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.
Public Health Relevance Statement: Public Health Relevance: Brain ischemia is a leading cause of morbidity and mortality in the United States and can occur both acutely or in response to loss of blood flow secondary to cardiovascular surgery. This proposal seeks to advance Hiltonol, a toll-like receptor 3 ligand that has shown efficacy as a prophylactic treatment, through preclinical studies using a mouse model of stroke and to identify potential biomarkers for Phase II studies in nonhuman primates.
Project Terms: Acute; Agonist; Area; arm; base; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Cells; Blood flow; body system; Brain; Brain Ischemia; Bypass; Carboxymethylcellulose; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular Surgical Procedures; Cell Death; Clinical; clinical application; Clinical Research; Clinical Trials; Data; deprivation; Development; Development Plans; Dose; Double-Stranded RNA; Drug Kinetics; Effectiveness; Event; experience; Family; functional disability; Functional disorder; Glucose; Goals; Health Sciences; high risk; Human; human TLR3 protein; Impaired cognition; In Vitro; in vivo; Infarction; Injury; insight; 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; Mortality Vital Statistics; mouse model; Mus; Neurologic; neuroprotection; Neuroprotective Agents; nonhuman primate; Operative Surgical Procedures; Oregon; Organ; Oxygen; pathogen; patient population; Patients; Pattern recognition receptor; Perioperative; Peripheral; Pharmaceutical Preparations; Phase; phase 2 study; Poly I-C; Poly ICLC; Populations at Risk; Positioning Attribute; pre-clinical; preclinical study; preconditioning; Primates; prophylactic; Prophylactic treatment; public health relevance; receptor; renal ischemia; Reperfusion Injury; Reperfusion Therapy; Reproducibility; response; Risk; Safety; Secondary to; Signal Transduction; Small Business Innovation Research Grant; Staging; stroke; Stroke prevention; success; Testing; Therapeutic; Therapeutic Index; Time; TLR3 gene; Toll-like receptors; Translations; Treatment Protocols; United States; Universities; Viral
