PAM-flexible adenine base editing rescues hearing loss in a humanized MPZL2 mouse model harboring an East Asian founder mutation

Shao Wei Hu, Sohyang Jeong, Luoying Jiang, Hansol Koo, Zijing Wang, Won Hoon Choi, Biyun Zhu, Heeyoung Seok, Yi Zhou, Min Gu Kim, Dan Mu, Huixia Guo, Ziyi Zhou, Sung Ho Jung, Yingting Zhang, Ho Byung Chae, Liheng Chen, Sung-Yeon Lee, Luo Guo, Myung-Whan Suh, Yang Xiao, Moo Kyun Park, Honghai Tang, Jae-Jin Song, Xi Chen, Ai Chen, Jun Ho Lee, Sangsu Bae (), Sang-Yeon Lee () and Yilai Shu ()
Additional contact information
Shao Wei Hu: Fudan University
Sohyang Jeong: Seoul National University College of Medicine
Luoying Jiang: Fudan University
Hansol Koo: Seoul National University College of Medicine
Zijing Wang: Fudan University
Won Hoon Choi: Seoul National University College of Medicine
Biyun Zhu: Fudan University
Heeyoung Seok: Seoul National University Hospital
Yi Zhou: University of South China
Min Gu Kim: Seoul National University College of Medicine
Dan Mu: Fudan University
Huixia Guo: Fudan University
Ziyi Zhou: Fudan University
Sung Ho Jung: Seoul National University College of Medicine
Yingting Zhang: Fudan University
Ho Byung Chae: Seoul National University College of Medicine
Liheng Chen: Fudan University
Sung-Yeon Lee: Macrogen Inc.
Luo Guo: Fudan University
Myung-Whan Suh: Seoul National University College of Medicine
Yang Xiao: Fudan University
Moo Kyun Park: Seoul National University College of Medicine
Honghai Tang: Fudan University
Jae-Jin Song: Seoul National University College of Medicine
Xi Chen: Fudan University
Ai Chen: Fudan University
Jun Ho Lee: Seoul National University College of Medicine
Sangsu Bae: Seoul National University College of Medicine
Sang-Yeon Lee: Seoul National University College of Medicine
Yilai Shu: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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 (hMPZL2Q74X/Q74X) 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 hMPZL2Q74X/Q74X 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.

Date: 2025
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DOI: 10.1038/s41467-025-62562-8

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