Otof, which encodes otoferlin, is a crucial gene at the synapse of inner hair cells (IHCs) in the auditory system. In the absence of the protein encoded by Otof, signal transmission of IHCs fails due to impaired release of synaptic vesicles at the IHC synapse, and biallelic pathogenic variants in Otof predominantly cause autosomal recessive profound prelingual deafness, DFNB9 [4].

Mutations to the Otof gene are among the most common reasons for auditory neuropathy. Studies on Otof -/- mice, a gene knockout (KO) mouse model, have shown promising results in treating Otof -related auditory neuropathies. For instance, a novel dual-AAV-mediated gene therapy system based on protein trans-splicing could reverse bilateral deafness in Otof -/- mice 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 [3]. Additionally, in OtofQ829X/Q829X mice, an RNA base-editing therapy achieved nearly 100% transfection efficiency in inner hair cells, restored Otof expression in nearly 100% of inner hair cells, and significantly improved auditory function, reaching similar levels as in wild-type mice [2]. AAV-OTOF gene therapy in DFNB9 mouse models demonstrated stable restoration of hearing in adult OTOFp.Q939*/Q939* mice with profound deafness for at least 150 days [1].

In conclusion, Otof is essential for the normal function of the auditory system, specifically for the synaptic transmission in inner hair cells. Studies using Otof KO mouse models have been instrumental in understanding the role of Otof in auditory neuropathy and developing potential gene therapy strategies for treating Otof-related deafness. These models have provided valuable insights into the underlying mechanisms of the disease and the efficacy of potential treatments [1,2,3].

References:

1. Qi, Jieyu, Zhang, Liyan, Tan, Fangzhi, Wang, Qiuju, Chai, Renjie. 2023. Preclinical Efficacy And Safety Evaluation of AAV-OTOF in DFNB9 Mouse Model And Nonhuman Primate. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2306201. doi:10.1002/advs.202306201. https://pubmed.ncbi.nlm.nih.gov/38014592/

2. Xue, Yuanyuan, Tao, Yong, Wang, Xing, Yang, Hui, Wu, Hao. 2023. RNA base editing therapy cures hearing loss induced by OTOF gene mutation. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 3520-3530. doi:10.1016/j.ymthe.2023.10.019. https://pubmed.ncbi.nlm.nih.gov/37915172/

3. Tang, Honghai, Wang, Hui, Wang, Shengyi, Li, Huawei, Shu, Yilai. 2022. Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin. In Human genetics, 142, 289-304. doi:10.1007/s00439-022-02504-2. https://pubmed.ncbi.nlm.nih.gov/36383253/

4. Vona, Barbara, Rad, Aboulfazl, Reisinger, Ellen. 2020. The Many Faces of DFNB9: Relating OTOF Variants to Hearing Impairment. In Genes, 11, . doi:10.3390/genes11121411. https://pubmed.ncbi.nlm.nih.gov/33256196/