Development of Peptide Inhibitor of Complement to treat neonatal asphyxial brain damage

补体肽抑制剂的研制治疗新生儿窒息性脑损伤

• 批准号: 9408828
• 负责人: Tushar A. Shah
• 金额: $ 27.06万
• 依托单位: CHILDREN'S SPECIALTY GROUP, PLLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408828
• 关键词: 7 year old; Address; Adjuvant; Aftercare; Alternative Complement Pathway; Amino Acids; Anatomy; Animal Disease Models; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Asphyxia; Attention; Autoimmune Process; Bass; Binding; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cells; Cessation of life; Classical Complement Pathway; Clinical; Complement; Complement 1q; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Complex; Cytolysis; Data; Decision Making; Development; Disease; Dose; Drug Design; Drug Kinetics; Exercise; FDA approved; Frequencies; Future; Goals; Human; Human body; Immunologic Surveillance; Immunology; Infarction; Inflammation; Inflammation Mediators; Inflammatory; International; Knockout Mice; Lead; Left; Measures; Mediating; Medical; Modeling; Neonatal; Neurocognitive; Neurological outcome; Neurology; Neuronal Injury; Orphan Drugs; Outcome; Pathogenesis; Pathway interactions; Peptides; Phagocytes; Pharmaceutical Preparations; Pharmacology; Phase; Play; Proteins; Rattus; Recruitment Activity; Reperfusion Injury; Research Project Grants; Risk; Role; Sales; Small Business Innovation Research Grant; Stream; Study of magnetics; Survivors; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Walking; Wild Type Mouse; complement system; disability; efficacy testing; experimental study; human disease; improved; in vivo; inhibiting antibody; mortality; natural hypothermia; neonatal hypoxic-ischemic brain injury; neurobehavioral; neurodevelopment; neuroimaging; neuroprotection; novel; performance tests; phase 2 study; preclinical development; prevent; pup; spectroscopic imaging; success

Abstract The hypothesis for the proposed project is that inhibition of the classical complement pathway with Peptide Inhibitor of complement C1 (PIC1) will be neuroprotective in a rat model of neonatal hypoxic-ischemic encephalopathy (HIE). HIE is an ischemia-reperfusion injury of the brain that occurs around the time of birth, with up to 60% mortality and 25% of survivors left with a significant disability. The complement system, the most potent inflammatory cascade in humans, and a critical mediator of inflammation , phagocytic cell recruitment and direct cell lysis, has been shown to play a major role in the pathogenesis of HIE in animal models and human studies. Therapeutic hypothermia, the only accepted treatment for neonatal HIE, slightly improves short-term survival and neurodevelopment in HIE, but does not significantly improve long-term outcomes. To date, none of the tested pharmacological adjuvants to therapeutic hypothermia have demonstrated clinical improvement. Deficiency of C1q, the initiator molecule of the classical complement pathway, has been shown to be neuroprotective in an animal model of neonatal HIE. Our current lead compound of PIC1 (PA-CPEG), is the product of years of rational drug design yielding a 15 amino acid peptide conjugated with PEG. Our compound binds to C1q, efficiently blocking complement activation at the first step in the cascade. Pilot experiments in the well-established Vannucci rat model of neonatal HIE have shown that PIC1 significantly reduces brain infarct volumes, and reduces neuronal injury. The proposed studies will refine dosing and frequency of PIC1 in the Vannucci model, and conduct fully powered studies to evaluate the efficacy of PIC1 in reducing brain injury in neonatal HIE. The success of the proposed studies will provide critical proof-of-concept that PIC1 can prevent complement- mediated pathogenesis in an animal model of human disease. This will provide the necessary evidence to propel the future pre-clinical development of PIC1 through pharmacokinetic and toxicology studies via SBIR Phase 2. Third-party market analysis shows the potential for healthy sales volumes for PIC1 in HIE. Third-party regulatory analysis suggests the potential for a stream-lined regulatory approach by seeking Orphan Drug and Breakthrough designations.

摘要

项目成果

Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.

• DOI: 10.3389/fnins.2021.616734
• 发表时间: 2021
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Shah TA;Pallera HK;Kaszowski CL;Bass WT;Lattanzio FA
• 通讯作者: Lattanzio FA