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: 9264475
• 负责人: George Norbert Cox
• 金额: $ 47.68万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264475
• 关键词: 2 year old; Acute; Address; Adult; Affect; Anemia; Animal Model; Animals; Area; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Cells; C57BL/6 Mouse; CSF3 gene; Cancer Patient; Cell Compartmentation; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Defect; Development; Disasters; Dose; Early treatment; Effectiveness; Elderly; Emergency Situation; Erythrocytes; FDA approved; Frequencies; G-substrate; 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; Impairment; 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; Nuclear Radiology; Organ; Pancytopenia; Patients; Pharmaceutical Preparations; Population; Production; Proteins; Radiation; Radiation Dose-Response Relationship; Radiation Syndromes; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radiation induced damage; Recovery; Research Priority; Residual state; Serum; Stem cells; Survivors; Thrombocytopenia; Time; Tissues; analog; cell type; chemotherapy; cytokine; improved; irradiation; mass casualty; neutrophil; older patient; patient population; prevent; public health relevance; radiation effect; radiation mitigator; response; screening; 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）：由于恐怖主义核袭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和美国政府的一个高度优先研究领域。骨髓是对辐射损伤最敏感的组织之一，造血功能受损是高剂量辐射暴露的最初临床体征之一，通常在数周内由于感染或不受控制的出血而导致死亡（称为急性辐射综合征的造血综合征，或H-ARS）。在高剂量辐射对造血系统的急性效应中存活的受试者表现出终身造血缺陷，认为这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是造血生长因子，其刺激骨髓细胞分裂和分化成嗜中性粒细胞（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在人中具有短的半衰期，这需要在癌症患者中每天给药两周或更长时间。最近的研究表明，这些蛋白质可以提高H-ARS动物模型的总生存率，尽管如在癌症化疗患者中所见，这些药物需要每天多次给药才能有效。每日剂量需要相当多的医疗保健提供者的时间，并可能证明在大规模伤亡的情况下，如以下的辐射/核灾难困难。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，并显示它们在充分表征的小鼠H-ARS模型中显著增加存活率并加速多谱系造血恢复。重要的是，当在致死辐射暴露后24小时开始仅施用一到三次时，蛋白质是有效的。这些蛋白质所需的降低的给药频率将在核紧急情况下提供显著的治疗优势，其中医疗保健提供者的时间将非常宝贵，并且患者的每日给药可能是不可能的。该补助金的重点是扩大我们对这些蛋白质用于治疗成人和老年人群中辐射暴露对造血系统的急性和延迟影响的效用的理解。我们将确定在小鼠H-ARS模型中蛋白质的组合对存活和造血恢复是否存在加和或协同相互作用。我们将通过分析造血干细胞和祖细胞群、骨髓形态和炎症状态随时间的变化，探索蛋白质在致死性辐照动物中的作用机制。我们将对存活的小鼠进行长达两年的随访，以确定早期用蛋白质或蛋白质组合治疗是否减轻了对造血系统和造血干细胞区室的长期损害。对老年患者人群的辐射敏感性和辐射缓解剂的影响知之甚少。为了满足这一需求，我们将开发一种老年小鼠H-ARS模型，可用于筛选该专业患者人群的候选辐射缓解剂。我们将确定是否长效G-CSF，GM-CSF和IL-11类似物，显着提高在成年小鼠H-ARS模型的生存，也显着提高在老年小鼠H-ARS模型的生存。这些研究将提供关于G-CSF、GM-CSF和IL-11蛋白的功能和作用机制的重要信息，用于治疗高剂量辐射暴露对造血系统的急性和延迟效应，并提供有价值的筛选工具，用于评估重要但服务不足的老年患者人群中的潜在辐射缓解剂。

项目成果

Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation.

• DOI: 10.1097/hp.0000000000000357
• 发表时间: 2015-11
• 期刊: Health physics
• 影响因子: 2.2
• 作者: Unthank JL;Miller SJ;Quickery AK;Ferguson EL;Wang M;Sampson CH;Chua HL;DiStasi MR;Feng H;Fisher A;Katz BP;Plett PA;Sandusky GE;Sellamuthu R;Vemula S;Cohen EP;MacVittie TJ;Orschell CM
• 通讯作者: Orschell CM

Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes.

• DOI: 10.1097/hp.0000000000001352
• 发表时间: 2020-11
• 期刊: Health physics
• 影响因子: 2.2
• 作者: Wu T;Plett PA;Chua HL;Jacobsen M;Sandusky GE;MacVittie TJ;Orschell CM
• 通讯作者: Orschell CM