MECHANISMS INVOLVED IN SKIN DEFECTS IN AEC SYNDROME AND DEVELOPMENT OF THERAPEUTIC STRATEGIES

Ankyloblepharon-Ectodermal Defect-Cleft Lip and/or Palate (AEC) syndrome is a complex disorder characterized by skin defects, including severe erosions at birth, skin thickening of palms and soles, cleft palate with or without cleft lip, and fusion of the eyelid margins. Other features include missing or conical shape teeth, and malformations of the inner ear that can lead to recurrent otitis and secondary conductive hearing loss. Scalp hair, eyebrows, and eyelashes are sparse. Nails may be abnormal. AEC syndrome is inherited in an autosomal dominant fashion, meaning that an abnormal allele from one parent is capable of causing disease, even though the matching allele from the other parent is normal. The affected gene, p63, encodes a crucial regulator of gene expression in skin and in other epithelia. Full understanding of AEC syndrome is impaired by genetic and clinical variability among unrelated patients, and by lack of biological fetal or neonatal biological samples. We recently generated a mouse model with a genetic alteration identical to the one found in human patients. The AEC mutant mouse displays several features typical of the human AEC syndrome, including severe skin defects, cleft palate, aberrant development of hair follicles and teeth. Our goal is to characterize in depth the molecular pathways that are affected by mutant p63 in the developing skin. These studies will help to identifying molecules whose changes are responsible for the pathogenesis of this disease, and that can be targeted by currently available drugs. In addition, we are investigating the possibility to correct the genetic defect by gene correction in epidermal cells derived from patients using Zinc-finger nuclease technology. If successful this technique could potentially be used to treat skin erosion by autologous transplantation of corrected epidermal cells.