The National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) has awarded Duke Anesthesiology’s David S. Warner, MD, a $475,175, two-year grant for his project, titled “Pharmacologic Suppression of Reperfusion Injury Following Endovascular Thrombectomy in Stroke.”
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 less than five percent of victims. Recently, major advance has been made with proven efficacy from endovascular mechanical thrombectomy in combination with tPA. Despite this, less than 50 percent 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.
Warner and members of his Multidisciplinary Neuroprotection Laboratory are working closely with chemists who have synthesized manganese porphyrins (MnP). MnP have been highly characterized for structure-activity 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. They have repeatedly shown enduring improvement in experimental stroke long-term outcome after therapeutic MnP dosing. MnP, now in human trials as a radioprotectant for normal tissue in the context of radiotherapy for brain malignancy, have achieved GMP synthesis, scale-up technology, and requisite preclinical toxicological screening.
Based on highly encouraging pilot data, Warner proposes MnP, given at endovascular thrombectomy reperfusion onset, as an adjunct pharmaceutical to optimize endovascular thrombectomy outcome. In Phase 1, he and his team of investigators 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 to monitor go/no-go end-points and develop protocols for human dose-escalation trials.
“This project is the preclinical culmination of nearly 15 years of investigation in our laboratory, which was enabled by the discovery of superoxide dismutase at Duke by Irwin Fridovich, PhD,” says Warner, a distinguished professor of anesthesiology. “Dr. Fridovich recently passed away. We are honored to continue his legacy of oxidative stress research by pursuing the very real possibility that these molecules he envisioned and created in collaboration with Ines Batinic-Haberle, PhD, will interrupt degradative enzymatic and transcriptional events initiated by ischemic insults and improve human stroke outcome. It also is my honor to have worked side by side with Dr. Huaxin Sheng, without whom’s expertise this work would never have happened.”