DB-OTO Gene Therapy for Inherited Deafness

Area of Science:

• Otolaryngology
• Genetics
• Molecular Biology

Background:

• Congenital deafness can result from genetic otoferlin (OTOF) deficiency, impacting synaptic transmission in auditory hair cells.
• Current treatments for OTOF-related deafness primarily involve cochlear implants, with limited medical therapies available.
• DB-OTO is an investigational gene therapy utilizing adeno-associated virus 1 to deliver human OTOF cDNA via a hair cell-specific promoter.

Purpose of the Study:

• To evaluate the safety and efficacy of DB-OTO gene therapy in children with OTOF-related congenital deafness.
• To assess the potential for DB-OTO to restore natural acoustic hearing and reduce the need for cochlear implantation.

Main Methods:

• An open-label, single-group, first-in-human study was conducted involving 12 children with OTOF variants and profound deafness (>90 dB HL).
• Participants received an intracochlear infusion of DB-OTO (7.2×10^12 vector genomes/ear) in one or both ears.
• Primary efficacy was measured by behavioral pure-tone audiometry (PTA) achieving ≤70 dB HL at 24 weeks; a key secondary endpoint was auditory brain-stem response (ABR) ≤90 dB nHL at 24 weeks.

Main Results:

• Nine of 12 participants (75%) achieved the primary efficacy endpoint of PTA ≤70 dB HL and the secondary endpoint of ABR ≤90 dB nHL at 24 weeks.
• Six participants gained the ability to hear soft speech without assistive devices, and three achieved average normal hearing sensitivity.
• A total of 67 adverse events were reported, none of which necessitated study discontinuation.

Conclusions:

• DB-OTO gene therapy demonstrated significant efficacy in improving hearing for children with OTOF-related deafness.
• The treatment enabled natural acoustic hearing and normalized hearing sensitivity in a substantial proportion of treated patients.
• DB-OTO represents a promising therapeutic approach for congenital deafness caused by otoferlin deficiency.