OTOF gene therapy: from the first human trial to a new era of precision intervention for congenital deafness

Autosomal recessive deafness type 9 (DFNB9), caused by mutations in the OTOF gene, is a key cause of congenital sensorineural hearing loss, comprising 2% to 8% of hereditary cases. Unlike other forms, DFNB9 patients have intact inner ear hair cells, but exhibit defects in neurotransmitter release at the ribbon synapse. This makes DFNB9 suitable for gene replacement therapy. In the past three years, notable progress has been made in designing AAV vectors, optimizing hair cell-specific promoters, and developing minimally invasive inner ear delivery methods. These advancements have rapidly moved OTOF gene therapy from preclinical stages to multicenter clinical trials. Between 2024 and 2026, the research team led by Yilai Shu at Fudan University published findings on unilateral, bilateral, and 42-participant multicenter cohorts, with a maximum follow-up duration of 2.5 years, in The Lancet, Nature Medicine, and Nature, respectively. The evidence consistently suggests that adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is both safe and feasible, with most participants experiencing clinically significant improvements in hearing. Notably, in 2026, the FDA approved the first OTOF gene therapy, Otarmeni (lunsotogene parvec-cwha), marking a pivotal milestone. Nonetheless, several critical challenges remain, including the precise delineation of the therapeutic window, manufacturing bottlenecks for large-scale vector production under current Good Manufacturing Practice (cGMP) conditions, the absence of long-term safety follow-up data, and accessibility barriers due to the prohibitive costs of gene therapy. This article provides a systematic review of the molecular pathological basis of OTOF gene therapy, vector technology, and preclinical evidence, alongside the latest data from global clinical trials, and discusses the bottlenecks and potential pathways for clinical translation.