In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model

Byunghwa Noh, John Hoon Rim, Ramu Gopalappa, Haiyue Lin, Kyu Min Kim, Min Jin Kang, Heon Yung Gee, Jae Young Choi, Hyongbum Henry Kim, Jinsei Jung

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Outer hair cell (OHC) degeneration is a major cause of progressive hearing loss and presbycusis. Despite the high prevalence of these disorders, targeted therapy is currently not available. Methods: We generated a mouse model harboring Kcnq4W276S/+ to recapitulate DFNA2, a common genetic form of progressive hearing loss accompanied by OHC degeneration. After comprehensive optimization of guide RNAs, Cas9s, vehicles, and delivery routes, we applied in vivo gene editing strategy to disrupt the dominant-negative allele in Kcnq4 and prevent progressive hearing loss. Results: In vivo gene editing using a dual adeno-associated virus package targeting OHCs significantly improved auditory thresholds in auditory brainstem response and distortion-product otoacoustic emission. In addition, we developed a new live-cell imaging technique using thallium ions to investigate the membrane potential of OHCs and successfully demonstrated that mutant allele disruption resulted in more hyperpolarized OHCs, indicating elevated KCNQ4 channel activity. Conclusion: These findings can facilitate the development of targeted therapies for DFNA2 and support the use of CRISPR-based gene therapy to rectify defects in OHCs.

Original languageEnglish
Pages (from-to)2465-2482
Number of pages18
Issue number5
Publication statusPublished - 2022

Bibliographical note

Funding Information:
We express our sincere gratitude to our honorable mentor, Prof. Won Sang Lee, for his devotion and unwavering support to establish the Precision Medicine Center for Yonsei Ear Science. We also thank Medical Illustration and Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work. This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (grant number 2018R1A5A2025079 to HYG, HHK; and 2019R1A2C1084033 to JJ; 2017M3A9B4062403 to HHK; 2020R1A2C3005787 to JYC); the Korean Health Technology R&D Project of the Ministry of Health and Welfare, Republic of Korea (HI18C0160 to JYC); and the Team Science Award of Yonsei University College of Medicine (grant number 6-2021-0003 to HYG and 6-2021-0002 to JJ).

Publisher Copyright:
© 2022 Ivyspring International Publisher. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)


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