Project Grant R43HL172300

DEVELOPMENT OF TARGETED CELLULAR THERAPY FOR ATHEROSCLEROTIC VASCULAR DISEASE IN MINORITY PATIENTS - ATHEROSCLEROTIC VASCULAR DISEASE IS A LEADING CAUSE OF DEATH AND DISABILITY IN THE UNITED STATES AND AROUND THE WORLD. DESPITE THE ADVANCES IN CARDIOVASCULAR DRUG DEVELOPMENT, AND PERCUTANEOUS AND SURGICAL INVASIVE PROCEDURES, CARDIAC AND CEREBRAL VASCULAR DISEASES REMAIN A MAJOR HEALTH CHALLENGE AND GROWING GLOBAL CONCERN. ADVANCED ATHEROSCLEROTIC PLAQUE OR ATHEROMA (ATH), IN THE INTIMAL LAYER OF ARTERIES, CAUSE MOST ACUTE MYOCARDIAL INFARCTIONS AND ISCHEMIC STROKES, LIFE-THREATENING EMERGENCIES WITH ENORMOUS HUMAN AND ECONOMIC BURDEN. MINORITY POPULATIONS WITH SOCIOECONOMIC DISADVANTAGES ARE HIGHLY VULNERABLE TO A DISPROPORTIONATE BURDEN OF ATHEROSCLEROTIC VASCULAR DISEASE. THE CARDIOVASCULAR HEALTH DISPARITIES ARE ASSOCIATED WITH REGIONAL VARIATIONS IN EXPOSURE TO RISK FACTORS FOR ATH, INCLUDING DIABETES, OBESITY, AND CIGARETTE SMOKING. ARTERIES WITH ATH INVOLVE HEIGHTENED LEVELS OF INFLAMMATION, THROMBOGENESIS, CELLULAR DEATH, AND EXTRACELLULAR MATRIX DEGENERATION, WHICH CONTRIBUTE TO THE VULNERABILITY TO DISRUPTION. IN THE CURRENT PHARMACEUTICAL ARMAMENTARIUM, FEW SINGLE THERAPEUTICS HAVE DEMONSTRATED ABILITY TO REPAIR OF VULNERABLE ATH. THE UNMET PATHOGENIC PROBLEM IS THE DYSFUNCTION OR LOSS OF VASCULAR CELLS, RESULTING IN AN INCREASED VULNERABILITY OF ATH ARTERIAL WALL TO DISRUPTION AND THROMBOSIS. VASCULAR STEM CELLS (VSC) GIVE RISE TO NEW VASCULAR CELLS THAT REPLACE OLD, DEAD, OR INJURED CELLS, AND MAY THEREBY REPAIR ATH-DAMAGED ARTERIAL WALL. ENDOGENOUS VSC ARE RARE, AND OFTEN BECOME DYSFUNCTIONAL WHEN EXPOSED TO PROATHEROGENIC RISK FACTORS. MOREOVER, ADMINISTRATION OF VSC IS LESS EFFECTIVE, DUE TO MECHANICAL STRESS AND THE ENDOTHELIAL BARRIER THAT BLOCKS STEM CELLS FROM ENTERING ATH LESIONS. LITTLE INFORMATION IS AVAILABLE CONCERNING THE VASCULAR STEM CELL QUANTITY AND QUALITY IN PERIPHERAL BLOOD OF MINORITY PATIENTS AS FEW PRECLINICAL OR CLINICAL STUDIES OF VSC HAVE BEEN PERFORMED IN MINORITY PATIENTS WITH ADVANCED VULNERABLE ATH. THIS RESEARCH TEAM HAS RECENTLY CONSTRUCTED AND TESTED SEVERAL PROTOTYPES OF ECHOGENIC IMMUNOLIPOSOMES (ELIP) DIRECTED AGAINST SURFACE MARKERS OF VSC AND INFLAMMATORY ATH FOR TARGETED VSC DELIVERY TO ATH. EVIDENCE FROM IN VITRO AND IN VIVO PILOT EXPERIMENTS SHOWS THE SUCCESS OF MANUFACTURING DUAL FUNCTIONAL, ECHOGENIC IMMUNOLIPOSOMES (DF- ELIP) THAT RECOGNIZE AND BRIDGE VSC TO ATH. DF-ELIP-HARBORING VSC CAN THEREFORE PROMOTE REPAIR OF THE ARTERIAL WALL INJURED BY ATH. THE PROJECT SCOPE AND PRODUCT OF THE CURRENT SBIR PHASE I PROPOSAL IS TO CONDUCT A PROOF-CONCEPT STUDY OF DF-ELIP TARGETED VSC (DFVSC) FOR TREATING DISEASED ARTERIES HARBORING ATH. SEVERAL PROTOTYPES OF DFVSC FROM MINORITY DONORS WILL BE PREPARED OR FORMULATED AS A CELLULAR THERAPEUTIC AGENT SELECTIVELY TARGETING THE INFLAMMATORY, VULNERABLE, AND RUPTURE-PRONE ATH. IN PRINCIPLE, DF-ELIP AND DFVSC WILL BE MANUFACTURED IN A GOOD LABORATORY PRACTICE FACILITY WITH THE STANDARD OPERATING PROCEDURE. THEIR BIOSAFETY, EFFICACY, AND FEASIBILITY OF MITIGATING RUPTURE-PRONE ATH.