Breakthrough in gene therapy for genetic deafness
Results from the ongoing Phase I/II CHORD trial for the investigational gene therapy DB-OTO have detailed improvements in the hearing of two children, both born with genetic deafness.
Regeneron Pharmaceuticals, Inc. (NY, USA) presented preliminary data at the recent American Society for Gene and Cell Therapy (ASGCT; MD, USA) annual meeting in May 2024. The investigational therapy DB-OTO aims to provide durable and physiological hearing to individuals affected by congenital hearing loss due to otoferlin gene (also known as OTOF) variants, marking a new chapter in treating genetic deafness at its root cause.
Congenital deafness, can result from otoferlin gene variations that impair the production of the gene’s protein product OTOF, which is essential for communication between inner ear sensory cells and the auditory nerve. Current devices like hearing aids and cochlear implants amplify sound but do not restore the full spectrum of hearing.
Regeneron’s first auditory program developed a cell-selective adeno-associated virus gene therapy that delivers a new otoferlin gene regulated by a proprietary Myo15 promoter. This therapy replaces the faulty gene through a single intracochlear injection, ensuring expression is limited to inner hair cells, which naturally express otoferlin. The surgical procedure utilizes techniques similar to those used in the administration of cochlear implants, making it suitable for young infants.
Laying the foundations for an inherited deafness gene-therapy
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Opal Sandy, one of the youngest patients to receive gene therapy for genetic deafness, was 11 months old when dosed in the trial. Within 24 weeks, her hearing had drastically improved to normal levels. A second child, dosed at age four, demonstrated initial hearing improvements at a 6-week assessment.
Hearing improvements in the trial were assessed through behavioral sound confirmation, pure tone audiometry (PTA), and auditory brainstem response (ABR). PTA is a gold standard measurement of hearing, while ABR provides objective confirmation by measuring electrical brainstem responses to sound at different decibels (dB).
At the 24-week assessment, Sandy, then 16 months old, demonstrated:
- An average improvement of 84 dB from baseline
- A frequency measure reaching 10 dB in hearing level per PTA
- An average improvement of 80 dB from baseline across all frequency tests
- Positive ABR responses reaching 45 dB
The second participant, aged four, at the 6-week assessment, experienced similar improvements, showing:
- An average improvement of 19 dB from baseline
- A frequency measure reaching 80 dB in hearing level per PTA
- An average improvement of 16 dB from baseline across all frequency tests
- Positive ABR responses, with best frequency reaching 75 dB
Both the surgical procedure and DB-OTO were well-tolerated, with no related adverse or serious adverse events reported following treatment.
This pioneering gene therapy could transform treatment options for children with otoferlin-related deafness, often missed during newborn hearing screenings since inner hair cells still function but signaling to the auditory nerve is hindered. The advancement of DB-OTO gene therapy could potentially extend to individuals with hearing loss from other common genetic conditions.
