Project 462430

Outer epidermis contains several proteases which collectively orchestrate vital skin functions, such as skin renewal, barrier function and innate immunity. Amongst them, evidence from genetic and biochemical studies have highlighted specifically two proteases (KLK5 and KLK7) as the most important epidermal KLKs. These powerful enzymes are exclusively expressed in outer skin. Evolutionary, several endogenous mechanisms have been selected (e.g. pH, endogenous inhibitors) in order to secure a delicately balanced proteolytic activity in upper skin. While vital for normal skin physiology, increased skin KLK proteolytic activity can lead to severe skin pathologies. Animal and human data demonstrate that aberrant skin KLK (and specifically aberrant skin KLK5 and KLK7) activity is central to development of skin inflammation, as best illustrated in Netherton Syndrome (NS). NS is a genetic skin inflammatory disease caused by loss-of-function mutation in the endogenous skin KLK inhibitor, LEKTI. The resulting unopposed skin KLK activity leads to severe atopic dermatitis (AD)-like manifestations and life-threatening destruction of skin barrier w with profound water loss, infection, itch and inflammation. Several lines of evidence have fully sealed the importance of KLK5 and KLK7 as critical therapeutic targets in NS. Recent data from mouse models of NS has shown that concurrent KLK5 and KLK7 deletion completely rescues the disease phenotypes in mice bearing the NS causing LEKTI mutations. Our team launched 5 years ago a program for the development of topical kLK5/7 inhibitors. We have already identified promising lead compound series. Here we wish to support the commercialization growth of our novel technology (i.e. the proprietary KLK5/7 inhibitors) as novel topical drugs for skin inflammation. Bringing these compounds to approval for clinical trial testing will significantly enhance the interest of relevant receptor companies, organizations, and potential investors.