Treatment of Acute Radiation Syndrome using PIF, a Natural Immune Modulator

使用天然免疫调节剂 PIF 治疗急性放射综合症

• 批准号: 8981580
• 负责人: Michael John Paidas
• 金额: $ 29.83万
• 依托单位: BIOINCEPT, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981580
• 关键词: Acute; Address; Advanced Development; Amino Acids; Antibiotics; Biological; Biological Response Modifiers; Blood; Blood Platelets; Body Weight decreased; Bone Marrow; Bone Marrow Transplantation; Brain; Burn injury; Cells; Cessation of life; Clinical; Complex; Data; Death Rate; Dehydration; Development; Diarrhea; Dose; Effectiveness; Embryo; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Exposure to; Functional disorder; Gene Expression; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Hematopoiesis; Hematopoietic; Hour; Human; Immune; Immune response; Immune system; Immunosuppression; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Investigational Drugs; Investigational New Drug Application; Lethal Dose 50; Leukocytes; Liver; Lymphoid Tissue; Medical; Modeling; Molecular; Monitor; Morbidity - disease rate; Mouse Strains; Multiple Organ Failure; Mus; Neuraxis; Nuclear Accidents; Nuclear Weapon; Organ; Peptides; Pharmaceutical Preparations; Phosphate Buffer; Population; Process; Public Health; Radiation; Radiation Dose-Response Relationship; Radiation Injuries; Radiation Syndromes; Recombinants; Recovery; Risk; Saline; Severities; Signal Pathway; Skin; Skin Tissue; Supportive care; Survival Rate; Testing; Tissues; Toxic effect; Trauma; Treatment Factor; base; cell type; cytokine; effective therapy; enhancing factor; graft vs host disease; hematopoietic tissue; immune function; improved; indexing; inflammatory marker; irradiation; mortality; novel; preclinical study; preimplantation; prevent; primary outcome; protective effect; public health emergency; public health relevance; repaired; secondary outcome; symptom management; synthetic peptide

 DESCRIPTION (provided by applicant): Recent nuclear accidents and threats have highlighted the growing risk of widespread radiation exposure causing a potentially devastating public health emergency. Acute radiation syndrome (ARS) develops after total-body or partial-body irradiation at a moderate to high dose and is especially damaging to the immune system. Damage to the skin, gut, and central nervous system is also common. Accordingly, complex injuries such as burns, multi-organ injury, and trauma increase the death rate from acute radiation syndrome. Despite advances in understanding the biological basis of radiation injury, medications that effectively treat radiation injury are limited. Medical management of accidentally irradiated victims remains based on treatment with immune factors that enhance renewal of immune cells. In more severe cases, a bone marrow transplant may be performed, but complications from graft immune rejection limit the utility of this approach. Furthermore, existing treatments have limited efficacy, are difficult to administer, and are expensive to produce. Therefore, there is an urgent need to develop new drugs to treat acute radiation syndrome that are both effective and easy to deploy in an emergency radiation exposure scenario. The goal of this proposal is to test the ability of synthetic PreImplantation Factor (sPIF), a natural immune regulatory peptide, to reverse ARS in mice when treatment begins 24-48 hours after exposure to various levels of radiation. The survival and health of mice will be monitored, and blood marker profiles will be performed. Additionally, details of the molecular basis of radiation damage and sPIF's protective effects on the immune system will be examined. Specifically, mice tissues will be scored for inflammation and organ damage. The types of immune cells present and the expression of inflammatory markers and immune regulators will be determined. The purpose of these studies will be to advance the development of sPIF as a treatment for ARS and to collect the necessary data for the submission of an investigational new drug (IND) application. The use of sPIF could revolutionize the treatment of ARS. Preclinical studies have demonstrated that sPIF completely protected mice from death when administered 2 hrs following lethal radiation exposure. Significantly, the sPIF-treated mice also maintained normal blood markers, indicating sPIF's underlying protective effect on immune function. Additional studies showed sPIF accelerated recovery of white blood cells when administered 24 hours following sub-lethal radiation exposure. Significantly, this project will more fully evaluate sPIF's potential as a non-toxic, effective treatment for radiation exposure that could be easily deployed during a public health emergency.

 描述（由申请人提供）：最近的核事故和威胁凸显了大范围辐射暴露的风险不断增加，在中度至高度的全身或部分身体辐射后，可能会导致潜在的破坏性公共卫生紧急情况，出现急性辐射综合症（ARS）。然而，对皮肤、肠道和中枢神经系统的损害也很常见，因此，烧伤、多器官损伤和创伤等复杂损伤会增加急性辐射综合症的死亡率。理解的进步由于放射损伤的生物学基础，有效治疗放射损伤的药物仍然是基于增强免疫细胞更新的免疫因子的治疗。在更严重的情况下，可以进行骨髓移植。此外，移植免疫排斥引起的并发症限制了这种方法的效用，难以实施且生产成本昂贵，因此，迫切需要开发治疗急性放射综合征的新药。在紧急辐射暴露场景中有效且易于部署的目标。该提案的目的是测试合成的植入前因子（sPIF）（一种天然免疫调节肽）在暴露于不同水平的辐射后 24-48 小时开始治疗时逆转小鼠 ARS 的能力。小鼠的生存和健康将受到影响。此外，还将检查辐射损伤的分子基础和 sPIF 对免疫系统的保护作用的详细信息。还将对小鼠组织的炎症和器官损伤进行评分。现在和这些研究的目的将是确定炎症标志物和免疫调节剂的表达，以推进 sPIF 作为 ARS 治疗方法的开发，并收集提交研究性新药 (IND) 申请所需的数据。 sPIF 可以彻底改变 ARS 的治疗。临床前研究表明，在致命辐射暴露后 2 小时内给予 sPIF 可以完全保护小鼠免于死亡。值得注意的是，经过 sPIF 治疗的小鼠血液也保持正常。标记物，表明 sPIF 对免疫功能的潜在保护作用表明，在亚致死辐射暴露后 24 小时施用 sPIF 可使白细胞恢复。值得注意的是，该项目将更全面地评估 sPIF 作为无毒、有效治疗的潜力。用于在公共卫生紧急情况下可以轻松部署的辐射暴露。