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Principal Investigator: Christopher Dockendorff
Organization: FUNCTION THERAPEUTICS, INC.
Fiscal Year: 2024
Award: $325,000
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Acute kidney injury (AKI) is the sudden and dangerous loss of kidney function that causes significant morbidity and mortality. A significant fraction of patients undergoing major surgery suffer from AKIs, particularly cardiac patients, with >10% probability of AKI frequently reported. Almost half of hospitalized COVID patients suffered from dangerous (and often deadly) AKIs early in the pandemic, and certain anti-cancer therapies and anti-infectives are known to cause AKIs. AKIs extend hospitalization, and even when kidney function returns to more normal levels, patients suffering from AKIs are at much greater risk of developing chronic kidney disease. Presently, there are no drugs approved by the FDA for the prevention of AKI.
Function Therapeutics and its collaborating labs have discovered a new class of antithrombotic and anti-inflammatory small molecules that are biased, allosteric modulators of signaling by the thrombin receptor, protease-activated receptor 1 (PAR1). These compounds, called parmodulins, act to inhibit thromboinflammation by biasing PAR1 signaling towards an anti-inflammatory pathway. They have achieved promising results with in vitro and in vivo models of disease, including infection-promoted thrombosis, coronary ischemia-reperfusion injury, sickle cell disease, and diabetic kidney disease. We hypothesize that their effects may be ideal for the prevention and treatment of AKI in at risk patients.
The objectives of this project are to 1) Optimize current lead series of parmodulins with the potential to meet a Target Product Profile suitable for hospitalized patients at risk for AKI; 2) Validate that parmodulins are efficacious in a mouse model of ischemic AKI.
Parmodulins will be designed, synthesized, and tested in primary and secondary in vitro assays in an iterative fashion. Drug-like profiling, including cytotoxicity, solubility, and stability assays, will be used to identify promising parmodulins for further safety and pharmacokinetic studies. Several optimal examples will ultimately undergo efficacy studies in a mouse model of ischemic AKI, using a protocol for bilateral ischemia-reperfusion injury in the lab of Dr. James George in the O’Brien Center for Acute Kidney Injury at the University of Alabama at Birmingham. This project will help to advance a unique approach to the treatment of AKI towards clinical stages.
Terms: <Academia><Acute Renal Failure with Renal Papillary Necrosis><Alabama><Anti-Infective Agents><Anti-Infective Drugs><Anti-Infectives><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-infective Preparation><Anti-inflammatory><Anticoagulant Agents><Anticoagulant Drugs><Anticoagulants><Apoptosis><Apoptosis Pathway><Assay><Bilateral><Bioassay><Biological Assay><Blood Plasma><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID19 patient><COVID19 positive patient><Cancer Treatment><Cardiac><Cell Communication and Signaling><Cell Protection><Cell Signaling><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clotting><Coagulation><Coagulation Factor II Receptor><Coagulation Process><Collaborations><Cytoprotection><Cytotoxin><Dangerousness><Data><Development><Diabetic Kidney Disease><Diabetic Nephropathy><Doctor of Medicine><Doctor of Philosophy><Dose><Drug Kinetics><Drugs><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Esteroproteases><Event><FDA approved><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Hb SS disease><HbSS disease><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hospital Admission><Hospitalization><Hospitals><In Vitro><Infection><Inflammatory><Injury><Injury to Kidney><Intracellular Communication and Signaling><Investigation><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Kidney Diseases><Lead><Leadership><Liver Microsomes><Lytotoxicity><M.D.><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Measures><Medication><Medicinal Chemistry><Mice><Mice Mammals><Modeling><Morbidity><Morbidity - disease rate><Murine><Mus><Myocardial Ischemia><Nephropathy><Operative Procedures><Operative Surgical Procedures><PAR-1 Receptor><PAR1 Receptor><Pathologic><Pathway interactions><Patients><Pb element><Peptidases><Peptide Hydrolases><Ph.D.><PhD><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Plasma><Plasma Serum><Prevention><Privatization><Probability><Process><Programmed Cell Death><Property><Protease Gene><Protease-Activated Receptor 1><Proteases><Proteinase-Activated Receptor 1><Proteinases><Proteolytic Enzymes><Protocol><Protocols documentation><Renal Cell><Renal Disease><Renal function><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Risk><Route><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><Safety><Series><Sickle Cell Anemia><Signal Transduction><Signal Transduction Systems><Signaling><Solubility><Staurosporine><Surgical><Surgical Interventions><Surgical Procedure><Systemic infection><Testing><Therapeutic><Thrombase><Thrombin><Thrombin Receptor><Thrombosis><Trauma><Universities><Validation><activated Protein C><acute kidney injury><analog><anti-cancer><anti-cancer therapy><biological signal transduction><blood thinner><cancer therapy><cancer-directed therapy><cardiac ischemia><chemotherapy><chronic kidney disease><communicable disease control agent><coronary ischemia><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><cytoprotective><cytotoxicity><design><designing><developmental><disease model><disorder model><drug discovery><drug/agent><efficacy study><experience><fibrinogenase><heart ischemia><heavy metal Pb><heavy metal lead><improved><in vitro Assay><in vivo><in vivo Model><inhibitor><injuries><kidney cell><kidney disorder><kidney function><kidney injury><kidney ischemia><lead series><meeting><meetings><member><mortality><mouse model><murine model><myocardial ischemia/hypoxia><myocardium ischemia><nano-molar><nanomolar><novel><pandemic><pandemic disease><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pharmacologic><pre-clinical development><preclinical development><prevent><preventing><programs><protective effect><renal disorder><renal injury><renal ischemia><reperfusion><response><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><sickle cell disease><sickle cell disorder><sickle disease><sicklemia><small molecule><stroke therapy><stroke treatment><surgery><thromboinflammation><thromboinflammatory><thrombopoiesis inhibitor><thrombotic><thrombotic disease><thrombotic disorder><treating stroke><validations>