Pcdh15, or protocadherin-15, is a gene of significant biological importance. In hair cells of the inner ear, it is a component of tip links, fine filaments that open mechanosensory transduction channels [3]. Mutations in Pcdh15 are among the leading causes of Usher syndrome type 1F (USH1F), which is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa [1,2,3,4].

In mouse models of USH1F, gene therapy strategies targeting Pcdh15 have been explored. Using a dual-adeno-associated virus (dual-AAV) strategy to deliver the full-length Pcdh15 coding sequence, it was possible to exceed the single AAV packaging limit. This approach effectively restored hearing and balance in mouse USH1F models [1,2]. Also, expressing PCDH15 in clinically relevant retinal models such as human retinal organoids and non-human primate retina was successful, with efficient targeting of photoreceptors and proper protein expression in the calyceal processes [1,2]. Another study engineered mini-Pcdh15s that could fit in an AAV. Injection of an AAV encoding one of these mini-Pcdh15s into the inner ears of mouse models of USH1F led to proper tip-link formation, prevention of hair cell bundle degeneration, and rescue of hearing [3]. In a founder allele-specific Pcdh15 knockin mouse model, dual-vector-based Pcdh15 gene therapy achieved sustained recovery of electroretinogram amplitudes, improved light-dependent translocation of phototransduction proteins, and enhanced levels of retinal pigment epithelium-derived enzymes, raising hope for future gene therapy trials in USH1F subjects [4].

In conclusion, Pcdh15 plays a crucial role in maintaining normal auditory and visual functions. Mouse models, especially those with targeted modifications like knockouts or knockins related to Pcdh15, have been instrumental in understanding its function and developing potential gene therapy strategies for USH1F. These models have provided valuable insights into how disruptions in Pcdh15 lead to the complex symptoms of USH1F, and how restoring its function can potentially reverse these deficits [1,2,3,4].