The proposed studies of this GO grant application are designed to translate our recent discovery of a new therapeutic target, MMP1-PAR1 on platelets. Using various animal models and blood samples from humans, we identified a blood clotting mechanism that is driven by matrix metalloprotease-1 (MMP-1) on the platelet surface. We found that MMP-1 activates protease-activated receptor-1 (PAR1) in an autocrine manner after platelets are exposed to collagen from the blood vessel wall. Treatments that block the MMP1-PAR1 pathway prevented blood clots from forming in the presence of collagen, suggesting that drugs targeting this metalloprotease-receptor system could offer a new way to treat patients with atherothrombotic disease and acute coronary syndromes. In this application we propose to use our novel Pepducin technology as a new treatment to prevent collagen-MMP1-PAR1 arterial thrombosis in the acute setting. Pepducins are lipidated peptides which target the cytoplasmic surface of their cognate receptor and interrupt signaling to internally-located G proteins. One of these PAR1-based pepducins, PZ-128 (P1pal-7), has been extensively tested in animals and proven to be highly effective in inhibiting PAR1-dependent platelet activation, collagen-driven arterial thrombosis, and atherosclerosis. PZ-128 has been shown to be safe and well tolerated in rodents when administered daily at high doses for 40-70 days. In the first stage of this CTRIP program, IND-enabling studies will be conducted to assess efficacy of PZ-128 in guinea pigs and non-human primates, and safety and toxicology in two other species with GMP material under GLP conditions. Clinical trials will be designed to evaluate the safety and efficacy of PZ-128 in normal volunteers and in patients with coronary artery disease. These studies will be conducted in collaboration with multiple academic, clinical, and CRO research laboratories across the United States. The major milestone at the end of the 24 month grant period will be an investigator-initiated IND submission to the FDA. If successful, we will then conduct phase I and II clinical studies as a five-year Stage 2 CTRIP award in normal volunteers and patients with acute coronary syndromes.
In the most recent data supplied by the American Heart Association, cardiovascular disease remained the major underlying cause of death in the United States with the majority of these deaths being due to coronary heart disease and stroke. Given the high prevalence of atherothrombotic disease and high MI and death rates, and incidence of adverse effects (bleeding and other safety issues), there remains a high unmet need for new therapeutics as exemplified by PZ-128, that can target both collagen and thrombin-dependent activation of platelets without unduly affecting hemostasis.
|Austin, Karyn M; Covic, Lidija; Kuliopulos, Athan (2013) Matrix metalloproteases and PAR1 activation. Blood 121:431-9|
|Zhang, Ping; Gruber, Andras; Kasuda, Shogo et al. (2012) Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Circulation 126:83-91|
|Kimmelstiel, Carey; Zhang, Ping; Kapur, Navin K et al. (2011) Bivalirudin is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention. Circ Cardiovasc Interv 4:171-9|
|Dowal, Louisa; Sim, Derek S; Dilks, James R et al. (2011) Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. Proc Natl Acad Sci U S A 108:2951-6|