Approaches and Vectors for Efficient Cochlear Gene Transfer in Adult Mouse Models

Author:

Zhao Yu,Zhang Longlong,Wang Daqi,Chen Bing,Shu Yilai

Abstract

Inner ear gene therapy using adeno-associated viral vectors (AAVs) in neonatal mice can alleviate hearing loss in mouse models of deafness. However, efficient and safe transgene delivery to the adult mouse cochlea is critical for the effectiveness of AAV-mediated therapy. Here, we examined three gene delivery approaches including posterior semicircular canal (PSCC) canalostomy, round window membrane (RWM) injection, and tubing-RWM+PSCC (t-RP) in adult mice. Transduction rates and survival rates of cochlear hair cells were analyzed, hearing function was recorded, AAV distribution in the sagittal brain sections was evaluated, and cochlear histopathologic images were appraised. We found that an injection volume of 1 μL AAV through the PSCC is safe and highly efficient and does not impair hearing function in adult mice, but local injection allows AAV vectors to spread slightly into the brain. We then tested five AAV serotypes (PHP.eB, IE, Anc80L65, AAV2, and PHP.s) in parallel and observed the most robust eGFP expression in inner hair cells, outer hair cells, and spiral ganglion neurons throughout the cochlea after AAV-Anc80L65 injection. Thus, PSCC-injected Anc80L65 provides a foundation for gene therapy in the adult cochlea and will facilitate the development of inner ear gene therapy.

Funder

National Key R&D Program of China

National Natural Science Foundation of China

Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission

Science and Technology Commission of Shanghai Municipality

Excellent physician—Excellent clinical researcher Plan of Eye & ENT Hospital of Fudan University

Shanghai Education Development Foundation and the Shanghai Municipal Education Commission

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry

Reference43 articles.

1. (2022, September 15). Deafness and hearing loss. Available online: https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearing-loss.

2. Why Do Hearing Aids Fail to Restore Normal Auditory Perception?;Lesica;Trends Neurosci.,2018

3. Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss;Gyorgy;Nat. Med.,2019

4. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model;Akil;Proc. Natl. Acad. Sci. USA,2019

5. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents;Gao;Nature,2018

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