Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin.
Honghai TangHui WangShengyi WangShao Wei HuJun LvMengzhao XunKaiyu GaoFang WangYuxin ChenDaqi WangWuqing WangHuawei LiYilai ShuPublished in: Human genetics (2022)
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.
Keyphrases
- hearing loss
- gene therapy
- wild type
- copy number
- endothelial cells
- genome wide
- induced pluripotent stem cells
- induced apoptosis
- genome wide identification
- high fat diet induced
- pluripotent stem cells
- preterm infants
- type diabetes
- dna methylation
- oxidative stress
- signaling pathway
- metabolic syndrome
- case report
- replacement therapy
- case control