Early-Stage Preclinical Validation of Carbon Monoxide Prodrugs for Acute Kidney Injury

一氧化碳前药治疗急性肾损伤的早期临床前验证

基本信息

批准号：
10525896
负责人：
LEO E OTTERBEIN
金额：
$ 75.03万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525896
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Affect Animal Model Animals Biological Biology Carbon Monoxide Cardiopulmonary Bypass Chemistry Chronic Kidney Failure Clinical Colon Crush Injury Development Disease Donor person Dose Drug Kinetics Event Exposure to FDA approved Family suidae Formulation Foundations Future Goals Grant Heme Hemeproteins Hemolysis Hospitalization Human Hypotension Incidence Industrialization Inflammation Injury Intervention Kidney Kidney Transplantation Kinetics Lead Literature Liver Maintenance Therapy Medical Mississippi Mitochondria Modeling Mus National Institute of Diabetes and Digestive and Kidney Diseases Nitric Oxide Operative Surgical Procedures Organ Organ Model Outcome Oxidative Stress Pancreas Patients Pharmaceutical Chemistry Pharmacologic Substance Pharmacology Plasma Prodrugs Property Reperfusion Injury Rhabdomyolysis Role Route Safety Sepsis Series Severities Sickle Cell Anemia Signal Transduction Signaling Molecule Stomach Supportive care Synthesis Chemistry Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Tissues Toxic effect Translating Transplant Recipients Trauma Treatment Efficacy Validation Warm Ischemia Work allotransplant base delayed graft function design drug discovery efficacy evaluation efficacy validation improved improved outcome in vitro Assay in vitro Model innovation interest liver injury mortality mouse model novel organ injury pill porcine model pre-clinical pre-clinical assessment prevent protective effect renal ischemia response safety assessment scaffold success systemic inflammatory response tissue injury transplant model validation studies

项目摘要

In response to PAR-19-294 (Early-Stage Preclinical Validation of Therapeutic Leads for Diseases of Interest to the NIDDK), we propose to conduct preclinical validation of carbon monoxide (CO) as a therapeutic agent for treating acute kidney injury (AKI), which afflicts a large number of patients with serious and sometimes fatal consequences. Currently, there are no treatment options available other than maintenance therapy. Therefore, developing disease modifying treatment for AKI will address an important, unmet medical need. The proposed work of developing CO-based therapeutics is based on CO’s endogenous signaling roles, the availability of a large amount of literature evidence to show CO’s cyto- and organ-protective effects, our unique chemistry work to pack “CO in a pill” through innovative prodrug design for easy delivery through pharmaceutically acceptable forms, and our own extensive preliminary results in demonstrating the organ-protective effects of such CO prodrugs in animal models of kidney ischemia reperfusion injury and rhabdomyolysis injuries, liver injury, systemic inflammation, and GI inflammation such as the colon and stomach, among others. In this application, we propose to examine some key preclinical validation issues and aim to produce one or more lead compounds ready for IND-enabling work by the end of the grant period. A very important aspect is our plan to use multiple animal models including the examination in large animals such as pig to conduct the pharmacological assessment, which should give enhanced chance of success when translating into human. Specifically, we propose to pursue the following specific aims (1) design, synthesis, and assessment of CO prodrugs, (2) therapeutic validation of CO prodrug efficacy in mouse models of AKI, and (3) therapeutic validation of CO prodrugs in pig models of AKI. The proposed work will bridge the gap between our long-term goal of developing CO-based therapeutics and the need for preclinical assessments. Upon completion of the project, we will have developed and fully validated the efficacy of a series of innovative CO prodrugs that can either deliver CO systemically or selectively target the kidney and allow for renal enrichment. Further, we will also have developed a pipeline for backup candidates. Collectively, the proposed work will be a major step in developing CO-based therapeutics against AKI and other forms of organ injury.

响应 PAR-19-294（针对感兴趣疾病的治疗先导药物的早期临床前验证） NIDDK），我们建议对一氧化碳（CO）作为治疗剂进行临床前验证治疗急性肾损伤 (AKI)，该病使大量患者出现严重甚至致命的症状目前，除了维持治疗外，没有其他治疗选择。开发针对 AKI 的疾病修饰疗法将解决一个重要的、未满足的医疗需求。开发基于 CO 的疗法的工作是基于 CO 的内源信号作用，大量文献证据显示 CO 的细胞和器官保护作用，我们独特的化学工作通过创新的前药设计将“CO 装入药丸中”，以便通过药学上可接受的方式轻松递送形式，以及我们自己在证明此类 CO 的器官保护作用方面的广泛初步结果肾缺血再灌注损伤和横纹肌溶解损伤、肝损伤动物模型中的前药在此应用中，全身炎症和胃肠道炎症例如结肠和胃等。我们建议研究一些关键的临床前验证问题，并旨在生产一种或多种先导化合物准备在资助期结束时开展 IND 工作，一个非常重要的方面是我们计划使用多个项目。动物模型，包括对猪等大型动物进行药理学检查评估，这应该会增加翻译成人类的成功机会。建议追求以下具体目标（1）CO前药的设计、合成和评估，（2） CO 前药在 AKI 小鼠模型中的疗效验证，以及 (3) CO 的治疗验证拟议的工作将弥补我们开发 AKI 的长期目标之间的差距。基于CO的疗法和临床前评估的需要在项目完成后，我们将有。开发并充分验证了一系列创新的 CO 前药的功效，这些药物可以传递 CO 系统地或选择性地靶向肾脏并允许肾脏浓缩。此外，我们还将开发。总的来说，拟议的工作将是开发基于 CO 的重要一步。针对 AKI 和其他形式的器官损伤的疗法。