A Novel Targeted Therapy for Subarachnoid Hemorrhage

总结 该项目的目标是开发一种能够治疗蛛网膜下腔出血的治疗方法 (SAH)是一种严重的中风，其特征是出血进入蛛网膜下腔。周围 美国人群中每年发生30，000例自发性SAH。它们通常 由脑动脉瘤破裂引起，其危险因素包括，高血压， 吸烟家族史和酗酒动脉瘤性SAH与高死亡率相关：50% 的患者在30天内死亡，许多幸存者保留神经功能缺损。我们有 最近表明，脂氧合酶ALOX 15在邻近巨噬细胞中增加， 蛛网膜下腔血液在SAH小鼠模型中的作用，有助于早期脑损伤。SAH诱导 脑水肿是ALOX 15依赖性的，ALOX 15基因敲除减少神经元细胞死亡 和改善的行为结果。Loxagen的先导化合物BPN-27332选择性抑制 ALOX 15具有高效力（IC 50 = 80 nM），可以减少神经元细胞死亡并改善 蛛网膜下腔出血后的神经学结局。在这个项目中，我们将追求以下目标：目标1： 合成足量的BPN-27332以支持体内研究。目标2：确定 最有效剂量，通过降低ALOX 15产物确认靶点接合，并确定 最佳治疗时间窗这些结果将使我们能够申请第二阶段SBIR 在那里，我们将扩大我们的研究，并开发BPN-27332作为新的治疗方法，以治疗 蛛网膜下腔出血导致的脑损伤

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.