Hiltonol provides potent neuroprotection from ischemic brain injury in stroke.

希尔顿提供有效的神经保护，防止中风引起的缺血性脑损伤。

• 批准号: 8448802
• 负责人: MARY P STENZEL-POORE
• 金额: $ 25.74万
• 依托单位: ONCOVIR, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2014-11-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448802
• 关键词: Acute; Agonist; Area; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Cells; Blood flow; Brain; Brain Ischemia; Bypass; Carboxymethylcellulose; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular Surgical Procedures; Cell Death; Clinical; Clinical Research; Clinical Trials; Data; Development; Development Plans; Dose; Double-Stranded RNA; Drug Kinetics; Effectiveness; Event; Family; Functional disorder; Glucose; Goals; Health Sciences; Human; Impaired cognition; In Vitro; Infarction; Injury; Interferons; Ischemia; Ischemic Brain Injury; Kidney; Legal patent; Lethal Dose 50; Ligands; Lysine; Macaca mulatta; Manufactured Materials; Measures; Medical; Middle Cerebral Artery Occlusion; Modeling; Monitor; Morbidity - disease rate; Mus; Neurologic; Neuroprotective Agents; Operative Surgical Procedures; Oregon; Organ; Oxygen; Patients; Pattern recognition receptor; Perioperative; Peripheral; Pharmaceutical Preparations; Phase; Poly I-C; Poly ICLC; Populations at Risk; Positioning Attribute; Primates; Prophylactic treatment; Reperfusion Injury; Reperfusion Therapy; Reproducibility; Risk; Safety; Secondary to; Signal Transduction; Small Business Innovation Research Grant; Staging; Stroke; Stroke prevention; TLR3 gene; Testing; Therapeutic; Therapeutic Index; Time; Toll-like receptors; Translations; Treatment Protocols; United States; Universities; Viral; arm; base; body system; clinical application; deprivation; experience; functional disability; high risk; human TLR3 protein; in vivo; insight; mortality; mouse model; neuroprotection; nonhuman primate; pathogen; patient population; phase 2 study; pre-clinical; preclinical study; preconditioning; prophylactic; public health relevance; receptor; renal ischemia; response; success

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.

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，以减少由脑缺血性损伤引起的损伤和功能障碍的程度，这是一个显著未满足的医疗需求领域。我们已经表明，模式识别受体的Toll样受体（TLR）家族的配体激活提供了对缺血性脑损伤的显着保护。在这项提议中，我们试图评估Hiltonol（R），一种合成的dsRNA TLR 3配体，作为预防中风损伤的神经保护剂。Hiltonol是一种临床阶段治疗药物，正在多项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稳定的聚肌苷酸-聚胞苷酸（聚-ICLC）组成。在我们的初步数据中，我们表明，在中风和肾缺血的小鼠模型中，全身给予Hiltonol可保护大脑和肾脏免受随后的损伤。这种类型的药物将在高危人群中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Hiltonol临床开发的丰富背景，我们的团队将评估Hiltonol作为候选中风治疗药物的可行性。我们的I期SBIR的具体目标是通过使用小鼠大脑中动脉闭塞（MCAO）模型的临床前研究推进Hiltonol，并确定小鼠中的翻译生物标志物，这将使我们能够在非人灵长类动物（NHP，恒河猴）中进行II期卒中研究。提出了以下具体目标：目标1。确定Hiltonol预处理在小鼠MCAO局灶性缺血模型中的有效治疗窗和时间窗。目标二。评估Hiltonol的保护持续时间。目标3.小鼠中的翻译生物标志物。