Gene Therapy for Hearing Loss due to Otoferlin Deficiency (DB-OTO)

Introduction: Otoferlin, a calcium sensor expressed in the inner hair cells, is necessary for synaptic transmission to afferent fibers of the spiral ganglion. Biallelic loss of function mutations in the OTOF gene lead to congenital severe-to-profound auditory neuropathy in humans and mice. These mutations are believed to be causal in 2-3% of individuals born with hearing loss. Infants with biallelic OTOF mutations are currently managed with assistive devices, but several groups are developing AAV-based gene therapies to address unmet needs in this population.

Methods: We have developed DB-OTO, an Adeno-Associated Virus (AAV)-based gene transfer therapy for rescue of hearing in Otoferlin deficiency. DB-OTO expresses a corrected OTOF cDNA from a hair cell-specific Myo15 promoter and is delivered using an AAV1-based capsid. Because human OTOF cDNA exceeds the AAV packaging capacity, DB-OTO uses a dual AAV system to reconstitute the full-length OTOF coding sequence.

Results: DB-OTO can instate hearing function in OTOF Q828X/Q828X mutant mice as measured by ABR and use of a cell-specific promoter is key to its function.
Good Laboratory Practice (GLP) studies were performed to support the conduct of human clinical trials of DB-OTO. OTOF-deficient mice and wild type non-human primates (NHP) were used to characterize the pharmacology, toxicity and biodistribution of DB-OTO after inner ear delivery. In NHP experiments, we modeled the surgical approach and delivery of DB-OTO that is being used in the first-in-human clinical trial.
In GLP studies, there were no adverse DB-OTO-related findings in otic or non-otic tissues in healthy NHP or OTOFQ828X/Q828X mice (five to seven week-old or postnatal day 14 to 16). We assessed distribution of vector genomes outside the ear following DB-OTO injection in NHP. Vector shedding and levels of systemic escape into tissues in NHP were limited.

Conclusions: Taken together, these safety and efficacy data supported approval of DB-OTO regulatory filings in US and Europe to initiate first-in-human clinical testing of DB-OTO in a global Ph1/2 clinical trial in children with congenital otoferlin deficiency.