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）：由于恐怖核袭击或核事故的潜在威胁，开发治疗急性辐射综合症（ARS）的放射/核医疗对策是 NIAID 和美国政府的高度优先研究领域。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第一个临床症状之一，常常导致患者在数周内因感染或不受控制的出血而死亡（称为急性造血综合征）。辐射综合症（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，这被认为是由于造血干细胞区室的残余损伤[称为残余骨髓损伤（RBMD）或急性辐射的延迟造血作用所致。辐射暴露（H-DEARE）]。 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在人体中的半衰期较短，因此癌症患者需要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 动物模型的总体生存率，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发挥作用。每日给药需要医疗保健提供者大量的时间，并且在大规模伤亡情况下（例如放射/核灾难后）可能会很困难。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，并表明它们在特征良好的小鼠 H-ARS 模型中显着提高存活率并加速多系造血恢复。重要的是，这些蛋白质在致命辐射暴露后 24 小时内仅施用一到三次即可有效。这些蛋白质所需的给药频率的减少将在核紧急情况下提供显着的治疗优势，在这种情况下，医疗保健提供者的时间将非常宝贵，并且可能无法每天对患者给药。这笔赠款的重点是扩大我们对这些蛋白质在治疗成人和老年人群中辐射暴露对造血系统的急性和迟发影响的用途的理解。我们将确定蛋白质组合对小鼠 H-ARS 模型中的存活和造血恢复是否存在累加或协同相互作用。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来探索蛋白质在受到致命辐射的动物中的作用机制。我们将对存活的小鼠进行长达两年的跟踪，以确定使用蛋白质或蛋白质组合进行早期治疗是否可以减轻对造血系统和造血干细胞区室的长期损害。人们对老年患者群体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，可用于针对这一特殊患者群体筛选候选辐射缓解剂。我们将确定长效 G-CSF、GM-CSF 和 IL-11 类似物是否显着提高成年小鼠 H-ARS 模型的存活率，也显着提高老年小鼠 H-ARS 模型的存活率。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迟发效应，并为以下疾病提供有价值的筛选工具：评估重要但服务不足的老年患者群体中潜在的辐射缓解剂。

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