Hiltonol provides potent neuroprotection from ischemic brain injury in stroke.

描述（由申请人提供）：脑缺血是美国发病率和死亡率的主要原因。我们寻求开发治疗方法，以减少脑缺血性损伤造成的损伤和功能障碍的程度，这是一个重要的未满足医疗需求的领域。我们已经表明，配体激活toll样受体（TLR）家族的模式识别受体对缺血性脑损伤提供了显著的保护。在本提案中，我们试图评估Hiltonol(R)，一种合成的dsRNA TLR3配体作为预防脑卒中损伤的神经保护剂。Hiltonol是一种临床阶段的治疗药物，正在多个I/II期临床试验中进行测试，由聚l -赖氨酸和羧甲基纤维素（poly-ICLC）稳定的多肌苷-多胞酸组成。在我们的初步数据中，我们表明，在小鼠中风和肾缺血模型中，全身给药Hiltonol可以保护大脑和肾脏免受随后的损伤。这类药物将对高危人群产生相当大的临床影响。凭借我们对tlr诱导的神经保护的独特理解和丰富的Hiltonol临床开发背景，我们的团队将评估Hiltonol作为候选卒中治疗药物的可行性。我们的I期SBIR的具体目标是通过小鼠大脑中动脉闭塞（MCAO）模型的临床前研究推进Hiltonol，并在小鼠中确定翻译生物标志物，这将使我们为非人类灵长类动物（NHPs，恒河猴）的II期中风研究做好准备。提出了以下具体目标：目标1。确定Hiltonol预处理对小鼠局灶性缺血MCAO模型的治疗窗和有效时间窗。目标2。评估希尔顿醇的保护时间。目标3。在小鼠中验证翻译生物标志物。

DESCRIPTION (provided by applicant): Brain ischemia is a leading cause of morbidity and mortality in the United States. We seek to develop therapeutics to reduce the extent of damage and functional impairment resulting from ischemic injury to the brain, an area of significant unmet medical need. We have shown that ligand activation of the Toll-like receptor (TLR) family of pattern recognition receptors provides significant protection against ischemic brain injury. In this proposal we seek to evaluate Hiltonol(R), a synthetic dsRNA TLR3 ligand as a prophylactic neuroprotectant against stroke injury. Hiltonol is a clinical stage therapeutic being tested in multiple Phase I/II clinical trials that consists of polyinosinic-polycytidylic acid stabilized by oly-L-lysine and carboxymethylcellulose (poly-ICLC). In our preliminary data we show that systemic administration of Hiltonol protects the brain and kidneys against subsequent injury in mouse models of stroke and renal ischemia. A drug of this type would have considerable clinical impact in at-risk populations. Armed with our unique understanding of TLR-induced neuroprotection and a rich background in Hiltonol clinical development, our team will evaluate the feasibility of Hiltonol as a candidate stroke therapeutic. Our specific goals for this Phase I SBIR are to advance Hiltonol through preclinical studies using a mouse middle cerebral artery occlusion (MCAO) model and identify translational biomarkers in the mouse that will position us for phase II stroke studies in nonhuman primates (NHPs, rhesus macaques). The following specific aims are proposed: Aim 1. Determine the therapeutic window and time window of effectiveness of Hiltonol preconditioning in a mouse MCAO model of focal ischemia. Aim 2. Evaluate the duration of protection with Hiltonol. Aim 3. Validate translational biomarkers in mice.