QRX007 is a bi-functional protein designed to be highly selective and potent inhibitor of the KLK5 and KLK7 kallikreins at nanomolar concentrations as a potential treatment for Netherton Syndrome.
Netherton syndrome (NS) is an autosomal recessive skin disorder with severe skin inflammation, scaling, constant allergy and specific hair defection. NS is caused by dysfunctional mutations in the LEKTI-encoding SPINK5 gene resulted in complete loss or reduction of LEKTI activity. As LEKTI is a key regulator of epidermal proteolytic activity, loss or reduction of LEKTI activity leads to hyperactivity of serine proteases, including KLK5, KLK7 and KLK14, and subsequent over-degradation of corneodesmosomes by these proteases. Therefore, skin sections of NS patients show thinning and detachment of the stratum corneum and partial or complete loss of the stratum granulosum. Further, KLK5 is postulated to activate phospholipase A2, possibly via the PAR-2 pathway, leading to release of inflammation-mediating prostaglandins. KLK7 is also postulated to stimulate inflammatory effects in NS by activation of pro-inflammatory cytokine interleukin-1β (IL-1β). It has been demonstrated that KLK5/KLK7 double knock-out mice are protected from developing NS, potentially validating KLK5/KLK7 dual inhibition as an important therapeutic goal.