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: 10845827
• 负责人: GABOR J TIGYI
• 金额: $ 31.04万
• 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/10845827
• 关键词: IND; enabling; development; Radioprotectin; dual

The US population at large, and particularly military personnel and first responders, are at risk of radiation expo-sure 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 mech-anism of action requirement of the Animal rule for Radioprotectin-1 (RP-1) a new radiation mitigator we devel-oped 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 mit-igation 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.

由于核装置的爆炸，核反应堆事故以及辐射恐怖主义的威胁，美国，尤其是军事人员和第一响应者的美国人口有辐射博览会的风险。 FDA批准了符合标准的辐射医学对策（RCM）药物 胃肠道（GI）放射线仪 - 一种降低急性GI辐射综合征（GI-ARS）的药物 暴露后进行管理。电离辐射杀死无法修复其DNA的细胞，主要通过 有丝分裂灾难和凋亡细胞死亡。辐射后遗传毒性应激和细胞损伤是未解决的 医疗问题。 RCM药物发展进展的关键障碍是传统人类 临床试验不是一个选择。因此，FDA批准RCM是根据需要的动物规则进行的 详细了解其作用机理，证明其安全性和在动物模型中的效率， 及其在人类中的安全。在这项过渡研究建议中，我们提出研究，以充分满足放射性原肽1（RP-1）动物规则对动作规则的机械性态度的满足，我们将使用先前的NIAID资金来脱离新的放射性缓解剂，并开发单剂量扩展的释放公式，以满足氧化氧 RCM的要求。我们的总体目标是准备RP-1作为一流合成的监管批准 GI辐射缓解剂。 RP-1是溶物磷脂酸（LPA）受体亚型2的第一个特异性激动剂2 （LPA2）与皮摩尔EC50，可降低小鼠辐射损伤诱导的死亡率。我们的中心假设 是由LPA2 G蛋白偶联受体介导的RP-1激活，独特的持久（> 16H）信号传导 （GPCR），负责缓解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）lpa2 gpcr的强制性刺激，2）超分子的顺序募集 信号传导相互作用造成了长时间的作用持续时间，3）DNA修复的增强和4） LGR5肠干细胞（ISC）的生存增强。我们的目标是：1）详细确定唯一 RP-1如何通过LPA2作用以募集克服Genotoxy所需的相互作用的分子机制 2）确定使用转基因小鼠在体内受到RP-1保护的ISC的特定亚群 在LGR5标记轴承ISC中表达荧光蛋白和3）产生单剂量延长释放 纳米颗粒公式可缓解GI-ARS。尽管此信息对于将RP-1向前移动是必需的 为了获得监管的批准，我们将产生的知识体也代表着重要的和以前 有关辐射保护信号机制的未知信息。我们的预期结果将包括1） 确定IEX-1 – TRIP6 – ERK1/2-Akt Itspetrolome的LPA2依赖性募集是缓解遗传毒性应激所必需的； 2）定义RP-1效应的作用，从而增强了DNA依赖性蛋白激酶依赖性DNA修复和生存信号； 3）证明RP-1是GI-AR的有效缓解剂 通过保护小鼠的ISC； 4）单剂量扩展释放RP-1公式。我们项目的影响将 直接影响我们在治疗辐射损伤患者方面的第一反应选择。该项目的目的是： AIM 1。检验以下假设，即通过LPA2介导LGR-5阳性肠干细胞中DNA修复和促生存信号的长期激活。 AIM 2。开发基于纳米颗粒的扩展释放RP-1公式来治疗GI-ARS 小鼠和恒河猕猴。 所有获得的数据将用于RP-1药物主文件，并在我们的预定会议期间呈现给FDA 在项目的最后一年，并与整个研究界分享。