DB-OTO Gene Therapy for Inherited Deafness

BackgroundGenetic deficiency of otoferlin, a protein critical to synaptic transmission by the sensory hair cells of the ear, causes congenital deafness. Medicines to treat the condition are lacking; children typically receive cochlear implants. DB-OTO is a dual adeno-associated virus 1 gene therapy that delivers human OTOF complementary DNA (encoding otoferlin) regulated by a hair cell–specific promoter. MethodsWe conducted an open-label, single-group, first-in-human registrational study to evaluate DB-OTO. Children with OTOF variants and profound deafness (defined by an average audiometric threshold of >90 decibel hearing level [dB HL], indicating an inability to hear a gas-powered lawn mower) received an intracochlear infusion of DB-OTO (7.2×1012 vector genomes per ear) in one or both ears. The primary efficacy end point was an average threshold on behavioral pure-tone audiometry (PTA) at week 24 of 70 dB HL or less, a clinical standard that generally avoids cochlear implantation and enables natural acoustic hearing. A key secondary end point was the presence of an auditory brain-stem response to a click stimulus at a threshold at or below 90 dB normalized hearing level (db nHL) at week 24. Safety assessments included adverse events, laboratory results, and vestibular testing. ResultsA total of 12 children have been enrolled in the study. After a single infusion of DB-OTO, a PTA average threshold of 70 dB HL or less at week 24 (primary end point) and an auditory brain-stem response at or below 90 dB nHL (key secondary end point) were found in 9 of the 12 participants (75%; 95% confidence interval, 43 to 95; P=1.1×10−13 for both end points). Six participants could hear soft speech without assistive devices, and 3 had average normal hearing sensitivity. A total of 67 adverse events occurred or worsened during or after treatment, none of which led to discontinued participation in the study. ConclusionsDB-OTO gene therapy improved hearing in patients with OTOF-related deafness, enabling natural acoustic hearing and normalizing hearing sensitivity in 3 of 12 treated patients. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT05788536.)