Long-acting growth factors for treating the acute and long term effects of lethal

用于治疗致命性急性和长期影响的长效生长因子

• 批准号: 8840884
• 负责人: George Norbert Cox
• 金额: $ 55.34万
• 依托单位: BOLDER BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840884
• 关键词: 2 year old; Acute; Address; Adult; Affect; Anemia; Animal Model; Animals; Area; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Cells; CSF3 gene; Cancer Patient; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Defect; Development; Disasters; Dose; Early treatment; Effectiveness; Elderly; Emergency Care; Emergency Situation; Erythrocytes; FDA approved; Frequencies; Goals; Government; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Half-Life; Health; Health Personnel; Hematopoiesis; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Human; Infection; Inflammatory; Injury; Interleukin-11; Long-Term Effects; Lymphopenia; Medical; Modeling; Morbidity - disease rate; Morphology; Mus; National Institute of Allergy and Infectious Disease; Neutropenia; Nuclear; Nuclear Accidents; Organ; Pancytopenia; Patients; Pharmaceutical Preparations; Population; Production; Proteins; Radiation; Radiation Dose-Response Relationship; Radiation Syndromes; Radiation Tolerance; Recovery; Research Priority; Residual state; Serum; Stem cells; Survivors; Syndrome; Thrombocytopenia; Time; Tissues; analog; base; cell type; chemotherapy; cytokine; improved; irradiation; mass casualty; neutrophil; older patient; patient population; prevent; radiation effect; response; screening; stem; tool

DESCRIPTION (provided by applicant): Development of radiological/nuclear medical countermeasures to treat Acute Radiation Syndrome (ARS) is a high priority research area for NIAID and the U.S. government due to the potential threat of a terrorist nuclear attack or nuclear accident. Bone marrow is one of the most sensitive tissues to radiation damage and impaired hematopoiesis is one of the first clinical signs of high dose radiation exposure, often resulting i death within weeks due to infections or uncontrolled bleeding (referred to as the hematopoietic syndrome of the Acute Radiation Syndrome, or H-ARS). Subjects that survive the acute effects of high dose radiation on the hematopoietic system display lifelong hematopoietic defects that are believed to be due to residual damage to the hematopoietic stem cell compartment [referred to as residual bone marrow damage (RBMD) or delayed hematopoietic effects of acute radiation exposure (H-DEARE)]. G-CSF, GM- CSF and IL-11 are hematopoietic growth factors that stimulate bone marrow cells to divide and differentiate into neutrophils (G-CSF and GM-CSF) or platelets (IL-11). These proteins are used to treat chemotherapy-related neutropenia and thrombocytopenia in cancer patients. G-CSF, GM- CSF and IL-11 have short half-life in humans, which necessitates daily dosing for two weeks or more in cancer patients. Recent studies indicate that the proteins can improve overall survival in animal models of H-ARS, although, as seen in cancer chemotherapy patients, the drugs require multiple daily administrations for effectiveness. Daily dosing requires considerable healthcare provider time and may prove difficult in a mass casualty situation such as following a radiological/nuclear disaster. To reduce the need for daily dosing we developed long-acting G- CSF, GM-CSF and IL-11 analogs and showed that they significantly increase survival and accelerate multilineage hematopoietic recovery in a well-characterized mouse H-ARS model. Importantly, the proteins are effective when administered only one to three times beginning 24 h following lethal radiation exposure. The reduced dosing frequency required for these proteins will provide significant treatment advantages in a nuclear emergency setting, where healthcare provider time will be at a premium and daily dosing of patients may not be possible. This grant focuses on expanding our understanding of the utility of these proteins for treating the acute and delayed effects of radiation exposure on the hematopoietic system in adult and geriatric populations. We will determine whether there are additive or synergistic interactions of combinations of the proteins on survival and hematopoietic recovery in the mouse H-ARS model. We will explore the mechanism(s) of action of the proteins in lethally-irradiated animals by analyzing changes in hematopoietic stem and progenitor cell populations, bone marrow morphology and inflammatory status over time. We will follow surviving mice for up to two years to determine whether early treatment with the proteins or combinations of the proteins mitigates long-term damage to the hematopoietic system and hematopoietic stem cell compartment. Little is known about the radiation sensitivity and effects of radiation mitigators in older patient populations. To address this need we will develop a geriatric mouse H-ARS model that can be used to screen candidate radiation mitigators for this specialized patient population. We will determine whether long-acting G-CSF, GM-CSF and IL-11 analogs, which significantly improve survival in the adult mouse H-ARS model, also significantly improve survival in the geriatric mouse H-ARS model. These studies will provide important information about the function and mechanisms of action of G-CSF, GM-CSF and IL-11 proteins for treating the acute and delayed effects of high dose radiation exposure on the hematopoietic system, and provide a valuable screening tool for evaluating potential radiation mitigators in the important but underserved geriatric patient population.

描述(由申请人提供)：由于恐怖分子核攻击或核事故的潜在威胁，开发治疗急性辐射综合征(ARS)的放射/核医学对策是NIAID和美国政府的优先研究领域。骨髓是对辐射损伤最敏感的组织之一，而造血功能受损是高剂量辐射暴露的首批临床症状之一，通常会导致在数周内因感染或失控出血而死亡(称为急性辐射综合征的造血综合征，简称H-ARS)。在高剂量辐射对造血系统的急性影响中幸存下来的受试者表现出终生的造血缺陷，这些缺陷被认为是由于造血干细胞室的残留损伤[称为残留骨髓损伤(RBMD)或急性辐射暴露的延迟造血效应(H-DEARE)]。G-CSF、GM-CSF和IL-11是能刺激骨髓细胞分裂分化为中性粒细胞(G-CSF和GM-CSF)或血小板(IL-11)的造血生长因子。这些蛋白质被用来治疗癌症患者化疗相关的中性粒细胞减少症和血小板减少症。G-CSF、GM-CSF和IL-11在人类体内的半衰期很短，癌症患者需要每天服用两周或更长时间的药物。最近的研究表明，这些蛋白质可以提高H-ARS动物模型的总体存活率，尽管正如在癌症化疗患者中看到的那样，这些药物需要每天多次给药才能有效。每天给药需要医疗保健提供者相当长的时间，在大规模伤亡的情况下可能会被证明是困难的，例如在辐射/核灾难之后。为了减少每日给药的需要，我们开发了长效G-CSF、GM-CSF和IL-11类似物，并表明它们显著提高了小鼠H-ARS模型的存活率并加速了多系造血恢复。重要的是，这些蛋白质在致命性辐射暴露后24小时开始只给药一到三次就有效。减少这些蛋白质所需的剂量频率将在核紧急情况下提供显著的治疗优势，在这种情况下，医疗保健提供者的时间将非常宝贵，患者的日常剂量可能无法实现。这笔赠款的重点是扩大我们对这些蛋白质在治疗辐射暴露对成人和老年人群造血系统的急性和延迟影响方面的效用的理解。我们将确定在小鼠H-ARS模型中，这些蛋白质组合在存活和造血恢复方面是否存在相加或协同作用。我们将通过分析造血干、祖细胞数量、骨髓形态和炎症状态随时间的变化来探讨蛋白质在致死性照射动物中的作用机制(S)。我们将对存活的小鼠进行长达两年的跟踪观察，以确定早期使用这些蛋白质或蛋白质组合是否可以减轻对造血系统和造血干细胞室的长期损害。关于辐射敏感性和辐射缓释剂在老年患者群体中的影响，人们知之甚少。为了解决这一需求，我们将开发一种老年性小鼠H-ARS模型，该模型可用于为这一专门的患者群体筛选候选辐射缓释剂。我们将确定在成年小鼠H-ARS模型中显著提高存活率的长效G-CSF、GM-CSF和IL-11类似物是否也显著提高老年小鼠H-ARS模型的存活率。这些研究将提供有关G-CSF、GM-CSF和IL-11蛋白在治疗大剂量辐射对造血系统的急性和延迟效应方面的功能和作用机制的重要信息，并为评估重要但服务不足的老年患者群体中潜在的辐射减释剂提供有价值的筛选工具。