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（由适用提供）：最近的核事故和威胁强调了宽度辐射暴露的日益增长的风险，导致潜在的毁灭性公共卫生紧急情况。急性辐射综合征（ARS）在现代至高剂量的总体或部分体体照射后发展，对免疫系统尤其损害。对皮肤，肠道和中枢神经系统的损害也很常见。彼此之间，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。尽管了解辐射损伤的生物学基础的进步，但有效治疗辐射损伤的药物仍有限。意外辐照违规行为的医疗管理仍基于对免疫因素的治疗，从而增强免疫细胞的更新。在更严重的情况下，可能会进行骨髓移植，但是移植免疫排斥的并发症限制了该方法的效用。此外，现有的治疗效果有限，难以管理，生产昂贵。因此，迫切需要开发新药来治疗急性辐射综合征，这些综合症既有效又易于部署在紧急辐射暴露情况下。该提案的目的是测试自然免疫调节肽合成植入术因子（SPIF）在接触各种辐射水平后24-48小时开始治疗时逆转AR的能力。将监测小鼠的生存和健康，并将进行血液标记谱。此外，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细节。具体而言，将为炎症和器官损伤评分小鼠组织。存在免疫细胞的类型以及炎症标记和免疫调节剂的表达这些研究的目的是推进SPIF作为ARS治疗的开发，并收集必要的数据以提交研究性新药（IND）应用。 SPIF的使用可能会彻底改变AR的处理。临床前研究表明，当致命辐射暴露后2小时时，SPIF完全保护了小鼠免受死亡的影响。值得注意的是，经SPIF处理的小鼠还保持正常的血液标记，表明SPIF对免疫功能的潜在保护作用。进一步的研究表明，在亚致死辐射暴露后24小时给药时，SPIF加速了白细胞的恢复。值得注意的是，该项目将更全面地评估SPIF的潜力，作为一种无毒的，有效的辐射暴露治疗方法，可以在公共卫生紧急情况下容易部署。