Gene therapy for hereditary deafness: Progress, challenges and translational implications from OTOF to GJB2

Abstract

Hereditary deafness is a common sensory disorder in infants and children. Gene therapy has achieved major clinical breakthroughs in OTOF ‐related deafness, establishing proof of concept for treating monogenic hearing loss. In contrast, GJB2 ‐related hearing loss remains more challenging because of its broad cochlear expression, complex supporting‐cell targets, developmental involvement, and narrow therapeutic window. We reviewed recent advances in hereditary deafness gene therapy, focusing on the translational progression from OTOF to GJB2 . We summarize early inner‐ear gene‐therapy efforts, clinical and preclinical developments in OTOF ‐targeted therapy, and current GJB2 ‐directed strategies, including gene replacement, cell‐specific delivery, base editing, pharmacological rescue, and potential in utero intervention. OTOF gene therapy has progressed to clinical trials, with dual‐adeno‐associated‐virus strategies producing substantial and durable hearing restoration in patients with DFNB9. Its success is supported by preserved cochlear architecture and efficient inner‐hair‐cell targeting. GJB2 therapy remains at the preclinical or early‐clinical stage. Major barriers include the broad distribution of connexin 26‐expressing cells, the need for precise supporting‐cell targeting, limitations of current disease models, developmental differences between mice and humans, and irreversible cochlear abnormalities before postnatal treatment. OTOF provides an important translational framework, but GJB2 requires distinct strategies involving precise cochlear delivery, controlled transgene expression, improved models, large‐animal validation, and potentially earlier intervention.