Gene Therapy Restores Auditory Functions in an Adult Vglut3 Knockout Mouse Model

Xingle Zhao; Huihui Liu; Hongchao Liu; Ruijie Cai; Hao Wu

doi:10.1089/hum.2022.062

Gene Therapy Restores Auditory Functions in an Adult Vglut3 Knockout Mouse Model

Hum Gene Ther. 2022 Jul;33(13-14):729-739. doi: 10.1089/hum.2022.062.

Authors

Xingle Zhao^{1

2

3}, Huihui Liu^{1

2

3}, Hongchao Liu^{1

2

3}, Ruijie Cai^{1

2

3}, Hao Wu^{1

2

3}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
² Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
³ Shanghai Key Laboratory of Translation Medicine on Ear and Nose Disease, Shanghai, P.R. China.

PMID: 35726398
DOI: 10.1089/hum.2022.062

Abstract

Adeno-associated virus (AAV)-based gene therapy has been demonstrated to be extremely effective for treating genetic hearing loss over the past several years. However, successful gene therapies for hereditary deafness have not been well-studied in adult mice. To explore the possibility of gene therapy after peripheral auditory maturity, we used AAV8 to express vesicular glutamate transporter 3 (Vglut3) in the cochleae of 5w, 8w, and 20w Vglut3^KO mice. Results indicated that AAV8-Vglut3 could mediate the exogenous expression of Vglut3 in all inner hair cells (IHCs). Auditory function was successfully restored, and the hearing threshold remained stable for at least 12 weeks after rescue. Moreover, the results revealed that the number of synaptic ribbons, as well as their morphology, was significantly recovered after gene therapy, potentially indicating the glutamate-dependent plasticity of IHCs. Taken together, our data introduce the possibility of gene therapy in adult mice and advance our knowledge of the role of Vglut3 in presynaptic plasticity.

Keywords: AAV; Vglut3; adult mouse; gene therapy; inner ear.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cochlea / metabolism
Genetic Therapy / methods
Hair Cells, Auditory, Inner* / metabolism
Hearing*
Mice
Mice, Knockout