Treatment of Deafness with Gene Therapy: Did You Know?

here was a recent perspective in the New England Journal of Medicine by V. Valayannopoulos et al, published on October 12, 2025 titled “DB-OTO Gene Therapy for Inherited Deafness. “ The article is attached in a PDF format for your information, and below is a summary for your convenience.

BACKGROUND

Genetic deficiency of otoferlin, a protein critical to synaptic transmission by the sensory hair cells of the ear, causes congenital deafness. Medicines to treat the condition are lacking; children typically receive cochlear implants. DB-OTO is a dual adeno-associated virus 1 gene therapy that delivers human OTOF complementary DNA (encoding otoferlin) regulated by a hair cell–specific promoter.

METHODS

We conducted an open-label, single-group, first-in-human registrational study to evaluate DB-OTO. Children with OTOF variants and profound deafness (defined by an average audiometric threshold of >90 decibel hearing level [dB HL], indicating an inability to hear a gas-powered lawn mower) received an intracochlear infusion of DB-OTO in one or both ears. The primary efficacy end point was an average threshold on behavioral pure-tone audiometry (PTA) at week 24 of 70 dB HL or less, a clinical standard that generally avoids cochlear implantation and enables natural acoustic hearing. A key secondary end point was the presence of an auditory brain-stem response to a click stimulus at week 24. Safety assessments included adverse events, laboratory results, and vestibular testing.

RESULTS

A total of 12 children have been enrolled in the study. After a single infusion of DB-OTO, a PTA average threshold of 70 dB HL or less at week 24 (primary end point) and an auditory brain-stem response at or below 90 dB nHL (key secondary

end point) were found in 9 of the 12 participants (75%; 95% confidence interval). Six participants could hear soft speech without assistive devices, and 3 had average normal hearing sensitivity. A total of 67 adverse events occurred or worsened during or after treatment, none of which led to discontinued participation in the study.

CONCLUSIONS

DB-OTO gene therapy improved hearing in patients with OTOF-related deafness, enabling natural acoustic hearing and normalizing hearing sensitivity in 3 of 12 treated patients.

DISCUSSION

congenital deafness affects 1.7 per 1000 babies born in the United States and is predominantly caused by genetic deficiencies. variants in the gene encoding otoferlin, account for 1 to 3% of cases of congenital genetic deafness. Otoferlin functions as a calcium sensor expressed in inner hair cells and regulates synaptic transmission between sensory inner hair cells and the cochlear nerve.

Children with pathogenic variants in OTOF are typically born with profound deafness. Medicines for the treatment of OTOF-related deafness are lacking, and management involves lifelong use of cochlear implants. Although such implants provide a benefit, they

limit speech understanding and music appreciation, and use of the device is difficult in certain settings.

Most participants had dramatic improvements that ended the need for cochlear implants and enabled natural acoustic hearing. None of the untreated ears showed spontaneous improvement, a finding consistent with those from our natural history benchmark analysis. By 24 weeks after treatment, several participants had had progression from an inability to hear a gas-powered lawn mower to the ability to detect whispers, which highlights intact inner ear structures that were amenable to gene therapy. Contrary to prevailing views that the efficacy of OTOF gene therapy might be limited to participants who receive it early in life, we observed benefits when DB-OTO was given to participants as old as 16 years of age.

By intervening early, the researchers expected DB-OTO to promote speech and language development. Of the four children followed for at least 48 weeks, one showed no response and was not assessed for efficacy outcomes after 36 weeks; the other three were tested for speech perception, and the resulting data provide supporting evidence that they have been learning to recognize and produce words and sounds in their native languages. One participant also showed distant sound detection; an inability to detect such sounds is a limitation of cochlear implants.