Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin.

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Abstract

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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Author and article information

Journal

Journal ID (iso-abbrev): Hum Genet

Title: Human genetics

Publisher: Springer Science and Business Media LLC

ISSN (Electronic): 1432-1203

ISSN (Print): 0340-6717

Publication date (Electronic): Feb 2023

Volume: 142

Issue: 2

Affiliations

[1 ] ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China.

[2 ] Institute of Biomedical Science, Fudan University, Shanghai, 200032, China.

[3 ] NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200032, China.

[4 ] Shanghai Refreshgene Therapeutics Co., Ltd., Waigaoqiao Free Trade Zone, Room 2001, Building 7-5, Free Trade No.1 Park, 160 Basheng Road, Shanghai, 200131, China.

[5 ] ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. wwuqing@eent.shmu.edu.cn.

[6 ] Institute of Biomedical Science, Fudan University, Shanghai, 200032, China. wwuqing@eent.shmu.edu.cn.

[7 ] NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200032, China. wwuqing@eent.shmu.edu.cn.

[8 ] ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. hwli@shmu.edu.cn.

[9 ] Institute of Biomedical Science, Fudan University, Shanghai, 200032, China. hwli@shmu.edu.cn.

[10 ] NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200032, China. hwli@shmu.edu.cn.

[11 ] ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. yilai_shu@fudan.edu.cn.

[12 ] Institute of Biomedical Science, Fudan University, Shanghai, 200032, China. yilai_shu@fudan.edu.cn.

[13 ] NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200032, China. yilai_shu@fudan.edu.cn.

Article

Publisher Item ID: 10.1007/s00439-022-02504-2

DOI: 10.1007/s00439-022-02504-2

PubMed ID: 36383253

SO-VID: b8d0e3b9-c500-4168-9b2e-a19b60917a5f

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