Neuregulin-1 as a Therapeutic Treatment of Ischemic Stroke

Howard University, Washington DC

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Abstract

PROJECT 1 ABSTRACT Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Significant racial/ethnic health disparities in stroke outcomes exist, particularly for African- Americans. Revascularization of the occluded cerebral artery, either by thrombolysis or thrombectomy, is the only effective therapy. However, only about 5-7% of acute stroke patients in the United States receive revascularization, so there is a significant need to develop new therapeutic strategies for stroke. We demonstrated that neuregulin-1 (NRG-1) reduced ischemia-induced neuronal death and neuroinflammation in rodent stroke models with a therapeutic window of >13 hours. NRG-1 administration also resulted in a significant improvement of neurological function when administered 3 days following ischemia, suggesting a role in neuronal repair. In addition, NRG-1 prevented neuronal injury and improved blood brain barrier integrity in animal models of brain hemorrhage. NRG-1 showed significant efficacy for improving cardiac function in multisite phase II patient studies and is currently in phase III human clinical trials for heart failure. NRG-1 has also shown a survival benefit in subjects with severe heart failure, which the ongoing phase III study in China is designed to assess for approval. The Good Manufacturing Practice (GMP) manufacturing of NRG-1 has also been approved for use in Phase III clinical trials in the US by the Food and Drug Administration (FDA). These studies provide evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke. The overall goal of this project is to develop NRG-1 as a novel neuroprotective stroke therapy. To achieve our goal, we propose the following set of specific aims: (1) determine the neuroprotective efficacy and therapeutic window for of NRG-1 following ischemic stroke; (2) evaluate therapeutic effect at time points relevant to stroke thrombectomy patients; (3) examine whether NRG-1 can reduce toxicity and extend the therapeutic window for tissue plasminogen activator (t-PA) following ischemic stroke; and (4) investigate the spatiotemporal regulation of transcriptional profiles initiated by NRG-1 induced neuroprotection following ischemic stroke. These findings could support the development of clinical studies using NRG-1 alone or in conjunction with other therapies, such as thrombolysis and thrombectomy, for the treatment of patients with acute stroke. If successful, this study could aid in the progression of NRG-1 towards clinical trial, FDA approval and deployment as a new treatment for ischemic stroke.