Human promoter-driven AAV tools enable precision gene therapy targeting cochlear hair cells
Approximately 50% of hereditary deafness cases and most age-related hearing loss result from cochlear hair cell dysfunction. Adeno-associated virus (AAV)-mediated gene therapy offers a promising strategy for hearing restoration. However, the cochlea's complex cellular composition poses a significant challenge for targeted gene delivery into hair cells. Here, we establish a cross-species screening platform for cochlear AAV tools, applicable from rodents to large animals. Using this platform, we identify human promoters that specifically target inner hair cells, outer hair cells, or all hair cells in mice. The hair cell-specific coProB2 promoter is further validated in Bama miniature pigs and cynomolgus monkeys, achieving specific transgene expression in hair cells without auditory toxicity. Importantly, coProB2-driven gene therapies in DFNB79 and DFNB9 mouse models restore auditory function to near wild-type levels. Thus, this study establishes a cross-species-compatible, hair cell-specific AAV system, providing a versatile toolbox for cochlear hair cell gene therapy.
Authors
- Huayan Jin (ORCID: https://orcid.org/0000-0002-5161-6273)
- Lulu Jiang (ORCID: https://orcid.org/0000-0003-2944-0539)
- Fangzhi Tan (ORCID: https://orcid.org/0000-0002-8230-1784)
- Xinru Zhang
- Yue Lu (ORCID: https://orcid.org/0000-0001-9800-3792)
- Yu Shrike Zhang (ORCID: https://orcid.org/0000-0002-0045-0808)
- Xianmin Wu
- Jieyu Qi
- Wu Cao
- Jinyi Fan
- Huawei Tuo
- Qiuhan Sun
- Yang Xu
- Hao Wei
- Ling Lu
- Liyan Zhang
- Fangyi Chen
- Nianci Li
- Beibei Ye
Institutions
- Cazenovia College (US)
- Beijing Institute of Technology (CN)
- Southern University of Science and Technology (CN)
- Zhongda Hospital Southeast University (CN)
- Nanjing Drum Tower Hospital (CN)
- State Key Laboratory of Digital Medical Engineering (CN)
- Inner Mongolia Medical University (CN)
- Southeast University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1016/j.xcrm.2026.102725
- Primary Topic
- Hearing, Cochlea, Tinnitus, Genetics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Academy of Medical Sciences
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province
- Natural Science Foundation of Beijing Municipality
- Natural Science Foundation of Shandong Province
- Southeast University
- Taishan Scholar Foundation of Shandong Province
- Graduate Research and Innovation Projects of Jiangsu Province
- National Key Research and Development Program of China
- Shenzhen Science and Technology Innovation Program