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

核爆炸或其他大规模伤亡的辐射事件必然会引起多器官辐射。 毒物加上身体创伤和热烧伤。死亡将是复杂和综合的结果 器官损伤以时间和剂量依赖的方式发生。虽然国家战略储备包括 治疗血液学急性辐射综合征(H-ARS)的药物，没有胃肠道候选药物被批准 ARS(GI-ARS)和少数(如果有的话)候选人被批准进入其他机构。作为皮肤辐射损伤[CRI (起泡、出血)]当与H/GI-ARS结合时会导致死亡，这是一种帮助多发性上皮细胞的药物 复合损伤的组织将是一种理想的医学对策。鉴于……的深远潜力 FGFs，我们开发了一种成纤维细胞生长因子-2多肽模拟物，成纤维细胞生长因子-PT；这种全长蛋白质的替代品是 经济，易于扩展和合成，并具有较长的储存期。我们假设全能的 成纤维细胞生长因子-PT对上皮细胞、间充质细胞和内皮细胞的影响 祖细胞的增殖，维持正常的细胞成熟和功能，并得到改善 组织灌流，将减轻联合放射损伤综合征。我们建议检验这一假设 通过以下具体目标： 目的1：我们将推进成纤维细胞生长因子-PT用于GI-ARS的研究新药(IND)。我们 已经与NIAID、FDA和BARDA的代表讨论了IND前流程。在此基础上 会议上，我们提出了一个6步过程，以确认GI-ARS/H中的缓解益处和行动机制- Wistar大鼠ARS模型的建立。研究将包括药代动力学(PK)、药效学(PD)和毒性 在大鼠体内试验，然后在恒河猴体内进行PK和PD，以确定全程给药的剂量和时间表 在不同的后续研究中对老鼠和猕猴进行良好实验室操作规范(GLP)测试。 目的2：我们已经证明FGFs可以减轻放射性皮炎和改善血小板功能。 在辐射后。在这个目标中，我们将阐明全身和局部的成纤维细胞生长因子-PT在CRI中的作用。 NIH瑞士模型(锶-90β燃烧)和Göttingen小型猪模型。在小型猪中，我们将测试我们的模型 用于小鼠、大鼠、猴子和猪之间的异速生长比例，并采用辐射烧伤愈合模型(16 4x4厘米/小型猪的位置)由Core B开发。 在第三年结束时，我们希望对剂量、时间表、机制有足够的了解 行动、人类相关性和安全性，以设计一项对大鼠和猴子都至关重要的研究，根据 GLP条件下GI-ARS的动物规则。这项研究将在第四年寻求资金。 完成第四年，我们预计将有类似的证据证明CRI。而预计小型猪将扮演一个关键角色 尽管如此，本月(2019年5月)召开的CRI NIAID会议尚未推荐车型设计。在第五年，我们 将改进我们的方法，以满足当时FDA批准CRI药物的更明确定义的标准。

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.