IND-enabling development of Radioprotectin 1: a dual GI/HE radiation mitigator

Radioprotectin 1 的 IND 开发：双重 GI/HE 辐射缓解剂

• 批准号: 10401460
• 负责人: GABOR J TIGYI
• 金额: $ 29.62万
• 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/10401460
• 关键词: Acute; Advanced Development; Affect; Agonist; Animal Model; Apoptosis; Apoptotic; Benzoic Acids; Biological Assay; Bone Marrow; Cell Death; Cell Survival; Cells; Cessation of life; Clinical Trials; Collaborations; Communities; Complex; DNA; DNA Integration; DNA Repair; DNA Repair Inhibition; DNA-dependent protein kinase; Data; Development; Devices; Dose; Drug Formulations; Drug Kinetics; Drug Targeting; Enzymes; Evaluation; Explosion; FDA approved; Formulation; Funding; G-Protein-Coupled Receptors; Generations; Genes; Genotoxic Stress; Goals; Growth Factor; Hematopoietic; Hematopoietic stem cells; Human; Immediate-Early Genes; Inhibition of Apoptosis; Injury; Intestines; Investigational Drugs; Ionizing radiation; Knowledge; LGR5 gene; Laboratories; Lethal Dose 50; Leucine-Rich Repeat; Lysophosphatidic Acid Receptors; MAPK3 gene; Macaca mulatta; Mediating; Medical; Military Personnel; Mitotic; Modeling; Molecular; Molecular Mechanisms of Action; Mus; National Institute of Allergy and Infectious Disease; Natural regeneration; Nuclear; Nuclear Reactor Accidents; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacy facility; Population; Property; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Radiation; Radiation Dose Unit; Radiation Induced DNA Damage; Radiation Injuries; Radiation Protection; Radiation Syndromes; Radiation Toxicity; Radiation exposure; Radiation induced damage; Research; Research Proposals; Role; Safety; Signal Transduction; Terrorism; Testing; Therapeutic; Toxicokinetics; Transgenic Mice; analog; animal rule; base; cell injury; cell killing; cell regeneration; cellular targeting; college; drug candidate; drug development; drug discovery; efficacy study; experience; first responder; gamma irradiation; gastrointestinal; gastrointestinal epithelium; gene product; in vivo; irradiation; lipid mediator; lysophosphatidic acid; medical countermeasure; meetings; mortality; nanoparticle; nanoparticle drug; nonhuman primate; prevent; progenitor; programs; radiation countermeasure; radiation mitigation; radiation mitigator; radiation risk; radiation-induced injury; receptor; recruit; regenerative; repaired; response; senescence; small molecule; stem cell survival; stem cells

The US population at large, and particularly military personnel and first responders, are at risk of radiation exposure due to the explosion of a nuclear device, a nuclear reactor accident, and the threat of radiation terrorism. There is no radiation medical countermeasure (RCM) drug approved by the FDA that meets the criterion of a gastrointestinal (GI) radiomitigator – an agent which mitigates the acute GI radiation syndrome (GI-ARS) when administered after the exposure. Ionizing radiation kills cells that are unable to repair their DNA, primarily via mitotic catastrophe and apoptotic cell death. Post-irradiation genotoxic stress and cell injury is an unsolved medical problem. A critical barrier to progress in development of RCM drugs is that a traditional human clinical trial is not an option. Therefore, FDA approval of a RCM is done under the Animal Rule that requires detailed understanding of its mechanism of action, demonstration of its safety, and efficacy in animal models, and its safety in humans. In this transitional research proposal, we propose studies to fully satisfy the mechanism of action requirement of the Animal rule for Radioprotectin-1 (RP-1) a new radiation mitigator we developed with previous NIAID funding and develop a single-dose extended release formulation that meets CONPOS requirements of a RCM. Our overall goal is to prepare RP-1 for regulatory approval as a first-in-class synthetic GI radiation mitigator. RP-1 is the first specific agonist of the lysophosphatidic acid (LPA) receptor subtype 2 (LPA2) with picomolar EC50, which reduces radiation injury-induced mortality in mice. Our central hypothesis is that RP-1–activated, uniquely long-lasting (> 16h) signaling mediated by the LPA2 G protein-coupled receptor (GPCR), is responsible for mitigation of genotoxic stress and promotion of cell survival. Our hypothesis predicts that RP-1 achieves this via 1) obligate stimulation of the LPA2 GPCR, 2) sequential recruitment of supramolecular signaling interactomes responsible for the long duration of its action, 3) augmentation of DNA repair and 4) enhanced survival of LGR5 intestinal stem cells (ISC). Our objectives are: 1) determine in detail the unique molecular mechanism of how RP-1 acts via LPA2 to recruit the interactomes required for overcoming genotoxic stress, and 2) identify the specific subpopulation of ISC that is protected by RP-1 in vivo using transgenic mice that express fluorescent protein in the LGR5 marker bearing ISC and 3) develop a single dose extended release nanoparticle formulation that mitigates the GI-ARS. Although this information is necessary to move RP-1 forward toward regulatory approval, the body of knowledge we will generate also represents significant and previously unknown information concerning radioprotective signaling mechanisms. Our expected outcomes will include 1) establishing that LPA2-dependent recruitment of the IEX-1–TRIP6–ERK1/2-AKT interactome is required for mitigation of genotoxic stress; 2) defining the role of RP-1 effects that enhance DNA-dependent Protein Kinase- dependent DNA repair and prosurvival signals; 3) demonstrating that RP-1 is an effective mitigator of GI-ARS by protecting ISC in mice; 4) a single-dose extended-release RP-1 formulation. The impact of our project will directly affect our first-response options in treating patients with radiation injury. The aims of the project are: Aim 1. Test the hypothesis that RP-1 via LPA2 mediates long-lasting activation of DNA repair and pro- survival signaling in LGR-5 positive intestinal stem cells. Aim 2. Develop a nanoparticle-based extended-release RP-1 formulation for the treatment of the GI-ARS of mice and Rhesus macaques. All data obtained will be used for a RP-1 Drug Master file and presented to the FDA during our PRE-IND meeting in the final year of the project and shared with the research community at large.

美国广大民众，特别是军事人员和第一反应人员，都面临着辐射的风险。 由于核装置爆炸、核反应堆事故和辐射恐怖主义的威胁而暴露。 FDA批准的放射医学对策（RCM）药物中没有一种符合 胃肠道（GI）放射抑制剂-一种缓解急性GI放射综合征（GI-ARS）的药物， 在暴露后服用。电离辐射杀死无法修复其DNA的细胞，主要是通过 有丝分裂灾难和凋亡性细胞死亡。辐射后遗传毒性应激和细胞损伤是一个未解决的问题 医疗问题。RCM药物开发进展的一个关键障碍是传统的人类 临床试验不是一个选择。因此，FDA对RCM的批准是根据动物规则进行的， 详细了解其作用机制，在动物模型中证明其安全性和有效性， 以及它在人体内的安全性。在这一过渡性研究提案中，我们提出研究，以充分满足 放射防护素-1（RP-1）是一种新型的放射防护剂， 开发与以前的NIAID资金，并开发一个单剂量延长释放配方，满足CONPOS 一个RCM的要求。我们的总体目标是准备RP-1的监管批准作为一流的合成 胃肠道辐射缓解器。RP-1是溶血磷脂酸（LPA）受体亚型2的第一个特异性激动剂 （LPA 2）具有皮摩尔EC 50，其降低了小鼠中辐射损伤诱导的死亡率。我们的核心假设 是RP-1激活的，独特的持久（> 16小时）的信号传导介导的LPA 2 G蛋白偶联受体 （GPCR）负责减轻遗传毒性应激和促进细胞存活。我们的假设预测 RP-1通过1）LPA 2 GPCR的专性刺激，2）超分子GPCR的顺序募集， 负责其作用持续时间长的信号相互作用体，3）DNA修复的增强和4） 增强LGR 5肠干细胞（ISC）的存活。我们的目标是：1）详细确定独特的 RP-1如何通过LPA 2募集克服遗传毒性所需的相互作用组的分子机制 应激，和2）使用转基因小鼠在体内鉴定受RP-1保护的ISC的特定亚群 在带有ISC的LGR 5标记物中表达荧光蛋白; 3）开发单剂量缓释剂 减轻GI-ARS的纳米颗粒制剂。尽管这些信息对于RP-1的前进是必要的 对于监管批准，我们将产生的知识体系也代表了重要的，以前 关于辐射防护信号传导机制的未知信息。我们的预期成果将包括1） 确定IEX-1-TRIP 6-ERK 1/2-AKT相互作用组的LPA 2依赖性募集是 缓解遗传毒性应激; 2）确定RP-1增强DNA依赖性蛋白激酶的作用- 依赖的DNA修复和促生存信号; 3）证明RP-1是GI-ARS的有效缓解剂 通过保护小鼠中的ISC; 4）单剂量延长释放RP-1制剂。我们项目的影响将 直接影响我们治疗辐射损伤患者的第一反应选择。该项目的目标是： 目标1.检验RP-1通过LPA 2介导DNA修复和促凋亡的长期激活的假设。 LGR-5阳性肠干细胞中的存活信号传导。 目标2.开发用于治疗GI-ARS的基于纳米颗粒的缓释RP-1制剂 老鼠和恒河猴的实验。 获得的所有数据将用于RP-1药物主文件，并在PRE-IND会议期间提交给FDA 在项目的最后一年，并与整个研究界分享。