Development of skin-humanized mouse models of pachyonychia congenita

Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p.Asn171Lys mutation of the keratin 6a gene (KRT6A), we were able to regenerate PC-derived human skin that appeared phenotypically normal, but developed sustained PC features after the use of an acute hyperproliferative stimulus (i.e., tape stripping). In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p.Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease.