Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Netherton Syndrome; From mechanism to therapies

Project Coordinator

Inserm, France


Marcin Drag Wroclaw University of Technology Wroclaw, Poland
Christian Heinis Ecole Polytechnique Federale de Lausanne (EPFL) Lausanne, Switzerland
Schilling Oliver University of Freiburg Freiburg, Germany
Eleftherios Diamandis University of Toronto Toronto, Canada

Netherton Syndrome (NS) is a life-threatening autosomal skin disease caused by genetic mutations in the SPINK5 gene, encoding the endogenous serine protease inhibitor LEKTI. LEKTI deficiency disrupts the normal inhibitor/protease balance in the skin and results in abnormally high epidermal proteolytic activity, aberrant desquamation and impaired skin barrier functions (hallmarks of NS). Our group has previously identified KLK5 and KLK7 as the most important targets of skin LEKTI and has established a causal relationship between KLK overactivity and NS pathogenesis. In the current proposal we aim to better comprehend the molecular mechanism underlying the pathobiological roles of KLK5 and KLK7 in NS and to evaluate the therapeutic benefit of blocking KLKs with specific KLK inhibitors. First, we aim to extensively profile the activity of KLK5 and KLK7 in a cohort of NS patients and use proteomic technologies to uncover the specific proteins and pathways that are predominantly affected. Delineation of the molecular basis of NS will offer indispensable insights into the key events that drive NS pathogenesis and will lay the foundation for the development of novel therapeutic strategies. Next, we propose the development of inhibitors for both KLK5 and KLK7 using phage display technologies and the evaluation of these inhibitors in mouse xenograft NS model systems. Taken together, we believe that these studies will provide a holistic understanding of NS patho-physiology and will set the stage for the development of the first KLK-based targeted therapies for Netherton Syndrome.

E-Rare 2012 - Created by Toussaint Biger