Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F

Mutations in the PCDH15 gene, encoding protocadherin-15, are amongst the leading causes of Usher syndrome type 1 (USH1F), and account for up to 12% USH1 cases worldwide. A founder truncating variant of PCDH15 has a ∼2% carrier frequency in Ashkenazi Jews accounting for nearly 60% of their USH1 cases. Although cochlear implants can restore hearing perception in USH1 patients, presently there are no effective treatments for the vision loss due to retinitis pigmentosa. We established a founder allele-specific Pcdh15 knockin mouse model as platform to ascertain therapeutic strategies. Using a dual-vector approach to circumvent the size limitation of adeno-associated virus (AAVs), we observed robust expression of exogenous PCDH15 in the retinae of Pcdh15 mice, sustained recovery of electroretinogram (ERG) amplitudes and key retinoid oxime, substantially improved light-dependent translocation of phototransduction proteins, and enhanced retinal pigmented epithelium derived enzymes. Thus, our data raises the hope and paves the way for future gene therapy trials in USH1F subjects.