Work

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

Year: 2026

Type: article

Abstract: Background 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. Methods 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. Results 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. Conclusion 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.

Source: Clinical and Translational Discovery

DOI: 10.1002/ctd2.70203

Authors: Jiahui Zhao, Mengzhao Xun, Yu Sun

Institutions: Wuhan Union Hospital, Huazhong University of Science and Technology

Language: English

Topic: Hearing, Cochlea, Tinnitus, Genetics

Subfield: Sensory Systems

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,420