FGF-2 mimetic peptides as pleuripotent mitigators of ARS and DEARE

FGF-2 模拟肽作为 ARS 和 DEARE 的多能缓解剂

基本信息

批准号：
10401462
负责人：
PAUL OKUNIEFF
金额：
$ 29.61万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10401462
关键词：
Accidents Acute Advanced Development Affect Biological Markers Biology Blood Platelets Bone Growth Bone Marrow Brain Diseases Bulla Burn injury CSF3 gene Cell Maintenance Cessation of life Clinical Complex Cutaneous Data Dose Drug Kinetics Endothelial Cells Epithelial Event FGF2 gene Family suidae Fibroblast Growth Factor Follow-Up Studies Functional disorder Funding Heart Diseases Hematologic Agents Hematology Hematopoietic Hemorrhage Human Individual Inflammation Injury Intervention Investigational Drugs Investigational New Drug Application Knowledge Lead Length Life Light Logistics Lung Macaca Macaca mulatta Maximum Tolerated Dose Mesenchymal Miniature Swine Modeling Monkeys Mus National Institute of Allergy and Infectious Disease Nerve Regeneration Nuclear Nuclear Radiology Nutrient Oral mucous membrane structure Organ Oxygen Perfusion Pharmaceutical Preparations Pharmacodynamics Play Process Production Proteins Radiation Radiation Accidents Radiation Injuries Radiation Syndromes Radiation Toxicity Radiation exposure Radiodermatitis Rattus Readiness Recombinants Research Project Grants Role Safety Schedule Site Skin Strontium Strontium-90 Supportive care Syndrome Testing Therapeutic Time Tissues Toxic effect Toxicity Tests Trauma United States National Institutes of Health Vascular regeneration Whole-Body Irradiation Wistar Rats Work animal rule base bone preservation cell type cost cytokine design efficacy study experience gastrointestinal good laboratory practice graft vs host disease healing improved irradiation mass casualty medical countermeasure meetings model design mouse model multiorgan damage nonhuman primate organ injury peptidomimetics pharmacokinetics and pharmacodynamics platelet function preclinical study preservation pressure prevent public health emergency radiation burn radiation countermeasure receptor binding response response biomarker senescence stem cell proliferation telomere wound wound healing

Accidents Acute Advanced Development Affect Biological Markers Biology Blood Platelets Bone Growth Bone Marrow Brain Diseases Bulla Burn injury CSF3 gene Cell Maintenance Cessation of life Clinical Complex Cutaneous Data Dose Drug Kinetics Endothelial Cells Epithelial Event FGF2 gene Family suidae Fibroblast Growth Factor Follow-Up Studies Functional disorder Funding Heart Diseases Hematologic Agents Hematology Hematopoietic Hemorrhage Human Individual Inflammation Injury Intervention Investigational Drugs Investigational New Drug Application Knowledge Lead Length Life Light Logistics Lung Macaca Macaca mulatta Maximum Tolerated Dose Mesenchymal Miniature Swine Modeling Monkeys Mus National Institute of Allergy and Infectious Disease Nerve Regeneration Nuclear Nuclear Radiology Nutrient Oral mucous membrane structure Organ Oxygen Perfusion Pharmaceutical Preparations Pharmacodynamics Play Process Production Proteins Radiation Radiation Accidents Radiation Injuries Radiation Syndromes Radiation Toxicity Radiation exposure Radiodermatitis Rattus Readiness Recombinants Research Project Grants Role Safety Schedule Site Skin Strontium Strontium-90 Supportive care Syndrome Testing Therapeutic Time Tissues Toxic effect Toxicity Tests Trauma United States National Institutes of Health Vascular regeneration Whole-Body Irradiation Wistar Rats Work animal rule base bone preservation cell type cost cytokine design efficacy study experience gastrointestinal good laboratory practice graft vs host disease healing improved irradiation mass casualty medical countermeasure meetings model design mouse model multiorgan damage nonhuman primate organ injury peptidomimetics pharmacokinetics and pharmacodynamics platelet function preclinical study preservation pressure prevent public health emergency radiation burn radiation countermeasure receptor binding response response biomarker senescence stem cell proliferation telomere wound wound healing

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项目摘要

A nuclear blast or other mass casualty radiation event will necessarily cause multiorgan radiation toxicities compounded by physical trauma and thermal burns. Deaths will result from complex and combined organ injuries that occur in a time- and dose-dependent manner. While the strategic national stockpile includes agents for hematological acute radiation syndrome (H-ARS), no candidates are approved for gastrointestinal ARS (GI-ARS) and few if any candidates are approved for other organs. As cutaneous radiation injury [CRI (blistering, bleeding)] when combined with H/GI-ARS can lead to death, an agent that aids multiple epithelial tissues for combined injuries would be an ideal medical countermeasure. In light of the far-reaching potential of FGFs, we developed an FGF-2 peptide mimetic, FGF-PT; this alternative to the full-length protein is economical, easily scaled and synthesized, and has a long storage life. We hypothesize that the pluripotent effects of FGF-PT on epithelial, mesenchymal, and endothelial cells, which include preservation and proliferation of progenitor cells, maintenance of normal cellular maturation and function, and improved tissue perfusion, will mitigate combined radiation injury syndromes. We propose to test this hypothesis through the following Specific Aims: Aim 1: We will move FGF-PT toward an investigational new drug (IND) application for GI-ARS. We have already discussed the pre-IND process with representatives of NIAID, FDA, and BARDA. Based on this meeting, we propose a 6-step process to confirm mitigation benefit and mechanism of action in a GI-ARS/H- ARS model in Wistar Rats. Studies will include pharmacokinetics (PK), pharmacodynamics (PD), and toxicity testing in rats followed by PK and PD in Rhesus macaques to determine the drug dose and schedule for full good laboratory practice (GLP) testing in rats and macaques in separate follow-up studies. Aim 2: We have shown that FGFs can mitigate radiation dermatitis and improve platelet function following irradiation. In this aim, we will elucidate the role of both systemic and topical FGF-PT for CRI using an NIH Swiss model (strontium-90 beta burn) and Göttingen minipig model. In the minipig, we will test our models for allometric scaling between mouse, rat, monkey, and pig, and employ a radiation burn healing model (16 sites of 4x4 cm /minipig) developed by Core B. At the completion of Year 3, we expect to have sufficient knowledge of dose, schedule, mechanism of action, human relevance, and safety to design a “pivotal” study for both the rat and monkey, according to the Animal Rule, for GI-ARS under GLP conditions. Funding for that study will be sought in Year 4. Near the completion of Year 4, we expect to have similar evidence for CRI. While minipigs are expected to play a key role, the CRI NIAID meeting this month (May 2019) has not yet recommended a model design. In Year 5, we will refine our approach to meet criteria more clearly defined at that time for FDA approval of agents for CRI.

核爆炸或其他质量休闲辐射事件必然会引起多机器人辐射物理创伤和热烧伤使毒性复合。死亡将由复杂和结合造成以时间和剂量依赖性方式发生的器官损伤。战略国家储备包括血液学急性辐射综合征（H-AR）的药物，未批准候选人胃肠道 ARS（GI-ARS），如果有任何候选人获得其他器官的批准，则很少。作为皮肤辐射损伤[CRI] （起泡，出血）]与h/gi-ar的结合时，可能会导致死亡，该代理有助于多个上皮结合损伤的组织将是理想的医学对策。鉴于 FGFS，我们开发了FGF-2 Pepper Mimetic，FGF-PT；全长蛋白的这种替代方案是经济，易于缩放和合成，并具有较长的存储寿命。我们假设多能 FGF-PT对上皮，间质和内皮细胞的影响，包括保存和祖细胞的增殖，正常细胞成熟和功能的维持，并改善组织灌注，会减轻辐射损伤综合征的组合。我们建议检验这一假设通过以下特定目的： AIM 1：我们将FGF-PT向GI-ARS的投资新药（IND）申请。我们已经讨论了代表NIAID，FDA和BARDA的预测过程。基于此开会，我们提出了一个6步的过程，以确认GI-ARS/H-中的缓解益处和作用机制 Wistar大鼠中的ARS模型。研究将包括药代动力学（PK），药效学（PD）和毒性在大鼠中进行测试，然后在恒河猕猴中进行PK和PD，以确定全面的药物剂量和时间表在单独的后续研究中，大鼠和猕猴进行了良好的实验室实践（GLP）测试。 AIM 2：我们已经表明，FGF可以减轻辐射皮炎并改善血小板功能辐照后。在此目标中，我们将使用A的CRI阐明系统性和局部FGF-PT的作用 NIH瑞士型号（STRONTIUM-90 BETA燃烧）和GöttingenMinipig模型。在Minipig中，我们将测试我们的模型对于小鼠，大鼠，猴子和猪和雇员之间的异量级缩放，辐射燃烧愈合模型（16 由CoreB开发的4x4 cm /minipig的位置。在第三年完成时，我们希望有足够的剂量，时间表，机制根据该行动，人类的相关性和安全性，以设计大鼠和猴子的“关键”研究。动物规则，用于GLP条件下的GI-ARS。该研究的资金将在4年级感知。第4年的完成，我们希望有类似的CRI证据。虽然小恶作剧有望扮演钥匙角色，本月（2019年5月）的CRI NIAID会议尚未推荐模型设计。在5年级，我们将完善我们在当时更明确地符合标准的方法，以授予FDA批准CRI的代理商。