Novel drugs combinations for improving survival from Acute Radiation Syndrome when administered 48h postirradiation
放射后 48 小时给药可提高急性放射综合症生存率的新型药物组合
基本信息
- 批准号:9976446
- 负责人:
- 金额:$ 29.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-12 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnemiaAngiotensin-Converting Enzyme InhibitorsAnimalsApplications GrantsAwarenessBlood CellsBlood PlateletsBone MarrowBone Marrow Stem CellCSF3 geneCause of DeathCell CountCellsDevelopmentDoseDrug CombinationsDrug KineticsEmergency SituationExposure toFDA approvedFilgrastimFormulationFutureGovernmentGrantGranulocyte-Macrophage Colony-Stimulating FactorGrowth FactorHematopoieticHematopoietic Cell Growth FactorsHematopoietic stem cellsHemorrhageHourIndividualInfectionInterleukin-11LifeLisinoprilLymphopeniaMeasuresMedicalModelingMusNational Institute of Allergy and Infectious DiseaseNeutropeniaNuclear RadiologyNuclear WarfarePatientsPegfilgrastimPharmaceutical PreparationsPharmacotherapyPhasePilot ProjectsPlasmaPolypharmacyPositioning AttributeProgram DevelopmentProteinsRadiationRadiation AccidentsRadiation Dose UnitRadiation ToxicityRadiation exposureRecoveryRunningSavingsSignal PathwaySignal TransductionSmall Business Innovation Research GrantSurvival RateTherapeuticThrombocytopeniaTimeTissuesToxicologyTreatment ProtocolsWhole-Body Irradiationcell typedrinking waterdrug developmentemergency settingsimprovedinnovationirradiationliquid formulationmanufacturing processmedical countermeasureneutrophilnovelnovel drug combinationpatient populationphase 2 studyproduct developmentradiation mitigatorresponsesargramostimstem cells
项目摘要
Abstract. Bone marrow is one of the most radiation-sensitive tissues, and patients acutely exposed to total
body irradiation (TBI) doses > 2 Gy develop severe neutropenia, thrombocytopenia, anemia, and lymphopenia
within days to weeks of exposure, often dying from infections (due to a lack of neutrophils) and uncontrolled
bleeding (insufficient platelets) (referred to as the hematopoietic acute radiation syndrome, or H-ARS). The few
drugs that have received FDA approval to treat H-ARS increase survival when administered within 24h of
radiation exposure, but do not increase survival when administered at later times such as 48h post-irradiation
in animal H-ARS models. In a radiological/nuclear emergency, hundreds of thousands of people potentially will
be exposed to > 2 Gy radiation and it is extremely unlikely that they all can be treated within the first 24 hours
of radiation exposure. Thus, there is a critical unmet medical need for drugs capable of increasing survival
from H-ARS when administered 48h or later post-irradiation. In a pilot study we identified a novel combination
of 3 long-acting hematopoietic growth factor proteins that significantly improves 30-day survival of LD40/30
irradiated mice when administered once 48h post-TBI. This is the only drug/drug combination we are aware of
capable of increasing survival when dosing is delayed until 48h post-TBI. When dosed once 24h post-TBI, the
3 proteins interact positively with each other to increase survival more than the individual proteins, most
evident at high TBI doses (> 9 Gy). By combining the 3 proteins with a 4th radiation mitigator, an angiotensin
converting enzyme inhibitor (ACEI), it is possible to obtain 100% 30-d survival of LD95/30 TBI mice, an
unprecedented survival rate. This SBIR grant will build upon these exciting findings by (1) determining if the 3
protein combination (+/- the ACEI) can increase survival of mice exposed to higher LD70/30 and LD90/30
radiation doses when the proteins are administered 48h post-TBI; (2) determine whether all 3 proteins or only a
subset of the proteins are required for increasing 30-d survival when dosed 48h post-TBI; (3) determine
whether the 3 drug combination (+/- ACEI) can improve 30-d survival when administered at even later times
post-TBI, e.g., 72h; and (4) perform a pharmacokinetic and mechanistic study of the 3 proteins and the ACEI in
TBI mice to measure effective plasma levels of the 3 proteins and the ACEI over time, and to determine if
increased 30d survival correlates with a more rapid increase in hematopoietic progenitor cell numbers early
after irradiation in the mice. Additional mechanistic studies include performing complete blood cell analyses at
various times post-TBI to determine if increased 30-d survival correlates with accelerated recovery of
neutrophils, platelets, and other peripheral blood cell types. In addition, we will finalize GMP manufacturing
processes and identify stable liquid formulations of the 3 proteins for use in future IND-enabling studies. These
studies will lead to the development of a life-saving treatment option for a heretofore untreatable H-ARS
population – patients who cannot be treated until 48h or later post-TBI.
抽象的。骨髓是对辐射最敏感的组织之一,患者急性暴露于总辐射
身体照射 (TBI) 剂量 > 2 Gy 会出现严重的中性粒细胞减少症、血小板减少症、贫血和淋巴细胞减少症
在接触后数天至数周内,常常因感染(由于缺乏中性粒细胞)而死亡并且不受控制
出血(血小板不足)(称为造血急性放射综合征,或 H-ARS)。少数人
已获得 FDA 批准治疗 H-ARS 的药物在 24 小时内服用可提高生存率
辐射暴露,但在较晚时间(例如辐射后 48 小时)施用不会增加存活率
在动物 H-ARS 模型中。在放射性/核紧急情况下,数十万人可能会
暴露于 > 2 Gy 的辐射,并且极不可能在最初 24 小时内全部接受治疗
的辐射暴露。因此,对能够提高生存率的药物的医疗需求亟待满足
照射后 48 小时或更晚进行 H-ARS 治疗。在一项试点研究中,我们确定了一种新颖的组合
3 种长效造血生长因子蛋白可显着提高 LD40/30 的 30 天存活率
TBI 后 48 小时给药一次,对受辐射的小鼠进行治疗。这是我们所知的唯一药物/药物组合
当给药延迟至 TBI 后 48 小时时,能够提高生存率。 TBI 后 24 小时给药一次时,
3 种蛋白质相互积极相互作用,比单个蛋白质更能提高生存率,大多数
在高 TBI 剂量 (> 9 Gy) 下很明显。通过将 3 种蛋白质与第四种辐射缓解剂(血管紧张素)结合起来
转换酶抑制剂(ACEI),可以获得 LD95/30 TBI 小鼠 100% 30 天存活率,
前所未有的存活率。这笔 SBIR 赠款将建立在这些令人兴奋的发现的基础上,通过 (1) 确定 3
蛋白质组合(+/- ACEI)可以提高暴露于较高 LD70/30 和 LD90/30 的小鼠的存活率
TBI 后 48 小时施用蛋白质时的辐射剂量; (2) 确定是全部 3 种蛋白质还是仅一种
TBI 后 48 小时给药时,需要使用这些蛋白质子集来提高 30 天存活率; (3)确定
更晚给药时,3 种药物组合 (+/- ACEI) 是否可以提高 30 天生存率
TBI后,例如72小时; (4) 对 3 种蛋白质和 ACEI 进行药代动力学和机制研究
TBI 小鼠随着时间的推移测量 3 种蛋白质和 ACEI 的有效血浆水平,并确定是否
30 天存活率的增加与早期造血祖细胞数量的更快增加相关
对小鼠进行照射后。其他机制研究包括在以下位置进行全血细胞分析:
TBI 后的不同时间,以确定 30 天生存率的增加是否与加速恢复相关
中性粒细胞、血小板和其他外周血细胞类型。此外,我们将完成GMP生产
处理并确定 3 种蛋白质的稳定液体配方,用于未来的 IND 研究。这些
研究将为迄今为止无法治疗的 H-ARS 开发出挽救生命的治疗方案
人群——TBI 后 48 小时或更晚才能接受治疗的患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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George Norbert Cox其他文献
George Norbert Cox的其他文献
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{{ truncateString('George Norbert Cox', 18)}}的其他基金
Stimulating innate immunity to protect against Ebola virus infection
刺激先天免疫力以预防埃博拉病毒感染
- 批准号:
10325941 - 财政年份:2021
- 资助金额:
$ 29.35万 - 项目类别:
Novel drug combinations for improving survival from acute radiation syndrome when administered 48 hours post- irradiation
放射后 48 小时给药可提高急性放射综合征生存率的新型药物组合
- 批准号:
10604184 - 财政年份:2019
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用于治疗致命性急性和长期影响的长效生长因子
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9264475 - 财政年份:2013
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7910657 - 财政年份:2010
- 资助金额:
$ 29.35万 - 项目类别:
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