Abstract: Patients received a single, unilateral intracochlear injection of DB-OTO (7.2x1012 vector genomes) and to date, surgical delivery has been uneventful. No dose-limiting toxicities or DB-OTO-related adverse events have been reported; no persistent vestibular manifestations have been observed. In Patient 1, hearing was restored to within normal limits at multiple key speech frequencies by Week 48. These early safety and efficacy results demonstrate a positive safety and tolerability profile and suggest DB-OTO gene therapy may produce high quality, physiological hearing in pediatric patients with profound OTOF-related deafness.
Summary: Rationale Otoferlin is critical for inner hair cell (IHC) signal transmission to auditory nerve fibers. Biallelic otoferlin gene (OTOF) variants typically cause severe-to-profound deafness. Preclinical data showed that DB-OTO gene therapy promotes IHC-selective otoferlin protein expression from the human OTOF gene, which may result in high-qualityhearing. In this ongoing, first-in-human, multicenter phase 1/2 open-label clinical trial (CHORD, NCT05788536), the safety, tolerability, and efficacy of DB-OTO (administered by intracochlear injection using a typical facial recess approach through the round window) is being evaluated in pediatric patients with profound OTOF-related deafness.
Design Pediatric patients with profound sensorineural hearing loss due to biallelic OTOF variants received a single, unilateral intracochlear injection of DB-OTO (7.2 x 1012 vector genomes).
Results To date, surgical delivery has been uneventful in all patients. No dose-limiting toxicities or DB-OTO-related adverse events have been reported, and no persistent vestibular manifestations have been observed. In Patient 1, hearing was restored to within normal limits at Week 48. Updated data from the on-going trial, including Week 48 safety and efficacy data (e.g. speech perception outcomes) will be presented at this meeting.
Conclusions Early results demonstrate a positive safety and tolerability profile and suggest that DB-OTO gene therapy may significantly improve hearing in patients with profound deafness caused by OTOF variants. Patient enrollment is ongoing.
Learning Objectives:
Upon completion, participants will be able to understand basic genetics of congenital hearing loss.
Upon completion, participants will be able to understand gene therapy development and approaches.
Upon completion, participants will be able to describe the early safety and efficacy results of DB-OTO gene therapy.
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