Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8

Wan Du; Volkan Ergin; Corena Loeb; Mingqian Huang; Stewart Silver; Ariel Miura Armstrong; Zaohua Huang; Channabasavaiah B Gurumurthy; Hinrich Staecker; Xuezhong Liu; Zheng-Yi Chen

doi:10.1016/j.ymthe.2023.05.005

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Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8

Journal article

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Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8

Wan Du, Volkan Ergin, Corena Loeb, Mingqian Huang, Stewart Silver, Ariel Miura Armstrong, Zaohua Huang, Channabasavaiah B Gurumurthy, Hinrich Staecker, Xuezhong Liu, …

Molecular therapy

2023-05-22

DOI: https://doi.org/10.1016/j.ymthe.2023.05.005

PMID: 37244253

Appears in Miller School of Medicine - Latest Publications

Abstract

hair cells

AAV

TMPRSS3

gene therapy

spiral ganglion neurons

aged mouse

DFNB10

DFNB8

genetic hearing loss

recessive

Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3 homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in Tmprss3 mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons. This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness. It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.

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Title: Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8
Creators: Wan Du
Volkan Ergin
Corena Loeb
Mingqian Huang
Stewart Silver
Ariel Miura Armstrong
Zaohua Huang - Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Channabasavaiah B Gurumurthy - University of Nebraska Medical Center
Hinrich Staecker - Kansas University Center for Hearing and Balance Disorders, Kansas City, KS 66160, USA
Xuezhong Liu - Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: x.liu1@med.miami.edu
Zheng-Yi Chen
Publication Details: Molecular therapy
Grant note: NIH: R01DC016875, UG3TR002636, UH3TR002636, R01DC019404 Ines -Fredrick Yeatts Fund: R01DC012115, R01DC005575 DOD: RH220053
This work was supported by NIH R01DC016875, UG3TR002636, and UH3TR002636 (to Z.-Y.C.) , R01DC019404 (to X.L. and Z.-Y.C.) , Ines -Fredrick Yeatts Fund (to Z.-Y.C.) , R01DC012115, R01DC005575, and DOD RH220053 (to X.L.) . We acknowledge the BioRender that was used to create the graphical abstract. We acknowledge Olivia Catalini for help with the illustration.
Academic Unit: UMMG Department of Otolaryngology; Miller School of Medicine
Language: English
Resource Type: Journal article
PMID: 37244253
Record Identifier: 991031804120802976