Gene therapy for inherited deafness

Also known as OTOF gene therapy, Otoferlin gene therapy, DB-OTO, AAV1-hOTOF, Otarmeni

Gene therapy delivers a working copy of the OTOF gene into the inner ear of children whose deafness is caused by OTOF faults. Small trials reported hearing gains in most treated children, and the FDA granted accelerated approval to Regeneron's Otarmeni in April 2026.

Pilot and early commercialDemonstratedReviewed 21 Oct 2026
AI illustration · Illustrative scene, not a photograph of the specific device or experiment.

In plain language

Some children are born deaf because both copies of a gene called OTOF are faulty. This gene makes otoferlin, a protein that helps the inner ear pass sound signals to the hearing nerve. Without working otoferlin, the signal does not get through, even when the rest of the ear is intact.

In gene therapy, a modified virus called adeno-associated virus (AAV) carries a working copy of the gene. The surgeon injects it into the cochlea, the snail-shaped part of the inner ear. Between 2024 and 2026, small trials reported that most treated children could hear sounds they had not heard before. In April 2026 the US regulator approved one of these therapies, but only for a defined group of patients and with conditions still to be met. The trials are small and follow-up is short, so the long-term picture is not yet known.

Technical explanation

OTOF encodes otoferlin. Autosomal recessive deafness 9 (DFNB9) is caused by faults in OTOF, and the approved indication for Otarmeni refers to biallelic OTOF variants. The Lancet trial (Lv and colleagues, 2024) used a single AAV1 vector carrying a human OTOF gene (AAV1-hOTOF), delivered by injection into the cochlea. Regeneron's DB-OTO is a dual AAV1 therapy given by intracochlear infusion (Valayannopoulos and colleagues, 2025).

The trials differ in design, vector regimen and endpoints, so they cannot be compared directly. The Lancet single-arm trial enrolled six children, and five showed hearing recovery, with 40 to 57 dB reductions in average ABR thresholds at 0.5 to 4.0 kHz. A bilateral study in Nature Medicine (Wang and colleagues, 2024) treated five children in both ears, and all five had bilateral hearing restoration. The NEJM report on DB-OTO (Valayannopoulos and colleagues, 2025) enrolled 12 children with profound deafness. At week 24, 9 of 12 (75%) reached an average pure-tone threshold of 70 dB HL or less and met the ABR endpoint of 90 dB nHL or less.

Safety data come from small numbers. The Nature Medicine study reported no serious adverse events, and its most common adverse events were raised lymphocyte counts and raised cholesterol. The Lancet abstract reports no dose-limiting toxicity. The NEJM report recorded 67 adverse events, and none led to discontinuation of treatment. On 23 April 2026 the FDA granted accelerated approval to Otarmeni (lunsotogene parvec) for severe-to-profound and profound sensorineural hearing loss associated with biallelic OTOF variants. Continued approval depends on post-marketing data that Regeneron must collect and submit.

What the evidence says

Each statement is typed by the strength of its evidence and linked to the source that supports it.

Demonstrated Shown in a published experiment, test or shipping product.

In the Lancet single-arm trial of six children, five showed hearing recovery, with 40 to 57 dB reductions in average ABR thresholds at 0.5 to 4.0 kHz.

Sources: [1] · Abstract

In the Lancet trial, the abstract reports no dose-limiting toxicity.

Sources: [1] · Abstract

In the Nature Medicine bilateral study of five children, all five had bilateral hearing restoration.

Sources: [2] · Abstract

In the Nature Medicine study, no serious adverse events occurred, and the most common adverse events were raised lymphocyte counts and raised cholesterol.

Sources: [2] · Abstract

In the NEJM DB-OTO study of 12 children, 9 of 12 (75%) met the week-24 primary endpoint of an average pure-tone threshold of 70 dB HL or less, and the same nine met the ABR endpoint of 90 dB nHL or less.

Sources: [3] · Abstract

The NEJM DB-OTO report recorded 67 adverse events, none of which led to discontinuation of treatment.

Sources: [3] · Abstract · medium confidence

On 23 April 2026 the FDA granted accelerated approval to Otarmeni (lunsotogene parvec) for severe-to-profound and profound sensorineural hearing loss associated with biallelic OTOF variants.

Sources: [4], [5] · Approval summary

Regeneron must collect and submit additional post-marketing data as a condition of the accelerated approval of Otarmeni.

Sources: [4] · Approval summary

Reported, unverified Stated by a company or team but not independently confirmed.

A news report on the approval states that it rests on CHORD trial data, in which 16 of 20 treated participants met the primary endpoint of 70 dB HL or less and 14 met the ABR endpoint of 90 dB or less, and that 48-week follow-up suggests a durable effect. These figures differ from the 9 of 12 week-24 result in the NEJM report and have not been checked against the trial's own publication.

Sources: [4] · Approval summary · medium confidence

Regeneron has announced that Otarmeni will be offered free of charge to patients in the United States.

Sources: [4] · Approval summary · medium confidence

Limitations and open problems

  • The studies are small: 6 children in the Lancet trial, 5 in the Nature Medicine study and 12 in the NEJM report. None had a randomised control group.
  • The trials used different endpoints (ABR and pure-tone thresholds), vector regimens and follow-up periods, so the results cannot be pooled or compared directly.
  • Most follow-up is short. ASGCT reports 48-week follow-up data that suggests a durable effect, but the long-term durability of the hearing gain is not yet established in the sources reviewed.
  • The approved indication covers severe-to-profound and profound sensorineural hearing loss associated with biallelic OTOF variants. The trial evidence in the sources reviewed comes from children, so the evidence base for other ages is limited.
  • Delivery is surgical, and the sources reviewed did not give procedure-related safety data. Regeneron has said the therapy will be offered free in the United States, but the cost of administration is not clear from the company statement.

Possible future uses

Speculative

Ideas, not predictions. None of these has been demonstrated.

  • Newborn screening for OTOF variants, so that treatment could start before speech and language development are affected.
  • Gene therapy for other single-gene forms of inherited deafness, if similar delivery methods prove safe and effective.
  • Combined use with cochlear implants in children who have partial benefit from gene therapy.

Timeline

  1. 24 Jan 2024The Lancet publishes Lv and colleagues' single-arm trial of AAV1-hOTOF in children with autosomal recessive deafness 9, with five of six children recovering hearing. Sources: [1]
  2. 5 Jun 2024Nature Medicine publishes the interim analysis of the bilateral trial of AAV1-hOTOF in five children. Sources: [2]
  3. 12 Oct 2025The New England Journal of Medicine publishes the DB-OTO study, in which 9 of 12 children met the week-24 primary endpoint. Sources: [3]
  4. 23 Apr 2026The FDA grants accelerated approval to Otarmeni (lunsotogene parvec) for OTOF-related hearing loss, described by ASGCT as the first gene therapy for inherited hearing loss. Sources: [4], [5]

Futures this could help bring about

AI illustration
How far away?

Restoring hearing to deaf children with gene therapy

Pilots · 4 of 8 steps done

Glossary

Otoferlin
A protein, made from the OTOF gene, that helps inner hair cells release signals to the hearing nerve.
Adeno-associated virus (AAV)
A small, modified virus that is used to carry genes into cells in gene therapy.
Auditory brainstem response (ABR)
A test that records the electrical response of the hearing pathway to sound, used to estimate hearing thresholds, especially in young children.
Accelerated approval
A regulatory pathway that allows a therapy to be approved on an intermediate marker of benefit, with confirmatory evidence required afterwards.

Sources

  1. peer reviewed paper
    AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial
    Lv J, Wang H, Cheng X. The Lancet, 24 Jan 2024. DOI: 10.1016/S0140-6736(23)02874-X. Accessed 21 Oct 2026.
  2. peer reviewed paper
    Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results
    Wang H, Chen Y, Lv J. Nature Medicine, 5 Jun 2024. DOI: 10.1038/s41591-024-03023-5. Accessed 21 Oct 2026.
  3. peer reviewed paper
    DB-OTO Gene Therapy for Inherited Deafness
    Valayannopoulos V, Bance M, Carvalho DS. New England Journal of Medicine, 12 Oct 2025. DOI: 10.1056/NEJMoa2400521. Accessed 21 Oct 2026.
  4. news
    FDA Approves Otarmeni, First Gene Therapy for Inherited Hearing Loss
    Terry Flotte, MD. American Society of Gene & Cell Therapy, 24 Apr 2026. Accessed 21 Oct 2026.
  5. review article
    Lunsotogene Parvec: First Approval
    McGuigan A. Drugs, 4 Aug 2026. DOI: 10.1007/s40265-026-02361-7. Accessed 21 Oct 2026.

Revision history

3 changes since this profile was created.

Changes on 21 Oct 2026
Published on owner instruction (content loop iteration 22)0c35beb
Sources and claims re-checked against originalsfbb434c
Initial profile drafted from primary sources7e66249