PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models

Maryna V. Ivanchenko; Daniel M. Hathaway; Eric M. Mulhall; Kevin TA Booth; Mantian Wang; Cole W. Peters; Alex J. Klein; Xinlan Chen; Yaqiao Li; Bence György; David P. Corey

doi:10.1172/JCI177700

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

Find articles by Ivanchenko, M. in: JCI | PubMed | Google Scholar |

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

Find articles by Hathaway, D. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

Find articles by Mulhall, E. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

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

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

Find articles by Wang, M. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

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

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

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

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

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

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

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

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

Find articles by György, B. in: JCI | PubMed | Google Scholar

¹Department of Neurobiology, Harvard Medical School, Boston, United States of America

²Department of Ophthalmology, University of Basel, Basel, Switzerland

Find articles by Corey, D. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI177700.
Copyright © 2024, Ivanchenko 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 October 23, 2024 - Version history

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus (AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 protein in clinically relevant retinal models, including human retinal organoids and non-human primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.

Version 1 (October 23, 2024): In-Press Preview

PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models

Maryna V. Ivanchenko,¹ Daniel M. Hathaway,¹ Eric M. Mulhall,¹ Kevin TA Booth,¹ Mantian Wang,² Cole W. Peters,¹ Alex J. Klein,¹ Xinlan Chen,¹ Yaqiao Li,¹ Bence György,² and David P. Corey¹

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PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models

Maryna V. Ivanchenko,1 Daniel M. Hathaway,1 Eric M. Mulhall,1 Kevin TA Booth,1 Mantian Wang,2 Cole W. Peters,1 Alex J. Klein,1 Xinlan Chen,1 Yaqiao Li,1 Bence György,2 and David P. Corey1

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Maryna V. Ivanchenko,¹ Daniel M. Hathaway,¹ Eric M. Mulhall,¹ Kevin TA Booth,¹ Mantian Wang,² Cole W. Peters,¹ Alex J. Klein,¹ Xinlan Chen,¹ Yaqiao Li,¹ Bence György,² and David P. Corey¹