Gene Therapy Revitalizes Children’s Hearing

Image Credit: [1]

Written by: Christopher Perez ‘27

Edited by: Grace Li ‘26

For the first time, children born completely deaf are hearing their parents’ voices without implants or electronic devices. In a landmark clinical trial published in The New England Journal of Medicine, researchers report that a one-time gene therapy, known as DB-OTO, restored natural hearing in children with a rare inherited form of deafness [2]. The results mark extraditing potential in sensory restoration.

Hearing loss is among the most common congenital disorders, affecting about 1.7 out of every 1,000 babies born in the United States [3]. Many cases arise from mutations in genes that control the inner ear’s ability to convert sound into electrical signals. One such gene, OTOF, carries instructions for producing otoferlin, a protein essential for communication between the hair cells of the cochlea and the auditory nerve. These inner hair cells act as microphones, translating sound waves into messages the brain can interpret. Without otoferlin, these messages cannot be sent, which results in permanent silence from birth [2].

Until now, the only option for these children has been the cochlear implant, a surgically implanted electronic device that bypasses damaged hair cells and sends electrical impulses directly to the brain. While cochlear implants have been transformative, they provide only an approximation of sound. Speech can sound mechanical and musical tones can be distorted,  failing to replicate the nuances of natural hearing.

Gene therapy, however, takes a fundamentally different approach from cochlear implants. Gene therapies treat and prevent disease by delivering working copies of genes into a patient’s cells. Instead of relying on mechanical devices or drugs, it corrects the underlying genetic error. In the case of DB-OTO, scientists used a harmless virus, adeno-associated virus type 1 (AAV1), as a delivery vehicle to carry a healthy version of the OTOF gene directly into the cells of the inner ear. Once inside, the gene begins producing otoferlin, restoring the cells’ ability to send sound signals to the brain [2].

Because the OTOF gene is unusually large, researchers engineered a dual-vector system, splitting the gene into two pieces that rejoin once inside the cell. This innovation allows delivery of genes previously considered too big for standard viral carriers and marks an important technical advancement in the field.

The first human trial of DB-OTO, called the CHORD study, enrolled twelve children between ten months and sixteen years of age with confirmed OTOF-related deafness. Each received a single, precise infusion of the therapy into one or both ears. By twenty-four weeks after treatment, nine of twelve children showed significant improvement in hearing, as evidenced by better results on pure-tone audiometry, a standard test that measures hearing sensitivity across sound frequencies. Six could detect soft speech, and three achieved normal hearing sensitivity, which allows them to hear a whisper [2]. None of the untreated ears in the study improved on their own, confirming that the changes were caused by the therapy.

Alongside newborns, two teenagers who were treated demonstrated measurable hearing restoration, suggesting the therapy’s benefits may not be limited to infants. In total, the treatment allowed several children to avoid cochlear implants entirely, and some began developing speech comprehension and language skills within months of treatment.

The safety profile was also encouraging. Among the sixty-seven reported side effects, most were mild and related to the surgical procedure, such as temporary dizziness or ear infections. No participants experienced serious or lasting complications, and all continued in the study [2]. Participants remain under long-term follow-up to determine whether the restored hearing is stable over time, ensuring that the effects of the gene therapy are not temporary.

The implications of this study reach far beyond the dozen children treated. It demonstrates that gene therapy can fully restore a complex sense by fixing the genetic cause at the cellular level. Earlier efforts in sensory gene therapy, such as those targeting inherited blindness, succeeded only in partially restoring sight [4,5]. In contrast, DB-OTO achieved near-complete recovery of natural hearing in some participants, setting a new benchmark for gene-based treatments.

Beyond treating OTOF-related deafness, researchers believe the same strategy could apply to other forms of hereditary and possibly age-related hearing loss. Future studies aim to test whether similar dual-vector systems can deliver different genes responsible for other auditory conditions.

Hearing is often the first sense we experience, even before birth, whether it's the rhythm of a mother’s heartbeat or the muffled cadence of speech. For children born without it, DB-OTO offers not just a medical treatment but an invitation into a world filled with sound and connection. As Dr. Jonathon Whitton, one of the study’s lead authors, observed, “We are no longer just treating deafness—we are restoring the biology of hearing” [2].

References

[1] Ying NS. This New Gene Therapy May Treat Genetic Deafness – Asian Scientist Magazine [Internet]. Asianscientist.com. 2025. Available from: https://www.asianscientist.com/2025/04/health/this-new-gene-therapy-may-treat-genetic-deafness/ 

[2] Valayannopoulos V, Bance M, Carvalho DS, Greinwald JH, Harvey SA, Ishiyama A, et al. DB-OTO Gene Therapy for Inherited Deafness. New England Journal of Medicine. 2025 Oct 12; https://pubmed.ncbi.nlm.nih.gov/41085057/ 

[3] CDC. Annual Summary Data: Early Hearing Detection and Intervention (EHDI) Program [Internet]. Hearing Loss in Children. 2025. Available from: https://www.cdc.gov/hearing-loss-children/data/ehdi-data.html 

[4] Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. The Lancet [Internet]. 2017 Aug 26;390(10097):849–60. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31868-8/fulltext 

[5] Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, et al. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset. Ophthalmology. 2021 May;128(5):649–60. https://www.sciencedirect.com/science/article/pii/S0161642020311878?via%3Dihub