Mitigation of Radiation Induced Immune Dysfunction by PrC-210 Treatment

PrC-210 治疗减轻辐射引起的免疫功能障碍

• 批准号: 10685261
• 负责人: WILLIAM E FAHL
• 金额: $ 55.49万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685261
• 关键词: Animals; Area; Bacterial Translocation; Biological Markers; Blood; Blood Cells; Body Weight; Bone Marrow; Bone Marrow Aspiration; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chernobyl Nuclear Accident; Clinical Trials; Dendritic Cells; Disasters; Dose; Drug Kinetics; Event; Exposure to; Female; Femur; Fukushima; Goals; Government; Growth Factor; Hematology; Hematopoietic stem cells; Histology; Human; Hypotension; Immune; Immune System Diseases; Immune system; Immunology; Inflammation; Inflammatory; Injury; Ionizing radiation; Lethal Dose 50; Liver; Macrophage; Measurable; Measures; Medical; Modeling; Mucous Membrane; Mus; Natural Killer Cells; Nausea; Nuclear; Nuclear Accidents; Nuclear Reactors; Nuclear Weapon; Oral; Organ; Pathology; Plasma; Proteome; Protocols documentation; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation exposure; Radiation induced damage; Recovery; Regulatory T-Lymphocyte; Reporting; Research; Rodent; Route; Site; Spleen; Sulfhydryl Compounds; Survivors; Testing; Thymus Gland; Time; Tissue Survival; Tissues; Vomiting; Whole-Body Irradiation; Work; aminothiol; chemokine; cytokine; dirty bomb; exposed human population; fluorescein isothiocyanate dextran; gastrointestinal; immune cell infiltrate; immune function; improved; invention; irradiation; jejunum; male; medical countermeasure; novel; pharmacologic; preclinical development; protective effect; radiation countermeasure; radiation mitigation; radiation risk; side effect; urban setting

Mitigation of Radiation-Induced Immune Dysfunction by PrC-210 Treatment PROJECT SUMMARY Human risk of radiation exposure, possibly catastrophic in proportion, has risen. Whether from intentional or unintentional nuclear events, such events could yield thousands to hundreds of thousands of surviving victims. A recent government report stated, “the ideal medical countermeasures for radiation would be those that can both mitigate and protect from injuries.., such a countermeasure remains a significant unmet medical need.” In our earlier work, we invented and have developed a novel, proprietary, compound, PrC-210, which has demonstrated a profound survival benefit to mice when it was administered once 24 hr after an LD95/30 dose of whole-body radiation to the mice. In its preclinical development, PrC-210 has shown multiple protective effects in multiple organ-protection settings; as a radiation countermeasure, PrC-210 was highly effective whether it was administered a day after or 15 min before a 95% lethal radiation dose. PrC-210 has neither nausea nor hypotension side effects. For this proposed U01 research our group will expand upon, and pharmacologically optimize, systemic delivery of PrC-210 at 24 h post-radiation to maximize animal survival and will explore underlying immune and gastrointestinal protection mechanisms to explain the post-radiation, PrC- 210-conferred, survival benefit. Our proof-of-concept studies showed a 45% survival benefit to mice that received a single systemic PrC-210 dose 24 h following a single LD95 dose of ionizing radiation (P=0.002); the PrC-210- treated mice also showed significantly greater body weights (P=0.012) following irradiation, and visibly improved bone marrow cellularity. In this U01, using two established mouse irradiation models, we will identify the best protocol for administering PrC-210 to post-radiation mice, establish the efficacy of PrC-210 in mitigating radiation-induced damage to both immune tissues and circulating immune cells, and establish the efficacy of PrC-210 in protecting the entire gastrointestinal setting from post-radiation immune infiltration and inflammation- associated GI tissue destruction. A host of scored immune endpoints will be measured in post-radiation mice, with and without PrC-210 protection, so we will have multiple, overlapping endpoints of immune function in post- radiation mice, and then see what impact PrC-210 has in protecting them. The goals of this U01 proposal are to: i) determine the optimum +24 hr PrC-210 administration route and dose that confers the greatest survival benefit against an LD95/30 radiation dose, and ii) determine the full extent to which PrC-210 mitigates radiation damage to immune organs and their blood-borne cells, and to gastrointestinal sites and their function in the post-radiation setting. These studies are proposed as a prelude to next-stage PrC-210 clinical trials.

PrC-210治疗减轻辐射诱导的免疫功能障碍 项目摘要 人类受到辐射的风险，可能是灾难性的，已经上升。无论是有意还是 如果发生意外核事件，这些事件可能造成成千上万的幸存者。 最近的一份政府报告指出，“理想的辐射医疗对策是那些可以 减轻和保护免受伤害，这种对策仍然是一个重大的未满足的医疗需求。 在我们早期的工作中，我们发明并开发了一种新颖的专有化合物PrC-210， 当在LD 95/30后24小时给药一次时， 对小鼠的全身辐射剂量。在其临床前开发中，PrC-210显示出多种保护作用， 在多种器官保护环境中的作用;作为辐射对策，PrC-210非常有效 无论是在95%致死辐射剂量后一天还是前15分钟给药。PrC-210两者都没有 恶心和低血压的副作用。对于这项拟议的U 01研究，我们的小组将扩大， 在药理学上优化辐射后24小时PrC-210的全身递送，以最大限度地提高动物存活率， 将探索潜在的免疫和胃肠道保护机制，以解释辐射后，PrC- 第210章生存的好处我们的概念验证研究显示，接受了以下治疗的小鼠的存活率提高了45%： 单次LD 95剂量电离辐射后24小时单次全身PrC-210剂量（P=0.002）; PrC-210- 经治疗的小鼠在照射后也显示出显著更大的体重（P=0.012），并且明显改善了 骨髓细胞构成在本U 01中，使用两种已建立的小鼠照射模型，我们将确定最佳的 在用于将PrC-210施用至辐射后小鼠的方案中，确定了PrC-210在减轻辐射后小鼠的疼痛中的功效。 辐射诱导的免疫组织和循环免疫细胞的损伤，并确定 PrC-210在保护整个胃肠道环境免受辐射后免疫浸润和炎症中的作用- 相关的胃肠道组织破坏。将在辐射后小鼠中测量许多评分的免疫终点， 有和没有PrC-210保护，因此我们在术后将有多个重叠的免疫功能终点 辐射小鼠，然后看看PrC-210在保护它们方面有什么影响。 本U 01提案的目标是：i）确定+24小时PrC-210给药途径的最佳方案，以及 对LD 95/30辐射剂量赋予最大生存益处的剂量，以及ii）确定 PrC-210减轻对免疫器官及其血液细胞的辐射损伤， 胃肠道部位及其在放射后环境中的功能。这些研究被提议作为一个前奏， PrC-210的下一阶段临床试验