Drug Discovery | Mechanism of Action
The Plasma kallikrein-kinin system is a central component of inflammation that has been recently implicated as a VEGF-independent pathway contributing to DME.
Plasma prekallikrein, an abundant circulating serine protease zymogen, is activated to plasma kallikrein at the site of vascular injury. Once activated, plasma kallikrein cleaves high molecular weight kininogen to release the peptide bradykinin, which is further metabolised to des-Arg-bradykinin. Both bradykinin and des-Arg-bradykinin are potent vasoactive hormones and neuropeptides that activate cell surface G protein coupled receptors with well-documented effects on vascular permeability, edema, pain, and inflammation. Recently, KalVista’s scientific founders have published research that shows the plasma kallikrein-kinin system is abnormally abundant in the vitreous of patients with DME.
Further studies using pre-clinical models of DME showed that inhibition of plasma kallikrein using various compounds, delivered either directly to the vitreous or systemically, reduces retinal leakage induced by diabetes. By contrast, vitreal activation of plasma kallikrein increases retinal vascular permeability, inflammation, haemorrhage and thickening. These findings have implicated the plasma kallikrein system as important in mediating DME.
Role of Kallikein activation in the pathophysiology of DME