Title : P53-reactivating drug repurposing to efficiently treat severe skin erosion of patients suffering from p63-related ectodermal dysplasia (AEC) syndrome
Ectodermal dysplasia are genetic diseases affecting the development and homeostasis of skin and at least two ectodermal derivatives including hair, teeth, nails and certain glands. Among them, the syndrome AEC [Ankyloblépharon, Ectodermal dysplasia, cleft (cleft) labio-palatine] results from a heterozygous mutation on the SAM domain of the TP63 gene, of the P53 gene family. The cutaneous involvement associates hypohidrosis, neonatal erythema and congenital erosions even real cutaneous aplasia of the vertex, the back, the palms and the plants. In some cases, severe skin erosions never heal and there is no cure so far, except cosmetic surgeries. By the use of induced pluripotent stem cells (iPSC), we found that patient-derived-iPSC displayed altered epidermal commitment that can be partially rescued by PRIMA-1MET, a p53-reactivating small compound. PRIMA-1MET molecule is the subject of clinical trials on p53-dependent cancers. Primary keratinocytes (KCs) isolated from two AEC patients with chronic aplasia confirmed an altered epidermal differentiation that can be efficiently rescued by PRIMA-1MET.
Because of the absence of therapeutic possibility, we considered to repurpose the small compound for AEC syndrome patients. We initiated a topical treatment of formulated PRIMA-1MET topically on two AEC patients of 9 and 10 years old that significantly reduced aplastic areas in both patients (patient 1, 10 months of daily treatment, patient 2, 4 months of treatment) with re-epidermization and oozing disappearance. The persistent pain has virtually disappeared (EVA 4 to 1 in 2 months). Therefore, the use of a topical form in patients with chronic aplasia, persistent in the second decade, is particularly encouraging. The potential mechanisms of action of the drug on AEC patient cells will be discussed.
Audience Take Away:
p63 mutations are responsible for ectodermal dysplasia (ED) syndromes
Patients affected by p63-related ED suffer from severe skin erosions (hands, foot, scalp) could not heal.
PRIMA-1MET, a small anti-tumoral compound, efficiently can rescue ED severe skin erosions by topical treattment.