Issue: Gene Therapy for Hearing Loss

In the last decade, gene therapy has shown promise in treating many genetic disorders. Hereditary hearing impairment represents one of the next promising frontiers. Many initial development efforts have focused on hearing impairment caused by mutations in the otoferlin gene (OTOF), as these mutations cause profound deafness in the setting of preserved auditory outer hair cells, which often remain for many years after birth. Animal models have shown that the target cells for gene delivery, the inner hair cells, are also present and viable, and they reside in a structurally intact organ that is otherwise functional. Recent remarkable successes reported with OTOF gene therapy serve as proof of concept that gene therapy can effectively and safely improve hearing for this and likely other forms of genetic deafness. Here, the authors review the otoferlin protein and its role in hearing, the role of pathogenic variants in OTOF in hearing loss, the natural history of the condition, and the results of preclinical studies and of current human clinical trials of OTOF gene therapy.