Cytoprotective-selective activated protein C therapy for ischaemic stroke

Abstract

SummaryDespite years of research and efforts to translate stroke research to clinical therapy, ischemic stroke remains a major cause of death, disability, and diminished quality of life. Primary and secondary preventive measures combined with improved quality of care have made significant progress. However, no novel drug for ischemic stroke therapy has been approved in the past decade. Numerous studies have shown beneficial effects of activated protein C (APC) in rodent stroke models. In addition to its natural anticoagulant functions, APC conveys multiple direct cytoprotective effects on many different cell types that involve multiple receptors including protease activated receptor (PAR) 1, PAR3, and the endothelial protein C receptor (EPCR). Application of molecular engineered APC variants with altered selectivity profiles to rodent stroke models demonstrated that the beneficial effects of APC primarily require its cytoprotective activities but not its anticoagulant activities. Extensive basic, preclinical, and clinical research provided a compelling rationale based on strong evidence for translation of APC therapy that has led to the clinical development of the cytoprotective-selective APC variant, 3K3A-APC, for ischemic stroke. Recent identification of non-canonical PAR1 and PAR3 activation by APC that give rise to novel tethered-ligands capable of inducing biased cytoprotective signaling as opposed to the canonical signaling provides a mechanistic explanation for how APC-mediated PAR activation can selectively induce cytoprotective signaling pathways. Collectively, these paradigmshifting discoveries provide detailed insights into the receptor targets and the molecular mechanisms for neuroprotection by cytoprotective-selective 3K3A-APC, which is currently a biologic drug in clinical trials for ischemic stroke.

2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis

“…The central importance of APC-induced cell signaling for neuroprotection is consistent with discoveries that signaling-selective recombinant APC mutants, 47–49 including 3K3A-APC, are neuroprotective. 50–55 So what is known in some detail about the mechanisms for APC-induced neuroprotective cell signaling?…”

“…17, 47–49, 58,70,71 In every case where we studied recombinant APC mutants, signaling-selective APC mutants were neuroprotective while a highly anticoagulant APC mutant was neurotoxic. 50–53, 72,73 Hence, clinical trial efforts were undertaken on the assumption that APC-initiated cell signaling provides all of its neuroprotective activities.…”

Activation-resistant homozygous protein C R229W mutation causing familial perinatal intracranial hemorrhage and delayed onset of thrombosis

“…As most routine laboratory coagulation assays for plasma PC utilize a snake venom protease to activate PC, they fail to detect TM-activation-resistant PC mutants. It seems that standard lab tests for PC functional activities are inadequate when physicians are faced with striking neonatal or postnatal hemorrhagic neuropathologies which might reflect some currently unappreciated neuroprotective activities of APC[19, 20]. Thus, we recommend that PROC genotyping and/or more advanced PC bioassays be considered for efforts made to understand the pathophysiology of such clinical presentations.…”

Protective and detrimental effects of neuroectodermal cell–derived tissue factor in mouse models of stroke

“…Attenuation of TF-dependent activation of this pathway is the most likely explanation for the reduced expression of inflammatory cytokines/ chemokines and the less vascular permeability observed in low-TF mice after brain I/R injury. Interestingly, effects mediated by thrombin-dependent activation of PAR-1 are in sharp contrast to the protective effects mediated by activated protein C–dependent (APC-dependent) activation of PAR-1, which results in the improvement of blood-brain barrier function and activation of prosurvival pathways in neurons (46, 47). A nonanticoagulant form of APC that cleaves PAR-1 has been shown to reduce brain infarct size in animal models of ischemic stroke (48) and is now being evaluated clinically as an adjunct therapy with tPA treatment (49) (ClinicalTrials.gov, NCT02222714P).…”