Human Genetics. 2022 Nov 16
Honghai Tang, Hui Wang, Shengyi Wang, Shao Wei Hu, Jun Lv, Mengzhao Xun, Kaiyu Gao, Fang Wang, Yuxin Chen, Daqi Wang, Wuqing Wang, Huawei Li & Yilai Shu
Products used in the paper Details Operation
AAV vector packaging The mouse otoferlin CDS (NM_031875.2) was divided into two segments at residues 818 or 1114 followed by packaging into two AAV-PHP.eB by PackGene Biotech. Request Quote

Research Field: hearing

AAV Serotype: AAV-PHP.eB

Dose: 1*10^13 vg/ml, 1 μl of AAV-PHP.eB-eGFP or 2 μl of mixed therapeutic agent (the vector genome ratio of N-terminal and C-terminal otoferlin was 1:1).

Routes of Administration: A post-auricular incision of the right ear was made and the tissue was dissected to expose the RMW covered by the auditory bulla.

Targeted organ: ear

Animal or cell line strain: Otof +/– mice


Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF. Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement. Here, we developed a novel dual-AAV-mediated gene therapy system based on the principles of protein trans-splicing, and we show that this system can reverse bilateral deafness in Otof –/– mice after a single unilateral injection. The system effectively expressed exogenous mouse or human otoferlin after injection on postnatal day 0–2. Human otoferlin restored hearing to near wild-type levels for at least 6 months and restored the release of synaptic vesicles in inner hair cells. Our study not only provides a preferential clinical strategy for the treatment of OTOF-related auditory neuropathies, but also describes a route of development for other large-gene therapies and protein engineering techniques.

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