The goal of the project is to test the efficacy of a protein kinase C epsilon peptide inhibitor (YT-001) in kidney ischemia reperfusion (I/R) in vivo (in mice) when given at the beginning of reperfusion. Injury and tissue damage associated with I/R in the kidney is a well-recognized phenomenon notably post kidney transplant. There are 20,000 kidney transplants per year in the US and twenty five percent of transplant recipients experience delayed graft function (DGF) within one week, a direct consequence of I/R. Currently, the only treatment for DGF is palliative support by managing fluid and electrolyte levels via dialysis; however, these measures provide only palliative care. Dr. Young has shown several cardiac I/R models both in-vivo and ex- vivo that giving YT-001 at the beginning of reperfusion restores organ function and reduces cell death. The FDA has recognized that the exact same mechanisms are at play in DGF. Phase 1 project is planned to study the effect of YT-001 in a murine bilateral kidney I/R model to different lengths of ischemia, and reperfusion will be carried out up to four days. During this time, serum plasma creatinine will be monitored as an index for kidney function. This proposed methodology best mimics the settings of I/R injury seen in DGF patients. Monitoring the role of YT-001 is crucial in the drug development process for treatment of DGF in post renal transplant patients. After phase 1, we can begin testing the effects of YT-001 in Phase 2 (murine kidney transplant model), which will support an IND and subsequent clinical trials.
Public Health Relevance Statement: PROJECR NARRATIVE The goal of the project is to develop a therapeutic capable of preventing delayed graft function (DGF) in the setting of post renal transplantation. DGF is a post renal transplant condition that currently has no cure and affects a quarter of kidney transplant recipients. Using a well-recognized model of ischemia/reperfusion (I/R), YT-001, a PKC-epsilon inhibitor, given at the beginning of reperfusion, resulted in a robust reduction in infarct size and restoration of post-reperfused cardiac function in porcine cardiac I/R in vivo. The goal will be to Incorporate a similar methodology in aa animal model of post renal ischemia allowing us to ultimately develop a therapeutic that can be used to prevent DGF.
Project Terms: Acute; Affect; Allografting; Animal Model; Animals; Applications Grants; Attenuated; Bilateral; Bolus Infusion; Cadaver; cardioprotection; Cell Death; Cell membrane; Cells; Clinical Trials; Closure by clamp; Comorbidity; Coupled; Creatinine; delayed graft function; design; Development; Dialysis procedure; Dose; drug development; Effectiveness; efficacy testing; Electrolytes; experience; Failure; Family suidae; Functional disorder; Genetic Transcription; Glomerular Filtration Rate; Goals; Graft Survival; heart function; Hospital Costs; Hospitalization; Hour; Human; immunogenicity; improved; in vivo; indexing; Industry; Infarction; inhibitor/antagonist; Injections; Injury; Intravenous Bolus; Ischemia; Ischemic Preconditioning; Kidney; kidney allograft; Kidney Transplantation; LCN2 gene; Legal patent; Length; Leukocytes; Liquid substance; male; Measures; Mediating; Methodology; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Morphology; mouse model; Mus; Myocardial Ischemia; Myristic Acids; Nitric Oxide; NOS3 gene; novel; off-patent; Organ; Organ Transplantation; Orphan Drugs; Outcome; palliative; Palliative Care; Patients; peptide structure; Peptides; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Play; prevent; preventable death; Prevention; Preventive treatment; PRKCA gene; Process; protein aminoacid sequence; Protein Inhibition; protein kinase C epsilon; Proteins; Regulation; renal artery; Renal dialysis; Renal function; renal ischemia; Reperfusion Injury; Reperfusion Therapy; Reporting; Respiration; restoration; Risk; Role; Safety; Serum; Source; Stroke; subcutaneous; Superoxides; Testing; Therapeutic; therapeutic target; Time; Tissues; Trans-Activators; transplant model; Transplant Recipients; Transplantation; Up-Regulation; Xanthine Oxidase
