DB-OTO Gene Therapy for Inherited Deafness

CLINICAL QUESTION

Can intracochlear DB-OTO gene therapy restore natural acoustic hearing in children with profound congenital deafness caused by biallelic OTOF variants?

BOTTOM LINE

In this first-in-human, open-label study, DB-OTO improved hearing in most children with OTOF-related deafness. At 24 weeks, nine of 12 participants met the primary efficacy endpoint, six could hear soft speech without assistive devices, and three achieved average normal hearing sensitivity.

BACKGROUND: OTOF-related deafness is caused by a deficiency of otoferlin, a protein required for synaptic transmission between the sensory inner hair cells and the auditory nerve. Affected children are typically born with profound deafness and are usually managed with cochlear implants. Because inner ear structures may remain intact, OTOF gene replacement could potentially restore physiologic sound detection.

STUDY DESIGN: Ongoing open-label, single-group, first-in-human phase 1–2 study amended to registrational status after early efficacy signals. DB-OTO is a dual adeno-associated virus 1 vector delivering human OTOF complementary DNA under a hair cell-specific promoter. Children received a single intracochlear infusion of DB-OTO in one or both ears.

SETTING: Multicenter CHORD trial in pediatric patients with OTOF-related profound congenital deafness

SYNOPSIS: The study included 12 children aged 10 months to 16 years with biallelic OTOF variants and profound deafness, defined as an average audiometric threshold greater than 90 dB HL. Nine participants received DB-OTO in one ear; three received DB-OTO in both ears during a single session. The primary endpoint was a behavioral pure-tone audiometry average threshold of less than 70 dB HL at week 24, a level the authors describe as generally avoiding cochlear implantation and enabling natural acoustic hearing.

At week 24, nine of 12 participants met the primary endpoint (75%; 95% confidence interval [CI], 43–95; P=1.1×10−13). The same proportion met the key secondary endpoint of auditory brainstem response to a click stimulus at less than 90 dB normalized hearing level. Among unilateral-treatment participants, six of nine treated ears met the primary endpoint compared with zero of nine untreated ears. All three bilateral-treatment participants met the primary endpoint based on the better-performing ear.

Clinically, six participants achieved soft-speech sensitivity, and three achieved average normal hearing sensitivity. Eight participants had follow-up beyond week 24, with hearing generally stable or improved.

A total of 67 adverse events occurred or worsened during or after treatment; 17 were considered related to surgical delivery. Two serious adverse events occurred—mastoiditis in an implanted contralateral ear and walking instability—and both resolved without sequelae. No adverse event led to study discontinuation, and no persistent vestibular safety signal was identified. Limitations include small sample size, single-group design, limited follow-up, and partial post hoc evolution of the trial design.

CITATION: Valayannopoulos V, et al. DB-OTO gene therapy for inherited deafness. N Engl J Med. 2026;394:1074-1083. doi:10.1056/NEJMoa2400521.