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造成潜在破坏性公共卫生紧急情况的风险日益增加。急性放射综合症（ARS）是在中度至高剂量的全身或部分身体照射后出现的，对免疫系统的损害尤其严重。皮肤、肠道和中枢神经系统的损伤也很常见。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征的死亡率。 尽管在了解辐射损伤的生物学基础方面取得了进展，但有效治疗辐射损伤的药物仍然有限。对意外受到辐射的受害者的医疗管理仍然基于增强免疫细胞更新的免疫因子治疗。在更严重的情况下，可以进行骨髓移植，但移植物免疫排斥引起的并发症限制了这种方法的实用性。此外，现有的治疗方法功效有限、难以施用且生产成本昂贵。因此，迫切需要开发在紧急辐射暴露情况下有效且易于部署的治疗急性辐射综合征的新药。 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 小时后开始治疗时逆转小鼠 ARS 的能力。将监测小鼠的存活和健康状况，并进行血液标记分析。此外，还将研究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。具体来说，将对小鼠组织的炎症和器官损伤进行评分。将确定存在的免疫细胞的类型以及炎症标记物和免疫调节剂的表达。这些研究的目的是推进 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 的使用可能会彻底改变 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，sPIF 治疗的小鼠还保持了正常的血液标记物，表明 sPIF 对免疫功能具有潜在的保护作用。其他研究表明，在亚致死辐射暴露后 24 小时内施用 sPIF 可以加速白细胞的恢复。值得注意的是，该项目将更全面地评估 sPIF 作为一种无毒、有效的辐射暴露治疗方法的潜力，并且可以在公共卫生紧急情况下轻松部署。