Research Project
8314513
DESCRIPTION (provided by applicant): Ischemic Stroke continues to be a major cause of morbidity and mortality in the United States. Currently approved thrombolytic therapy suffers for a narrow therapeutic window and clearly other therapeutic strategies are needed, such as neuroprotective or restorative agents. Unfortunately the quest for a therapeutic remains beset by a history of failed clinical trials involving promising neuroprotective candidates. Instead of targeting a single pathway in the cascade leading to ischemic neuronal damage, treatment with multifunctional compounds or supplements of endogenous multi-role factors might be better choices for preventing ischemic brain injury. One of the most exciting areas of research for treatment of cerebral ischemia is the use of angiogenic growth factors, agents that exert direct neuroprotective effects and augment blood flow to the ischemic region. Hepatocyte growth factor (HGF) a neurotrophic factor, reduces cerebral infarct size, augments cerebral blood flow and promotes neuritogenesis and synaptogenesis, the growth of mature, functional neurons specifically in the peri-infarct region or penumbra. While administration of HGF as gene or protein therapy has potential for the treatment of ischemic stroke, the therapeutic feasibility of this approach is limited by the presence of the blood-brain-barrier, and other issues such as immune and inflammatory responses evoked by adenovirus proteins, inherent instability of proteins in solution, their limited tissue half-life and cost-prohibitive production. We have identified BB3, an organic small-molecule HGF mimetic that crosses the blood brain barrier, exerts neuroprotective effects (even when administered in a delayed setting) and augments post ischemic blood flow in rat models of temporary and permanent mid-cerebral artery occlusion, tMCAO and pMCAO, respectively. More recently under rigorously controlled studies, we have confirmed the activity of BB3 at Angion and independently in the laboratory of Dr. David Warner, Duke University. Excitingly, Dr Warner's group has demonstrated a significant effect of BB3 both on infarct size and neurologic function at day 28 in both permanent and temporary models of mid-cerebral artery occlusion (MCAO) in the rat, when first dosed 6 hours after occlusion. This research effort under SBIR phase II funding is near completion and we look to further validate the drug as potential therapy for stroke under the guideline of the Stroke Therapy Academic Industry Roundtable (STAIR) of 1999, which still remains the standard for preclinical drug development for stroke neuroprotective and restorative drugs. The additional pre-clinical studies proposed here will satisfy these guidelines as promulgated by STAIR under a collaborative effort with Dr. Warner and Dr. Cenk Ayata of Massachusetts General Hospital (MGH). Upon completion of the pre-clinical studies, we propose to enter the clinic by conducting a dose-escalating safety trial in stroke patients at MGH with Dr Karen Furie, Director MGH Stroke Services. PUBLIC HEALTH RELEVANCE: Ischemic stroke is a major cause of death in the United States. Unfortunately attempts at finding new neuroprotective therapies have failed miserably in clinical trials. BB3/Refanalin, a small molecular weight mimetic of HGF has been shown to protect brain cells in animal models and may prove to be a novel therapy to treat ischemic stroke.
