Netherton Syndrome: From mechanisms to therapeutics

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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 skinbarrier 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 over-activity 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 pathophysiology and will set the stage for the development of the first KLK-based targeted therapies for Netherton Syndrome.