The primary objective of this project is to demonstrate the feasibility of developing C23 as a novel and effective therapeutic for patients with ischemic acute kidney injury (AKI), a significant cause of prolonged hospitalization and mortality. Ischemic AKI often complicates hemorrhagic shock, septic shock, and surgery. Yet, despite it being a frequent, life-shortening, and costly complication, no FDA-approved drugs are currently available to treat patients with ischemic AKI. We have discovered that cold-inducible RNA-binding protein (CIRP) acts as a novel damage-associated molecular pattern (DAMP) to increase inflammation after ischemic injury. In our preliminary studies, we show that CIRP is released into the circulation after renal ischemia and reperfusion (RIR) and promotes the development of AKI. We screened CIRP-derived small peptides and identified C23 to have high affinity for the CIRP receptor and inhibit CIRP activities. We also show that administration of C23 at the beginning of reperfusion attenuates renal inflammation and damage. Administration of C23 at the time of reperfusion after ischemia also increased the seven-day survival of mice subjected to RIR from 37% to 70%. Therefore, we hypothesize that C23 can be developed as a new and effective drug to improve renal function and prevent renal damage after ischemic AKI. In this project, we will demonstrate the feasibility of developing C23 to treat ischemic AKI by determining C23s optimal dose to improve renal function after RIR and after sepsis, C23s therapeutic window to improve survival after RIR and after sepsis, and C23s pharmacokinetic and safety profile in healthy animals. Our future steps of drug development (SBIR Phase II and beyond) include completing preclinical studies, establishing ADME, advanced pharmacokinetics and safety studies in healthy and diseased animals, and filing an investigational new drug (IND) application with the FDA to initiate clinical trials. Our ultimate goal is to obtain commercial utilization of C23 as a safe and effective drug for patients with ischemic AKI caused by renal hypoperfusion.
Public Health Relevance Statement: Public Health Relevance Statement: A drop in the blood flow to the kidneys after trauma, sepsis, or during surgery is common and can result in acute kidney injury, leading to longer hospital stays, higher health care costs, and increased risk of chronic kidney disease and death. We have shown that inhibition of the CIRP protein with C23 strongly protects experimental animals from acute kidney injury and improves their survival. Therefore, we propose to develop C23 as a new and powerful way to treat surgery- associated acute kidney injury.
Project Terms: absorption; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affinity; Amino Acids; Animal Diseases; Animals; Area Under Curve; Attenuated; Bilateral; Biological Markers; Blood; Blood Circulation; Blood flow; Blood specimen; C57BL/6 Mouse; cecal ligation puncture; Cell Death; Cessation of life; Chronic Kidney Failure; Clinical Trials; Complication; cost; Creatinine; cytokine; Data; Development; Dose; Drops; drug development; Drug Kinetics; effective therapy; Excretory function; FDA approved; Female; Fibrosis; Future; glomerulosclerosis; Goals; Half-Life; Health Care Costs; Hemorrhagic Shock; Hepatic; High Pressure Liquid Chromatography; Histologic; Hospitalization; Hospitals; Human; hypoperfusion; improved; Inflammation; Injury; Injury to Kidney; Interleukin-1; Interleukin-18; Interleukin-6; interstitial; Intravenous; Investigational New Drug Application; Ischemia; Kidney; Kidney Diseases; kidney dysfunction; LCN2 gene; Length of Stay; Lethal Dose 50; Life; Liver; Lung; macrophage; male; Maximum Tolerated Dose; Measures; Metabolism; Modeling; Molecular; mortality; Mus; Neutrophil Infiltration; Normal saline; novel; novel therapeutics; Operative Surgical Procedures; Patients; Pattern; Peptides; Perfusion; Peroxidases; Pharmaceutical Preparations; Phase; post gamma-globulins; preclinical study; prevent; Proteins; public health relevance; receptor; Renal Blood Flow; renal damage; Renal function; renal ischemia; Reperfusion Injury; Reperfusion Therapy; Risk; RNA-Binding Proteins; Safety; safety study; Secondary to; Sepsis; Septic Shock; Small Business Innovation Research Grant; Small Intestines; Sprague-Dawley Rats; Stains; Survival Rate; Testing; Therapeutic; Time; TNF gene; Toxic effect; Toxicology; Trauma; Treatment Efficacy; Tubular formation
