Advertisement

ResearchIn-Press PreviewOtology Open Access | 10.1172/JCI187872

Single-Dose Genome Editing Therapy Rescues Auditory and Vestibular Functions in Adult Mice with DFNA41 Deafness

Wei Wei,1 Wenliang Zhu,1 Stewart Silver,1 Ariel M. Armstrong,1 Fletcher S. Robbins,1 Arun Prabhu Rameshbabu,1 Katherina Walz,2 Yizhou Quan,1 Wan Du,1 Yehree Kim,1 Artur A. Indzhykulian,1 Yilai Shu,3 Xue-Zhong Liu,2 and Zheng-Yi Chen1

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Wei, W. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Zhu, W. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Silver, S. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Armstrong, A. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Robbins, F. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Rameshbabu, A. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Walz, K. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Quan, Y. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Du, W. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Kim, Y. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Indzhykulian, A. in: PubMed | Google Scholar |

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Shu, Y. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Liu, X. in: PubMed | Google Scholar

1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Spe, Harvard Medical School, Boston, United States of America

2Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

3ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

Find articles by Chen, Z. in: PubMed | Google Scholar

Published August 14, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187872.
Copyright © 2025, Wei et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 14, 2025 - Version history
View PDF
Abstract

Genome editing has shown the potential to treat genetic hearing loss. However, current editing therapies for genetic hearing loss have shown efficacy only in hearing rescue. In this study, we evaluated a rescue strategy using AAV2-mediated delivery of SaCas9/sgRNA in the mature inner ear of the P2rx2V61L/+ mouse model of DFNA41, a dominant, delayed-onset, and progressive hearing loss in humans. We demonstrate that local injection in adult mice results in efficient and specific editing that abolishes the mutation without notable off-target effects or AAV genome integration. Editing effectively restores long-term auditory and vestibular function. Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss (NIHL), a phenotype also observed in DFNA41 patients. Intervention at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention. An effective and specific gRNA for the human P2RX2 V60L mutation has been identified. Our study establishes the feasibility of editing to treat DFNA41 caused by P2RX2 V60L mutation in humans and opens an avenue for using editing to rescue hearing and vestibular function while mitigating noise-induced hearing loss.

Supplemental material

View

Version history
  • Version 1 (August 14, 2025): In-Press Preview
Advertisement
Advertisement