Designing therapeutic strategies to rescue epidermal defects in AEC syndrome

AEC (Ankyloblepharon- Ectodermal defects- Cleft lip/palate) syndrome is a rare genetic disease mainly characterized by severe skin lesions, defects in the hair, nails, sweat glands and teeth, closure of eyelids margins, and cleft lip and/or palate. Skin erosions appear at birth or soon after, are often devastating and can last several years, resulting in recurrent infections. This disease is caused by genetic defects in p63, a gene that encodes a crucial regulator of the skin. We recently characterized an AEC mouse model that faithfully recapitulates the skin defects and cleft palate found in AEC patients. We found that skin lesions and inflammation can lead to a systemic autoimmune disorder. This project aims at identifying novel therapeutic approaches to alleviate the skin lesions and prevent systemic inflammation. We will set-up a large molecular screening using a simple test to identify drugs able to reactivate the function of p63 protein in mutant cells. Active drugs will be tested in the mouse model for their ability to rescue skin lesions and suppress skin and systemic inflammation. As an alternative approach, we will use a DNA repair strategy (i.e. by exon-skipping, a mechanism that prevent the inclusion of specific mutant exons in the mature mRna) in human cells to shift expression of the mutant p63 to a non-pathogenic p63 form. If successful this treatment will be considered for repairing long-lasting lesions. The combination of studies in human cells derived from patients and in mouse model using different approaches will be instrumental to design novel therapies for this untreatable disease.