Gene Therapy Improves Hearing in Children with Profound Genetic Hearing Loss
Regeneron’s investigational gene therapy, DB-OTO, has been found to provide meaningful improvements in hearing for nearly all of the participants in the CHORD clinical trial.
Recent results from a pivotal clinical trial have demonstrated that Regeneron’s investigational gene therapy, DB-OTO, enables improved hearing within weeks of treatment for nearly all pediatric patients treated who suffer from hearing loss as a result of variants of the otoferlin (OTOF) gene (1). Out of the 12 participants of the trial (aged between 10 months and 16 years), 11 experienced clinically meaningful hearing improvements after receiving a single administration of DB-OTO via intracochlear infusion.
“Until now, genetic OTOF-related hearing loss was considered permanent, which is why many of us have dedicated our careers to this field,” said Lawrence R. Lustig, M.D., Chair of the Department of Otolaryngology-Head and Neck Surgery at the Columbia University College of Physicians and Surgeons and a trial investigator, in a Regeneron press release (1). “This registrational data set showcases consistent, rapid and robust responses to DB-OTO, and for those followed to later timepoints, we’ve seen hearing stability as well as continued improvement in understanding of speech. These results are even more poignant when viewed by the families — as one of the parents said, their situation is now ‘unimaginable’ from one year ago. This truly represents a new era in the treatment of hearing loss.”
OTOF-related hearing loss is an ultra-rare congenital condition affecting approximately 20–50 newborns born in the U.S. every year. Caused by variants in the OTOF gene, these patients suffer from a lack of a functional otoferlin protein, which is vital to allow communication between the sensory cells of the inner ear and the auditory nerve.
The CHORD clinical trial is a Phase I/II multicenter, open-label trial aimed at evaluating the safety, tolerability, and efficacy of DB-OTO in pediatric patients with OTOF-related hearing loss. The trial is being conducted in two parts, an initial dose-escalation cohort (Part A), whereby participants will receive a single intracochlear infusion of the gene therapy in one ear, and an expansion cohort (Part B), where DB-OTO will be administered in both ears.
In the recent update, the investigators had evaluated 12 patients in total, nine of whom received DB-OTO in one ear and three who received it in both ears. Nine of the 12 participants met the primary efficacy endpoint of the trial — a pure-tone audiometry (PTA) of 70 dB hearing level (HL) or less at week 24. Six of the trial participants could hear soft speech without the assistance of devices, and three were found to have average normal hearing sensitivity. The gene therapy was generally found to be well-tolerated with no related adverse findings reported (2).
DB-OTO is an investigational cell-selective, dual adeno-associated virus (AAV) vector gene therapy that is aimed at delivering a working copy of the OTOF gene as a replacement for the non-functional otoferlin protein in individuals with OTOF-related hearing loss. The therapy replaces the protein through a modified, non-pathogenic virus that is delivered by infusion into the cochlea under general anesthesia (1).
The updated results of the trial have been published in The New England Journal of Medicine (2) and presented during an oral presentation at the annual American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNSF) meeting (3). Regeneron is planning to submit a regulatory application for DB-OTO later in 2025, pending discussions with the FDA.
References
Regeneron. DB-OTO Results in the New England Journal of Medicine Showcase Dramatic and Sustained Improvements in Hearing and Speech Perception in Children with Profound Genetic Hearing Loss. Press Release, Oct. 12, 2025.
Valayannopoulos, V.; Bance, M.; Carvalho, D.S.; et al. DB-OTO Gene Therapy for Inherited Deafness. N. Engl. J. Med. Published Oct. 12, 2025.
Wu, C.-C. Preliminary Efficacy and Safety of AK-OTOF Gene Therapy for OTOF-Mediated Hearing Loss. Scientific Oral Presentation, Pediatric Otolaryngology, AAO-HNSF Meeting, Oct. 12, 2025.