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- W4366190503 abstract "Pachyonychia congenita (PC) is a rare skin disease that is inherited in an autosomal dominant pattern. PC is associated with mutations in the genes encoding keratins K6, K16 or K17, which are related to epidermal hyperproliferation. Pachyonychia patients experience severe and painful palmoplantar keratoderma accompanied by blistering that is highly disabling as it greatly impairs ambulation. No curative treatment is currently available so therapy focuses on pain management using emollients to reduce hyperkeratosis and measures to limit friction and trauma to the feet. Gene therapy approaches to restore the function of the gene associated with this pathology should focus on inactivating the pathogenic allele, as it exerts a dominant negative effect on the healthy allele. The recent development of gene editing technology allows us to contemplate gene therapy protocols for pachyonychia patients using CRISPR tools. We have found that the c.513C>A (p.Asn171Lys) mutation in the human keratin 6 gene KRT6A generates a novel PAM motif for the Cpf1/Cas12 nuclease (VTTT). We have designed a gRNA complementary to the sequence adjacent to this PAM and evaluated its potency and allelic specificity in vitro, finding that electroporation with this guide in the form of CRISPR/Cas12 RNPs into keratinocytes from patients carrying this mutation results in highly efficient and specific disruption of the pathogenic allele and restoration of the intermediate filament cytoskeleton in these cells. As a first approach, we present a mouse model of humanized skin made from corrected keratinocytes to evaluate its efficacy in correcting the hyperkeratinization phenotype characteristic of this disease." @default.
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- W4366190503 date "2023-05-01" @default.
- W4366190503 modified "2023-10-01" @default.
- W4366190503 title "869 Gene editing for ex vivo pachyonychia congenita correction" @default.
- W4366190503 doi "https://doi.org/10.1016/j.jid.2023.03.879" @default.
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