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: 8573195
• 负责人: George Norbert Cox
• 金额: $ 48.88万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573195
• 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 Situation; Erythrocytes; FDA approved; Frequencies; Goals; Government; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Half-Life; 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; neutrophil; older patient; patient population; prevent; public health relevance; 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）：由于恐怖核袭击或核事故的潜在威胁，对治疗急性辐射综合征（ARS）的放射/核医学对策的发展是NIAID和美国政府的高优先研究领域。骨髓是辐射损伤最敏感的组织之一，造血性受损是高剂量辐射暴露的第一个临床迹象之一，通常导致由于感染或不受控制的出血而导致我在数周内死亡（称为急性辐射综合症的造血综合症）。高剂量辐射对造血系统的急性影响的受试者表现出终生造血缺陷，被认为是由于对造血干细胞室的残留损害所致[被称为残留的骨髓损伤（RBMD）或延迟的急性造成急诊式曝光的血骨损伤（RBMD））。 G-CSF，GM-CSF和IL-11是造血生长因子，刺激骨髓细胞分裂并分化为中性粒细胞（G-CSF和GM-CSF）或血小板（IL-11）。这些蛋白质用于治疗癌症患者中与化学疗法相关的中性粒细胞减少和血小板减少症。 G-CSF，GM-CSF和IL-11在人类中的半衰期短，癌症患者需要每天服用两周或更长时间。最近的研究表明，蛋白质可以改善H-AR的动物模型的总体生存，尽管如癌症化学疗法患者所见，这些药物需要每日多次施用才能有效。每日给药需要大量的医疗保健提供者时间，并且在大规模的伤亡情况下可能很困难，例如遵循放射线/核灾难。为了减少日常剂量的需求，我们开发了长效的G-CSF，GM-CSF和IL-11类似物，并表明它们在良好的小鼠H-ARS模型中显着提高了生存率并加速了多级多裂造血恢复。重要的是，蛋白质在致死辐射暴露后24小时仅1到3次时，蛋白质是有效的。这些蛋白质所需的剂量频率降低将在核紧急情况下提供显着的治疗优势，在核急诊室中，医疗保健提供者的时间将保持溢价，并且可能无法进行患者的每日剂量。该赠款的重点是扩展我们对这些蛋白质对治疗辐射暴露对成人和老年群体造血系统的急性和延迟作用的效用的理解。我们将确定蛋白质组合在小鼠H-ARS模型中的生存​​和造血恢复中是否存在加性或协同相互作用。我们将通过分析造血茎和祖细胞群体的变化，骨髓形态和随着时间的推移炎症状态来探讨蛋白质在致命辐照动物中的作用机制。我们将跟随幸存的小鼠长达两年，以确定用蛋白质或蛋白质组合的早期治疗是否会减轻对造血系统和造血干细胞室的长期损害。关于老年患者人群中辐射缓解剂的辐射敏感性和影响知之甚少。为了满足这一需求，我们将开发一种老鼠H-ARS模型，该模型可用于筛选该专业患者人群的候选辐射剂。我们将确定长效的G-CSF，GM-CSF和IL-11类似物是否显着提高了成年小鼠H-ARS模型的生存率，也显着提高了老鼠H-ARS模型中的生存​​率。这些研究将提供有关G-CSF，GM-CSF和IL-11蛋白作用功能和机制的重要信息，以治疗高剂量辐射暴露对造血系统的急性和延迟作用，并为评估重要但不错的囊肿患者的潜在辐射剂的潜在辐射剂提供了有价值的筛查工具。