Otof, encoding otoferlin, is a crucial gene at the synapse of auditory sensory inner hair cells (IHCs) [4]. In the absence of otoferlin, signal transmission of IHCs fails due to impaired release of synaptic vesicles at the IHC synapse. It is mainly associated with auditory neuropathy.

Mutations in the Otof gene are the principal causes of auditory neuropathy [1]. In Otof -/- mice, a novel dual-AAV-mediated gene therapy system based on protein trans-splicing can reverse bilateral deafness after a single unilateral injection, effectively expressing exogenous mouse or human otoferlin and restoring hearing to near wild-type levels for at least 6 months, as well as restoring the release of synaptic vesicles in inner hair cells [3]. Also, gene therapy with AAV-OTOF in adult OTOFp.Q939*/Q939* mice with profound deafness can stably restore hearing, with the longest duration being at least 150 days, and the best therapeutic effect showing no difference in hearing from wild-type mice [1]. RNA base editing therapy in humanized OtofQ829X/Q829X mice can achieve an approximately 80% adenosine-to-inosine conversion efficiency, restore OTOF expression in nearly 100% of inner hair cells, and significantly improve auditory function, reaching similar levels as in wild-type mice, with the enhancement persisting for at least 7 months [2]. AAV1-hOTOF gene therapy in children with autosomal recessive deafness 9 caused by Otof mutations is safe and efficacious, with five out of six children having hearing recovery shown by a reduction in average auditory brainstem response thresholds and improved speech perception [5].

In conclusion, Otof is essential for normal signal transmission at the IHC synapse. Studies using Otof-related gene knockout mouse models have revealed its crucial role in auditory function, and have provided potential gene therapy strategies for treating auditory neuropathy caused by Otof mutations [1,2,3,5].