A Novel Targeted Therapy for Subarachnoid Hemorrhage

Summary The goal of this project is to develop a therapeutic capable of treating subarachnoid hemorrhage (SAH), a severe form of stroke characterized by bleeding into the subarachnoid space. Around 30,000 cases of spontaneous SAH occur in the US population every year. They are typically caused by a ruptured cerebral aneurysm, whose risk factors include, high blood pressure, smoking, family history and alcoholism. Aneurysmal SAH is associated with high mortality: 50% of patients die within 30 days, and of the survivors many retain neurological deficits. We have recently shown that the lipoxygenase ALOX15 is increased in macrophages adjacent to the subarachnoid blood in a mouse model of SAH, contributing to early brain injury. SAH induced brain edema was ALOX15 dependent and ALOX15 gene knockout reduced neuronal cell death and improved behavioral outcome. Loxagen’s lead compound, BPN-27332, selectively inhibits ALOX15 with high potency (IC50 = 80 nM) and can reduce neuronal cell death and improve neurological outcome after SAH. In this project, we will pursue the following aims: Aim 1: Synthesize sufficient amounts of BPN-27332 to support in vivo studies. Aim 2: Determine the most effective dose, confirm target engagement by lowering ALOX15 product and determine the optimal time window for treatment. These results will allow us to apply for a Phase II SBIR where we will expand our investigations and develop BPN-27332 as novel therapeutic to treat the brain injury resulting from subarachnoid hemorrhage.