324 Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET

P63 is a major transcription factor regulating skin development and homeostasis : cell proliferation, adhesion, and early differentiation. P63 is mutated in several rare syndromes called p63-related ectodermal dysplasia syndromes (ED). One of the main form, called AEC syndrome, associates ankyloblepharon, clef/lip palate, ED, and severe skin erosions that not always heal. P63 belongs to the p53 gene family. We found that ED-iPSC epidermal commitment can be rescued by a p53-reactivating compounds called PRIMA-1MET currently used in anticancer clinical trials. We established primary epidermal culture from two AEC teen with persistent skin erosions. The patients carry missense mutations on the SAM domain (I576T and I537T) of P63. We found that these primary keratinocytes (KCs) underwent altered epidermal differentiation that was rescued by PRIMA-1MET treatment. PRIMA-1MET was topically and daily applied on the right hand of one patient and on the scalp of the second patient. In both, the treatment allowed re-epithelialization of the eroded skin and drastic pain control after few weeks. Normally, mutant p63 exerts a dominant-negative effect, mainly through the formation of aggregate with WT p63 and p73. PRIMA-1MET did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1MET targets cell differentiation and not p63 activity directly. Thus repurposing of the antitumoral PRIMA-1MET compound could become a general treatment of AEC skin erosions and maybe other genodermatoses related to defective epidermal differentiation and/or wound repair.