Gene therapy restores hearing in patients with deafness gene

The assumption in hearing loss research was clinical common sense: treat young, treat early. Younger auditory systems were presumed malleable; older ones, shaped by years of silence, were assumed to have closed. Nobody had tested that assumption rigorously — it was simply how the field worked. Then a trial began enrolling patients up to age 24, and the results, published in Nature Medicine and covered this week by STAT News, suggest the assumption was wrong. Ten patients with mutations in a gene called OTOF — which, when working normally, produces a protein essential for transmitting sound signals from the inner ear to the brain — received a single injection of a functional copy of that gene into the inner ear. All ten showed measurable hearing improvement within six months — and for the first time, that included teenagers and young adults, not just young children.

That result raises a question the field has largely avoided: what exactly were we assuming when we decided deaf children needed to be fixed?

The patients in the trial all carried mutations in OTOF, a gene that produces a protein called otoferlin. Otoferlin sits at the junction between the inner ear's sound-sensing hair cells and the auditory nerve. When it functions normally, it transmits electrical signals across that synapse — sound enters the ear, and the brain receives it. When the gene is mutated, that chain is broken. The therapy delivers a working copy of the gene using a modified adeno-associated virus, injected through a membrane at the base of the cochlea. Cells that take up the gene begin producing otoferlin themselves, rebuilding the signal pathway.

On average, the sound level participants could detect improved from 106 decibels — clinically deaf — to 52 decibels, according to the Karolinska Institutet press release. Most recovered some hearing within one month. Children between 5 and 8 showed the strongest response; a 7-year-old regained nearly full hearing within four months and now holds daily conversations with her mother. No serious adverse events were reported during the 6- to 12-month follow-up; the most common side effect was a temporary drop in neutrophils, a type of white blood cell.

The results extend prior work in younger children. Regeneron published results from its own OTOF program, DB-OTO, in the New England Journal of Medicine last year: 11 of 12 participants showed hearing improvements, and 3 achieved normal hearing. The two programs use different viral variants but point in the same direction — gene therapy can restore hearing in people with OTOF mutations.

Whether the adult auditory system fully recovers after prolonged deafness remains an open question. The auditory nerve and the cortical pathways that interpret sound may be permanently altered by years without input, or they may be more adaptable than assumed. This trial does not settle that question — but it makes the question harder to ignore.

Researchers are already planning to extend the approach to more common genetic causes of congenital hearing loss, including mutations in GJB2 and TMC1, which account for a larger share of cases than OTOF mutations do. OTOF accounts for roughly 1 to 8 percent of congenital deafness globally, according to ScienceDaily's coverage of the Nature Medicine paper.

The trial was small — 10 participants — and the follow-up period relatively short. Longer data will determine whether the improvements last. For now, the findings represent the most comprehensive evidence yet that gene therapy can restore clinically meaningful hearing across a wider age range than previously demonstrated.

The study was financed by several Chinese research programmes and Otovia Therapeutics Inc., the company that developed the gene therapy and employs many of the researchers involved.