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ResearchIn-Press PreviewGeneticsOtology Open Access | 10.1172/JCI193812

Postnatal Slc26a4 gene therapy improves hearing and structural integrity in a hereditary hearing loss model

Yi-Hsiu Tsai,1 Peng-Yu Wu,1 Yu-Chi Chuang,1 Chun-Ying Huang,1 Hiroki Takeda,2 Hiroshi Hibino,2 Chen-Chi Wu,3 and Yen-Fu Cheng4

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

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

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

Find articles by Wu, P. in: PubMed | Google Scholar

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

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

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

Find articles by Huang, C. in: PubMed | Google Scholar

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

Find articles by Takeda, H. in: PubMed | Google Scholar

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

Find articles by Hibino, H. in: PubMed | Google Scholar |

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

Find articles by Wu, C. in: PubMed | Google Scholar

1Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

2Division of Glocal Pharmacology, Department of Pharmacology, The University of Osaka, Graduate School of Medicine, Osaka, Japan

3Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

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

Published February 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI193812.
Copyright © 2026, Tsai 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 February 17, 2026 - Version history
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Abstract

Mutations in SLC26A4 are the second most common cause of hereditary hearing loss in many Asian countries, leading to DFNB4, a condition characterized by progressive hearing loss and inner ear malformations. While gene therapy holds great potential, its postnatal application has remained unexplored due to the lack of suitable animal models and the challenges of prenatal intervention. This study represents the first preclinical investigation of postnatal gene therapy for DFNB4 using a clinically relevant Slc26a4 mutant mouse model that closely replicates human auditory phenotypes. Utilizing the synthetic AAV.Anc80L65 vector, we achieved robust SLC26A4 delivery to critical cochlear regions, including the endolymphatic sac and cochlear lateral wall. Comprehensive phenotypic analyses revealed a critical therapeutic window spanning the neonatal and juvenile stages, within which AAV.Anc80L65-mediated SLC26A4 delivery significantly improved hearing, as evidenced by lower auditory brainstem response thresholds. Moreover, the therapy preserved hair cells, reduced endolymphatic sac enlargement, partially restored the endocochlear potential, and mitigated inner ear structural degeneration. These therapeutic effects persisted into adulthood, highlighting the long-term efficacy of postnatal gene therapy. Together, these findings establish a critical therapeutic window for DFNB4 and demonstrate the feasibility of targeting the endolymphatic sac and cochlear lateral wall for effective intervention.

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