PAM-flexible adenine base editing rescues hearing loss in a humanized MPZL2 mouse model harboring an East Asian founder mutation
Hearing loss is one of the most prevalent sensory disorders, but no commercial biological treatments are currently available. Here, we identify an East Asia-specific founder mutation, the homozygous c.220 C > T mutation in MPZL2, that contributes to a significant proportion of hereditary deafness cases in our cohort study. We find that the disease-causing mutation can be targetable by adenine base editors (ABEs) that enable A·T-to-G·C base corrections without DNA double-strand breaks. To demonstrate this, we develop a humanized mouse model (hMPZL2<sup>Q74X/Q74X</sup>) that recapitulates human MPZL2 deafness and leads to progressive hearing loss. A PAM-flexible ABE variant with reduced bystander and off-target effects (ABE8eWQ-SpRY:sgRNA3) is packaged in dual adeno-associated viruses (AAVs) and injected into the inner ear of hMPZL2<sup>Q74X/Q74X</sup> mice and effectively corrects the mutation. This treatment significantly restores hearing function, improves inner ear structural integrity, and reverses altered gene expression. Base editing may hold therapeutic potential for hereditary deafness, including most cases of MPZL2 deafness.
Authors
- Ho Byung Chae
- Shao Wei Hu
- Honghai Tang
- Yi Zhou (ORCID: https://orcid.org/0000-0002-7119-7408)
- Won Hoon Choi
- Heeyoung Seok (ORCID: https://orcid.org/0000-0003-2699-9935)
- Hansol Koo
- Yingting Zhang (ORCID: https://orcid.org/0000-0003-1722-5022)
- Jae‐Jin Song (ORCID: https://orcid.org/0000-0002-6631-3232)
- Sung Ho Jung (ORCID: https://orcid.org/0000-0002-5585-1086)
- Xi Chen (ORCID: https://orcid.org/0000-0002-5674-9446)
- Luoying Jiang
- Sangsu Bae (ORCID: https://orcid.org/0000-0003-3615-8566)
- Moo Kyun Park (ORCID: https://orcid.org/0000-0002-8635-797X)
- Ai Chen (ORCID: https://orcid.org/0000-0003-3481-999X)
- Liheng Chen (ORCID: https://orcid.org/0000-0002-9545-7809)
- Luo Guo (ORCID: https://orcid.org/0000-0001-7293-5591)
- Yilai Shu (ORCID: https://orcid.org/0000-0001-8893-434X)
- Huixia Guo (ORCID: https://orcid.org/0000-0001-9660-9520)
- Biyun Zhu (ORCID: https://orcid.org/0009-0006-0608-5262)
- Myung‐Whan Suh (ORCID: https://orcid.org/0000-0003-1301-2249)
- Jun Ho Lee (ORCID: https://orcid.org/0000-0002-8668-7047)
- Mingu Kim (ORCID: https://orcid.org/0000-0003-2984-762X)
- Zijing Wang (ORCID: https://orcid.org/0000-0002-1256-6955)
- Sang‐Yeon Lee (ORCID: https://orcid.org/0000-0003-3566-8708)
- Xiao Yang (ORCID: https://orcid.org/0000-0003-2005-3188)
- Ziyi Zhou (ORCID: https://orcid.org/0009-0006-7034-9808)
- Sung‐Yeon Lee (ORCID: https://orcid.org/0000-0002-1047-2357)
- Sangki Jeong
- Dan Mu (ORCID: https://orcid.org/0000-0002-4860-2620)
Institutions
- Seoul National University (KR)
- Cancer Research Institute (US)
- Fudan University (CN)
- Seoul National University Hospital (KR)
- Eye & ENT Hospital of Fudan University (CN)
- National University College (PR)
- Macrogen (South Korea) (KR)
- First Affiliated Hospital of University of South China (CN)
- Hengyang Academy of Agricultural Sciences (CN)
- University of South China (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-05
- DOI
- https://doi.org/10.1038/s41467-025-62562-8
- Citations
- 4
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- National Natural Science Foundation of China