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 multirole 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. Scatter factor/hepatocyte growth factor (SF/HGF) neurotrophic, reduces cerebral infarct size, augments cerebral blood flow and promotes neuritogenesis and synaptogenesis, the growth of mature, functional neurons specifically in the per-infarct region or penumbra. These cellular effects lead to improved memory and learning in long term rodent studies even when HGF is given 7 days after the start of the ischemic insult. While administration of SF/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 Refanalin, an organic small-molecule SF/HGF mimetic that crosses the blood brain barrier , exerts neuroprotective effects (even when administered in a delayed setting) and augments psot ischemic blood flow in rat models of temporary and permanent mid-cerebral artery occlusion, tMCAO and pMCAO, respectively. This research effort is a collaborative agreement between Angion Biomedica Corp. and Dr. David Warner of Duke University to rigorously and independently test the dose, therapeutic window, and therapeutic duration of Refanalin in short and long term rat models of tMCAO and pMCAO, and addressing gender differences and activity in aged animals. This aggressive research plan will meet most of the recommendations 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. With the anticipated, positive outcome for Refanalin in our studies, Angion will be prepared to complete preclinical development, including testing Refanalin in non-human primate models before approaching the FDA with an IND package.
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. 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.
| Chaparro, Rafael E; Izutsu, Miwa; Sasaki, Toshihiro et al. (2015) Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice. J Cereb Blood Flow Metab 35:1044-53 |
