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PCDH15 dual-AAV gene therapy for deafness and blindness in Usher syndrome type 1F models
Maryna V. Ivanchenko, … , Bence György, David P. Corey
Maryna V. Ivanchenko, … , Bence György, David P. Corey
Published October 23, 2024
Citation Information: J Clin Invest. 2024;134(23):e177700. https://doi.org/10.1172/JCI177700.
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Research Article Ophthalmology Otology Article has an altmetric score of 72

PCDH15 dual-AAV gene therapy for deafness and blindness in Usher syndrome type 1F models

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Abstract

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 (dual-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 nonhuman 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.

Authors

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

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Figure 3

Delivery of PCDH15 with dual AAVs preserves the morphology of stereocilia bundles, mechanotransduction, and tip links in the Pcdh15fl/fl, Myo15a-Cre+/− conditional knockout mouse model.

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Delivery of PCDH15 with dual AAVs preserves the morphology of stereocili...
(A) Representative confocal microscopy images captured from the middle turn of 5-week-old cochleae, showing OHCs stained with phalloidin. The panels illustrate OHCs from Pcdh15fl/fl hearing control mice (n = 3), uninjected Pcdh15fl/fl, Myo15a-Cre+/− conditional knockout mice (n = 3), and knockout mice that received dual-AAV injections (n = 5). (B) Scanning electron micrographs of hair bundles of a hearing control mouse and untreated conditional knockouts. In the knockouts, the bundles were severely disrupted. However, in the OHCs of a conditional knockout treated with dual AAVs encoding PCDH15, normal bundle morphology was preserved (n = 5). (C) Representative confocal microscopy images at 5 weeks from the middle turn of the cochlea show anti-HA staining at the tips of stereocilia in knockout cochleae treated with dual AAVs encoding HA.PCDH15 at P1 (n = 4). (D) Transduction efficiency in IHCs and OHCs at 5 weeks in treated Pcdh15fl/fl, Myo15a-Cre+/− conditional knockout mice (n = 4). Data are presented as mean ± SEM. (E) Immunogold scanning electron microscopy localization of HA-tagged PCDH15 in OHC stereocilia of treated knockout mice. Multiple 12 nm gold beads (light yellow) were detected in a scanning electron microscopy image, confirming that HA-tagged PCDH15 goes to the tips of stereocilia, except the tallest (n = 3). (F) Rescue of FM1-43 uptake in a treated cochlea. (G) Average percentage of IHCs and OHCs loaded with FM1-43 in conditional knockout mice injected with dual AAVs (n = 4) and in control mice (n = 4). Data are presented as mean values ± SEM. Scale bars: 5 μm (A–C and F), 100 nm (E).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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