AAV-ie enables safe and efficient gene transfer to inner ear cells

Fangzhi Tan; Cenfeng Chu; Jieyu Qi; Wenyan Li; Dan You; Ke Li; Xin Chen; Weidong Zhao; Cheng Cheng; Xiaoyi Liu; Yunbo Qiao; Bing Su; Shuijin He; Chao Zhong; Huawei Li; Renjie Chai; Guisheng Zhong

doi:10.1038/s41467-019-11687-8

AAV-ie enables safe and efficient gene transfer to inner ear cells

Nat Commun. 2019 Aug 19;10(1):3733. doi: 10.1038/s41467-019-11687-8.

Authors

Fangzhi Tan¹, Cenfeng Chu^{2

3

4}, Jieyu Qi^{5

6}, Wenyan Li⁷, Dan You⁷, Ke Li^{4

8

9}, Xin Chen^{3

4}, Weidong Zhao⁷, Cheng Cheng^{10

11}, Xiaoyi Liu^{2

3

4}, Yunbo Qiao¹², Bing Su^{2

3

4}, Shuijin He³, Chao Zhong⁸, Huawei Li¹³, Renjie Chai^{14

15

16

17

18}, Guisheng Zhong^{19

20

21}

Affiliations

¹ iHuman Institute, ShanghaiTech University, 201210, Shanghai, China. tanfzh@shanghaitech.edu.cn.
² iHuman Institute, ShanghaiTech University, 201210, Shanghai, China.
³ School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China.
⁴ University of the Chinese Academy of Sciences, 100049, Beijing, China.
⁵ MOE Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, 210096, Nanjing, China.
⁶ Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China.
⁷ ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, 200031, Shanghai, China.
⁸ School of Physical Science and Technology, ShanghaiTech University, 201210, Shanghai, China.
⁹ Shanghai Institute of Ceramics, Chinese Academy of Sciences, 200050, Shanghai, China.
¹⁰ Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory), No. 321 Zhongshan Road, 210008, Nanjing, China.
¹¹ Research Institute of Otolaryngology, No. 321 Zhongshan Road, 210008, Nanjing, China.
¹² Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, 510006, Guangzhou, China.
¹³ ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, 200031, Shanghai, China. hwli@shmu.edu.cn.
¹⁴ MOE Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, 210096, Nanjing, China. renjiec@seu.edu.cn.
¹⁵ Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China. renjiec@seu.edu.cn.
¹⁶ ENT Institute and Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, Key Laboratory of Hearing Medicine of NHFPC, Shanghai Engineering Research Centre of Cochlear Implant, State Key Laboratory of Medical Neurobiology, Fudan University, 200031, Shanghai, China. renjiec@seu.edu.cn.
¹⁷ Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China. renjiec@seu.edu.cn.
¹⁸ Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, 100069, Beijing, China. renjiec@seu.edu.cn.
¹⁹ iHuman Institute, ShanghaiTech University, 201210, Shanghai, China. zhongsh@shanghaitech.edu.cn.
²⁰ School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China. zhongsh@shanghaitech.edu.cn.
²¹ Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China. zhongsh@shanghaitech.edu.cn.

Abstract

Hearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.

Publication types

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

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics*
Cells, Cultured
Dependovirus / genetics*
Female
Gene Transfer Techniques
Genetic Therapy / methods*
Genetic Vectors / genetics
Hair Cells, Auditory, Inner / cytology*
Hearing Loss / genetics*
Hearing Loss / therapy*
Male
Mice
Mice, Inbred C57BL

Substances

Atoh1 protein, mouse
Basic Helix-Loop-Helix Transcription Factors