Calpastatin Peptide-based Calpain Inhibitor as a Traumatic Brain Injury Therapeutic

基于钙蛋白酶肽的钙蛋白酶抑制剂作为创伤性脑损伤的治疗药物

• 批准号: 10002114
• 负责人: JOHN Y ANAGLI
• 金额: $ 26.96万
• 依托单位: NEUROTHERANOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002114
• 关键词: Acute; Acute Brain Injuries; Area; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Chemical Analysis; Blood Pressure; Blood gas; Brain; Brain Injuries; Calcium; Calpain; Caring; Cause of Death; Cell Survival; Cells; Cerebrovascular system; Clinical; Clinical Research; Clinical Treatment; Cognitive; Consumption; Craniocerebral Trauma; Cytoskeletal Proteins; Data; Diffuse Axonal Injury; Direct Costs; Disease; Dose; Drug usage; Edema; Emotional; Enzymes; Event; FDA approved; Facilities and Administrative Costs; Failure; Family suidae; Feasibility Studies; Feedback; Functional disorder; Funding; Future; Generations; Glial Fibrillary Acidic Protein; Glucose; Goals; Growth Associated Protein 43; Head; Health; Health Expenditures; Heart Rate; Hemorrhage; Homeostasis; Hospitalization; Hour; Image; Impaired cognition; Incidence; Injury; Intravenous; Investigation; Ischemia; Knowledge; Laboratories; Lead; Letters; Manufacturer Name; Measurement; Mediating; Medical; Medical Care Costs; Modeling; Natural regeneration; Nature; Neurodegenerative Disorders; Neurologic; Neurons; Neurosurgeon; Outcome; Pathologic; Pathology; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Physiological; Preclinical Drug Development; Proteins; Public Health; Quality of life; Rattus; Research; Rodent Model; Scientist; Secure; Signal Transduction; Small Business Innovation Research Grant; Specificity; Spectrin; Supportive care; Surgeon; TBI Patients; Technology; Temperature; Therapeutic; Therapeutic Human Experimentation; Translational Research; Translations; Trauma; Traumatic Brain Injury; Treatment Efficacy; United States National Institutes of Health; base; biomarker panel; brain cell; brain repair; brain tissue; calpain inhibitor; calpastatin; clinical care; cognitive function; cognitive recovery; commercial application; cost; cost outcomes; data submission; disability; drug development; emotional functioning; experience; forced swim test; functional outcomes; improved; in vivo; inhibitor/antagonist; interest; intravenous administration; mild traumatic brain injury; morris water maze; neurological recovery; neurorestoration; novel marker; patient population; peptide drug; pre-clinical; preclinical study; protein TDP-43; receptor; response; standard of care; success; therapy development; transcription factor; traumatic event

Abstract: TBI is a leading cause of death and long-term disability worldwide. Although TBI is a significant medical crisis, there are no FDA-approved pharmacological therapies that have been shown to improve functional outcomes. The long-term goal of this project is to improve the immediate and long-term outcomes of patients inflicted with severe TBI. Successful translation of the therapy to the clinical care of patients with TBI would have an enormous direct impact on function, wellness, and overall quality of life of victims of TBI, while shifting the current clinical treatment paradigm to one that includes a restorative thrust. The product of this SBIR, B27- HYD is an intravenous (IV) peptide drug, used in conjunction with the current standard of care, administered to patients within hours of their suffering a severe TBI. The following two specific aims will be pursued: 1) Determine the dose-response effects of intravenous B27-HYD on a TBI biomarker panel, as well as the drug's effects on general health and physiological measurements in sham and severe TBI rats. Milestone: A safe and effective IV dose of B27- HYD that results in a minimum 40% reduction of 3 out of 5 pharmacodynamic TBI biomarkers (calpain-mediated proteolytic breakdown products of αII-spectrin, GFAP, CRMPs, GAP-43, and TDP-43). Effects of B27-HYD on arterial blood pressure, heart rate, body and head temperature, and blood chemistry (blood gases, glucose) will be determined; and 2) Demonstrate that a safe and effective dose of B27-HYD administered in the correct timeframe protects brain cell and tissue, and improves recovery from cognitive and emotional dysfunction after severe TBI. Milestone: A minimum 35% brain cell and tissue protection, 35% reduction in the sensorimotor deficits (mNSS) and 40% overall improvement in cognitive and emotional deficits (Morris water maze, Elevated Plus Maze, Forced Swimming Test) will be criteria for success to move on to Phase II. As an outcome of the proposed SBIR Phase I investigations, we expect that a safe and effective IV dose of B27-HYD, that significantly reduces TBI biomarkers, will i) increase brain cell survival, ii) enhance brain repair and regeneration, and iii) lead to marked improvement in cognitive and emotional functions. After successful completion of our Phase I feasibility study, we plan to confirm the in vivo efficacy of B27-HYD in a swine model of severe TBI. We have assembled a team of neuroscientists, neurosurgeons, neuroprotective/neurorestorative drug development scientists and regulatory experts with expertise and experience in TBI pathology, preclinical drug development and regulatory experience to pursue the translational research outlined in this proposal.

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