Citation:
Ivanchenko MV, Hathaway DM, Klein AJ, Pan B, Strelkova O, De-la-Torre P, Wu X, Peters CW, Mulhall EM, Booth KT, Goldstein C, Brower J, Sotomayor M, Indzhykulian AA, Corey DP. Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F. Nat Commun. 2023 Apr 26;14(1):2400. doi: 10.1038/s41467-023-38038-y. PMID: 37100771; PMCID: PMC10133396.
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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.
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Last updated on 11/19/2019