Pharmacologic Suppression of Reperfusion Injury Following Endovascular Thrombectomy In Stroke.

点击翻译按钮获取中文摘要

Ischemic stroke is a leading cause of death and disability in the United States. This often is attributable to thrombus formation at an atherosclerotic plaque or thromboembolism. Patients who present within 4.5 hours of symptom onset are eligible for thrombolysis with tissue plasminogen activator (tPA). This serves <5% of victims. Recently, major advance has been made with proven efficacy from endovascular mechanical thrombectomy in combination with tPA. Despite this, <50% of treated patients have a good recovery. Basic and clinical science indicate that abrupt restoration of oxygen delivery to ischemic tissue causes reperfusion injury that amplifies/propagates adverse cascades initiated by the initial ischemic insult. There has been widespread call for pharmacologic intervention to mitigate reperfusion injury. The mechanistic basis for reperfusion injury is diverse, but fundamentally associated with rapid onset dysfunction of intracellular mechanisms responsible for regulation of oxygen metabolism. This leads to oxidative stress, inflammation, apoptosis, blood-brain barrier disruption and tissue damage. We are working closely with chemists who have synthesized manganese porphyrins (MnP). MnP have been highly characterized and serve as potent catalytic oxidoreductants. MnP have extraordinary efficacy to favorably modulate redox-mediated activation of transcription factors (e.g., NF-kB, Nrf2) and MAPK and phosphatases. MnP also serve as potent catalytic reductants of reactive oxygen/nitrogen species. We have repeatedly shown enduring improvement in experimental stroke long-term outcome after therapeutic MnP dosing. The lead MnP, BMX-001, now in human trials as a radioprotectant for normal tissue in the context of radiotherapy for brain malignancy, has achieved GMP synthesis, scale-up technology, and requisite preclinical toxicological screening. Based on highly encouraging pilot data, we propose BMX-001, given at endovascular thrombectomy reperfusion onset, as an adjunct pharmaceutical to optimize endovascular thrombectomy outcome. In Phase 1, we will define optimal dosing and maximal ischemia duration before reperfusion and treatment onset that retains efficacy, measure long-term functional outcome in aged, metabolic syndrome, and spontaneously hypertensive rats, define interactions with tPA activity, and obtain independent laboratory efficacy validation. A Clinical Trial Consulting Team, consisting of independent stroke experts, will work in collaboration with Biomimetix to monitor go/no-go end-points and develop protocols for human dose-escalation trials.