Pcdh15, or protocadherin-15, is a gene with 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 a leading cause of Usher syndrome type 1F (USH1F), which is characterized by congenital deafness, lack of balance, and progressive blindness in the form of retinitis pigmentosa [1,2,3,4].

In mouse models of USH1F, gene therapy approaches targeting Pcdh15 have shown promise. Using a dual-adeno-associated virus (AAV) strategy to deliver the full-length Pcdh15 coding sequence, researchers demonstrated the restoration of hearing and balance in these mice [1,2]. Moreover, this approach successfully expressed Pcdh15 in clinically relevant retinal models like human retinal organoids and non-human primate retina, efficiently targeting photoreceptors [1,2]. AAV-based delivery of mini-Pcdh15s, engineered with deletions in some extracellular cadherin repeats, also rescued hearing in USH1F mouse models by properly forming tip links and preventing hair cell bundle degeneration [3]. In a founder allele-specific Pcdh15 knockin mouse model, dual-vector AAV-based Pcdh15 gene therapy led to robust expression of exogenous Pcdh15 in the retinae, sustained recovery of electroretinogram amplitudes, and improvement in light-dependent translocation of phototransduction proteins [4].

In conclusion, Pcdh15 is crucial for the normal function of the inner ear and retina. Mouse models, especially those with Pcdh15-related knockouts or engineered alleles, have been instrumental in understanding its role in USH1F. These models have also paved the way for developing gene therapy strategies, offering hope for treating the hearing and vision impairments associated with USH1F [1,2,3,4].

References:

1. Ivanchenko, Maryna V, Hathaway, Daniel M, Mulhall, Eric M, György, Bence, Corey, David P. 2023. PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.11.09.566447. https://pubmed.ncbi.nlm.nih.gov/38014037/

2. Ivanchenko, Maryna V, Hathaway, Daniel M, Mulhall, Eric M, György, Bence, Corey, David P. 2024. PCDH15 dual-AAV gene therapy for deafness and blindness in Usher syndrome type 1F models. In The Journal of clinical investigation, 134, . doi:10.1172/JCI177700. https://pubmed.ncbi.nlm.nih.gov/39441757/

3. Ivanchenko, Maryna V, Hathaway, Daniel M, Klein, Alex J, Indzhykulian, Artur A, Corey, David P. 2023. Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F. In Nature communications, 14, 2400. doi:10.1038/s41467-023-38038-y. https://pubmed.ncbi.nlm.nih.gov/37100771/

4. Riaz, Sehar, Sethna, Saumil, Duncan, Todd, Carvalho, Livia S, Ahmed, Zubair M. 2023. Dual AAV-based PCDH15 gene therapy achieves sustained rescue of visual function in a mouse model of Usher syndrome 1F. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 3490-3501. doi:10.1016/j.ymthe.2023.10.017. https://pubmed.ncbi.nlm.nih.gov/37864333/