Hearing restoration by gene replacement therapy for a multisite-expressed gene in a mouse model of human DFNB111 deafness

Luoying Jiang; Shao Wei Hu; Zijing Wang; Yi Zhou; Honghai Tang; Yuxin Chen; Daqi Wang; Xintai Fan; Lei Han; Huawei Li; Dazhi Shi; Yingzi He; Yilai Shu

doi:10.1016/j.ajhg.2024.08.008

Hearing restoration by gene replacement therapy for a multisite-expressed gene in a mouse model of human DFNB111 deafness

Am J Hum Genet. 2024 Oct 3;111(10):2253-2264. doi: 10.1016/j.ajhg.2024.08.008. Epub 2024 Sep 5.

Authors

Luoying Jiang¹, Shao Wei Hu¹, Zijing Wang², Yi Zhou³, Honghai Tang¹, Yuxin Chen¹, Daqi Wang¹, Xintai Fan¹, Lei Han¹, Huawei Li⁴, Dazhi Shi⁵, Yingzi He⁶, Yilai Shu⁷

Affiliations

¹ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
² ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Otorhinolaryngology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
³ Department of Otorhinolaryngology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
⁴ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
⁵ Department of Otorhinolaryngology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
⁶ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China. Electronic address: yingzihe09611@126.com.
⁷ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Shanghai 200031, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: yilai_shu@fudan.edu.cn.

PMID: 39241775
PMCID: PMC11480802 (available on 2025-04-03)
DOI: 10.1016/j.ajhg.2024.08.008

Abstract

Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2^-/- mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.

Keywords: DFNB111; MPZL2; gene therapy; hereditary hearing loss.

MeSH terms

Animals
Cochlea / metabolism
Cochlea / pathology
Deafness* / genetics
Deafness* / therapy
Dependovirus / genetics
Disease Models, Animal*
Evoked Potentials, Auditory, Brain Stem
Genetic Therapy*
Genetic Vectors
Hearing / genetics
Humans
Mice
Mice, Knockout