Ischemia-reperfusion injury (IRI) occurs in organs when circulation is interrupted, causing ischemia, and then ischemic tissue is reperfused. This leads to a series of biologic consequences, resulting in edema and inflammation. IRI is a significant problem in organ transplantation, because IRI is the major cause of primary graft failure and organ dysfunction after transplant. IRI is also a major problem in many clinical scenarios, including cardiopulmonary bypass (CPB) used in cardiac surgery, myocardial infarction (MI), and stroke. There are currently no effective therapies to prevent or reduce IRI. Graft injury due to IRI at the time of implantation is now recognized as a major contributor to delayed graft dysfunction, also known as chronic rejection. Lung transplantation (LTX) has extended and improved the lives of thousands of patients with end-stage lung disease, but is severely constrained by an inadequate supply of suitable donors from conventional organ donors (brain-dead, ventilated patients whose organs are retrieved after controlled cardiac arrest). Among solid organs transplanted, lungs have one of the highest rates of acute graft failure, and the highest incidence of late graft failure. Hundreds of transplant candidates die every year before receiving LTX, and thousands of others are not even considered candidates because of the lung donor shortage. If lungs could be retrieved from non-heart-beating donors (NHBDs) - victims of sudden death - at intervals after circulatory arrest and transplanted safely, the shortage of lungs for transplant could be eliminated, and the lives of thousands more patients with end-stage lung disease could be extended or enhanced by LTX. Transplant using lungs retrieved from NHBDs is also associated with IRI. Any therapy to reduce lung IRI would have significant clinical impact;it could improve both short- and long-term results of conventional LTX, and it could facilitate LTX from NHBDs. In addition, reducing IRI in other organs would have far-reaching implications in organ transplantation and in CPB, MI, and stroke. We have identified receptors and effector pathways of the innate immune system as important contributors to inflammation due to IRI. Among these, there is growing evidence from our group and others that toll-like receptor 4 (TLR4) is a critical contributor to IRI in transplant and to other IRI models. The purpose of the Phase I STTR is to determine if CRX-526, a TLR4 inhibitor that we showed prevents edema due to IRI, can ameliorate lung IRI. X-In8 is a biotechnology company whose mission is to develop strategies to temporarily turn off innate immunity to prevent IRI. Demonstrating effectiveness of CRX-526 to reduce IRI in relevant translational cell culture models of IRI and LTX models will justify Phase II studies using survival LTX models to evaluate commercial applications in the LTX market, followed by studies in other types of organ transplant and other clinical scenarios of IRI such as CPB, MI, and stroke. , ,
Public Health Relevance: Ischemia-reperfusion injury (IRI), which occurs when blood flow stops and then starts again, causes damage to tissue or organs in heart attacks, strokes, heart bypass surgery, and organ transplantation. Toll-like receptors (TLRs) of the innate immune system, in particular TLR4, contribute to edema and inflammation in IRI. In Phase I, we will determine the benefit of inhibiting TLR4 activation with CRX-526, an agent that we showed prevents edema due to IRI;in Phase II we plan to determine efficacy of CRX-526 in lung transplantation. This work may expand the supply of healthy lungs for transplant and could stop IRI in heart attack, stroke or heart bypass.
Thesaurus Terms: Acute;Affect;Allografting;Animals;Apoplexy;Asystole;Biotechnology;Blood Circulation;Blood Flow;Bloodstream;Body Tissues;Brain Dead;Brain Death;Bronchiolitis Obliterans;Bronchiolitis, Exudative;Bronchiolitis, Proliferative;Cardiac Arrest;Cardiac Surgery;Cardiac Surgery Procedures;Cardiac Surgical Procedures;Cardiac Infarction;Cardiopulmonary Bypass;Cell Culture Techniques;Cells;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Cerebrovascular Accident;Cessation Of Life;Chronic;Circulation;Clinical;Clinical, Transplantation, Organ;Coma Depasse;Common Rat Strains;Death;Disease;Disorder;Dropsy;Dysfunction;Edema;Effectiveness;Endothelial Cells;Environmental Air Flow;Epithelial Cells;Event;Family Suidae;Functional Disorder;Gene Expression;Grafting Procedure;Grafting, Lung;Heart;Heart Arrest;Heart-Lung Bypass;Human;Human, General;Hydrops;Inflm;Immune;Immune System;Immunity, Innate;Immunity, Native;Immunity, Natural;Immunity, Non-Specific;Incidence;Inflammation;Inflammatory;Injury;International;Interruption;Ischemia;Ischemia-Reperfusion Injury;Life;Liquid Substance;Lung;Lung Parenchyma;Lung Tissue;Lung Transplantation;Lung Diseases;Mammals, Rats;Man (Taxonomy);Man, Modern;Marketing;Mediating;Mission;Modeling;Myocardial Infarct;Myocardial Infarction;Natural Immunity;O Element;O2 Element;Operation;Operative Procedures;Operative Surgical Procedures;Organ;Organ Donor;Organ Transplantation;Organ Transplants;Organ Transplants, Including Bone Marrow For Dct;Outcome;Oxygen;Pathway Interactions;Patients;Perfusion;Permeability;Phase;Physiopathology;Pigs;Pulmonary Diseases;Pulmonary Disorder;Pulmonary Edema;Rat;Rattus;Receptor Protein;Reperfusion Damage;Reperfusion Injury;Reperfusion Therapy;Respiratory Disease;Respiratory Disorder;Respiratory System Disease;Respiratory System Disorder;Respiratory System, Lung;Respiratory Physiology;Retrieval;Risk Factors;Role;Sttr;Series;Signal Pathway;Simulate;Small Business Technology Transfer Research;Solid;Staging;Stroke;Structure Of Parenchyma Of Lung;Sudden Death;Suidae;Surgical;Surgical Interventions;Surgical Procedure;Surgical Procedures, Heart;Survival Rate;Swine;Syndrome;Tlr Protein;Tlr4 Receptor;Testing;Time;Tissues;Toll-4 Receptor;Toll-Like Receptors;Transplantation;Transplantation Surgery;Vascular Accident, Brain;Ventilation;Warm Ischemia;Work;Body System, Allergic/Immunologic;Brain Attack;Cardiac Infarct;Cerebral Death;Cerebral Vascular Accident;Clinical Efficacy;Commercial Application;Coronary Attack;Coronary Infarct;Coronary Infarction;Cost;Cytokine;Disease/Disorder;Early Experience;Effective Therapy;Experience;Fluid;Graft Failure;Hazard;Heart Attack;Heart Bypass;Heart Infarct;Heart Infarction;Heart Surgery;Implantation;Improved;Inflammatory Marker;Inhibitor;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Liquid;Lung Disorder;Lung Edema;Lung Function;Lung Ischemia;Organ Allograft;Organ Graft;Organ System, Allergic/Immunologic;Organ Xenograft;Pathophysiology;Pathway;Phase 2 Study;Porcine;Pre-Clinical;Preclinical;Prevent;Preventing;Public Health Relevance;Pulmonary;Receptor;Reperfusion;Respiratory Function;Restoration;Social Role;Stroke;Success;Suid;Surgery;Toll-Like Receptor 4;Transplant
