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

• 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
• 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

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.

核爆炸或其他大规模伤亡辐射事件必然会导致多器官辐射 身体创伤和热烧伤导致的毒性。死亡将由复杂的和综合的 以时间和剂量依赖性方式发生的器官损伤。虽然国家战略储存包括 药物用于血液学急性放射综合征（H-ARS），没有候选人被批准用于胃肠道 亚美尼亚救济协会（GI-ARS），其他机构的候选人即使有也很少。皮肤放射性损伤 （起泡，出血）]与H/GI-ARS结合时可导致死亡，这是一种有助于多发性上皮细胞癌的药物。 复合伤组织是一种理想的医疗对策。考虑到 为了研究FGF，我们开发了FGF-2肽模拟物FGF-PT;这种全长蛋白质的替代品是 经济、易规模化合成、贮存期长。我们假设多能细胞 FGF-PT对上皮细胞、间充质细胞和内皮细胞的作用，包括保存和 增殖祖细胞，维持正常的细胞成熟和功能，并改善 组织灌注将减轻复合辐射损伤综合征。我们建议检验这一假设 通过以下具体目标： 目标1：我们将把FGF-PT推向GI-ARS的研究性新药（IND）申请。我们 已经与NIAID、FDA和巴尔达的代表讨论了IND前流程。基于此 会议上，我们提出了一个6步流程来确认GI-ARS/H中的缓解效益和行动机制- Wistar大鼠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，然后在恒河猴中进行PK和PD，以确定完全给药的药物剂量和时间表。 在单独的随访研究中，在大鼠和猕猴中进行药物非临床研究质量管理规范（GLP）试验。 目的2：我们已经证明FGF可以减轻放射性皮炎，改善血小板功能 辐照后。在这个目标中，我们将阐明全身和局部FGF-PT对CRI的作用， NIH Swiss模型（锶-90 β烧伤）和哥廷根小型猪模型。在迷你猪中，我们将测试我们的模型 用于小鼠、大鼠、猴和猪之间的异速生长比例，并采用辐射烧伤愈合模型（16 中心B开发的4x 4 cm /小型猪）。 在第3年结束时，我们希望对剂量、时间表、 行动，人类相关性和安全性，以设计一个“关键”的研究，为大鼠和猴子，根据 GLP条件下GI-ARS的动物规则。这项研究的资金将在第四年筹集。附近 完成第四年，我们预计将有类似的证据CRI。虽然迷你猪被认为是 尽管如此，CRI NIAID本月（2019年5月）的会议尚未推荐模型设计。第五年，我们 我们将改进我们的方法，以满足当时FDA批准CRI药物的更明确的标准。