493 Recapitulating the Ehlers-Danlos Syndrome skin phenotype in a novel xenograft model

Abstract

The Ehlers-Danlos Syndrome (EDS) is a connective tissue disease characterized by hyperextensible skin, joint hypermobility and cutaneous fragility. EDS is primarily caused by mutations in fibrillar collagens or genes involved in the biosynthesis of these proteins. No cure exists for EDS, and in many cases the genetic cause of the disease cannot be reliably determined. The lack of appropriate in vitro and in vivo EDS models that faithfully recapitulate the clinical phenotype of the disease further complicates studies of EDS mechanisms and hampers progress toward developing efficient therapeutic strategies for the disease. To develop a clinically relevant EDS model and validate its usefulness in identifying mechanisms of the disease, we focused on an EDS patient who did not harbor known EDS-associated mutations but exhibited classical symptoms of the disease. We grafted fibroblasts isolated from a skin biopsy of this patient together with healthy keratinocytes onto an immunocompromised mouse using a silicone chamber to recapitulate the EDS skin phenotype in a xenograft model. We found that the grafts formed with EDS fibroblasts exhibited a disorganized collagen network typical to human EDS skin. By manipulating gene expression in EDS fibroblasts in our in vivo model, we can now validate the genetic component responsible for the disease in our patient based on candidate genes already identified by RNA Sequencing. We have also generated induced pluripotent stem cells from this patient to initiate gene-correction studies to develop a stem cell-based therapy for EDS.