Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F

Maryna V. Ivanchenko, Daniel M. Hathaway, Alex J. Klein, Bifeng Pan, Olga Strelkova, Pedro De-la-Torre, Xudong Wu, Cole W. Peters, Eric M. Mulhall, Kevin T. Booth, Corey Goldstein, Joseph Brower, Marcos Sotomayor, Artur A. Indzhykulian and David P. Corey ()
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Maryna V. Ivanchenko: Harvard Medical School
Daniel M. Hathaway: Harvard Medical School
Alex J. Klein: Harvard Medical School
Bifeng Pan: Harvard Medical School
Olga Strelkova: Harvard Medical School and Massachusetts Eye and Ear
Pedro De-la-Torre: Harvard Medical School and Massachusetts Eye and Ear
Xudong Wu: Harvard Medical School
Cole W. Peters: Harvard Medical School
Eric M. Mulhall: Harvard Medical School
Kevin T. Booth: Harvard Medical School
Corey Goldstein: Harvard Medical School
Joseph Brower: Harvard Medical School and Massachusetts Eye and Ear
Marcos Sotomayor: The Ohio State University
Artur A. Indzhykulian: Harvard Medical School and Massachusetts Eye and Ear
David P. Corey: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Usher syndrome type 1 F (USH1F), caused by mutations in the protocadherin-15 gene (PCDH15), is characterized by congenital deafness, lack of balance, and progressive blindness. In hair cells, the receptor cells of the inner ear, PCDH15 is a component of tip links, fine filaments which pull open mechanosensory transduction channels. A simple gene addition therapy for USH1F is challenging because the PCDH15 coding sequence is too large for adeno-associated virus (AAV) vectors. We use rational, structure-based design to engineer mini-PCDH15s in which 3–5 of the 11 extracellular cadherin repeats are deleted, but which still bind a partner protein. Some mini-PCDH15s can fit in an AAV. An AAV encoding one of these, injected into the inner ears of mouse models of USH1F, produces a mini-PCDH15 which properly forms tip links, prevents the degeneration of hair cell bundles, and rescues hearing. Mini-PCDH15s may be a useful therapy for the deafness of USH1F.

Date: 2023
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DOI: 10.1038/s41467-023-38038-y

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