Metanoia

CED BUSINESS EXPANSION PROJECT

BUSINESS EXPANSION FOR JOB CREATION

TARGETING PFKFB3 KINASE FOR ACTIVATION OF CELL COMPETITION AND ELIMINATION OF DYSFUNCTIONAL BETA-CELLS IN TYPE-2 DIABETES - ABSTRACT TYPE-2 DIABETES (T2D) IS THE SECOND MOST PREVALENT AGE-RELATED DISEASE, AFFECTING A STAGGERING 463 MILLION PEOPLE WORLDWIDE. ITS ONSET AND PROGRESSION ARE ATTRIBUTED TO A PROGRESSIVE DECLINE IN Β-CELL FUNCTION, WHERE THE STRESSED Β-CELLS RESEMBLE DAMAGED (“LOSER”) CELLS THAT FAILED TO UNDERGO CLEARANCE BY CELL FITNESS COMPETITION (CFC). IN ESSENCE, CFC IS A HOMEOSTATIC PROCESS THAT EMBODIES THE CONSTANT MONITORING FOR, AND REPLACING OF, AGED, INJURED, OR DYSFUNCTIONAL CELLS IN ADULT TISSUE WITH HEALTHY FULLY FUNCTIONAL (“WINNER”) CELLS. THESE Β-CELLS DEMONSTRATE A WIDE RANGE OF ABNORMALITIES, WITH THE RESULTANT METABOLIC STRESS CORRELATING WITH AN EARLY LOSS OF Β-CELL GLUCOSE RESPONSIVENESS PRIOR TO T2D ONSET. TO DATE, DIFFERENT PHARMACOLOGICAL APPROACHES HAVE FOCUSED ON INCREASING THE INSULIN SECRETION OF THESE DYSFUNCTIONAL -CELLS. WE INSTEAD PROPOSE A MODEL WHEREBY Β-CELL FUNCTION IS RESTORED THROUGH THE RE-ESTABLISHMENT OF CFC. RECENT BREAKTHROUGH STUDIES FROM THE METANOIA-UCLA COLLABORATION DEMONSTRATED THAT HYPOXIA INDUCIBLE FACTOR- 1-ALPHA (HIF1) AND ITS TARGET 6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 3 (PFKFB3) FORM A SIGNALING AXIS, WHICH, WHEN ACTIVATED IN THE CONTEXT OF DIABETES, REMODELS CELLULAR METABOLISM TO FAVOR THE SURVIVAL AND BLOCK THE REMOVAL OF DYSFUNCTIONAL Β-CELLS AT THE EXPENSE OF Β-CELL FUNCTION—MIMICKING THE Β-CELL PHENOTYPE IN PREDIABETES. USING A NOVEL “CFC” MOUSE MODEL OF DIABETES, THEY WERE ABLE TO DEMONSTRATE THAT DEPLETION OF PFKFB3 RESULTED IN REGENERATION OF FUNCTIONAL Β-CELLS. HERE, METANOIA WILL DEVELOP NEW COMPOSITION ENTITIES (NCE) FOR PFKFB3 INHIBITION (AIM 2) AND ESTABLISH IN VIVO PROOF-OF-CONCEPT THAT PHARMACOLOGIC TARGETING OF PFKFB3 IS ABLE TO RESTORE CFC (AIM 1), THUS TRIGGERING FUNCTIONAL -CELL REGENERATION. THIS WILL INCLUDE: (AIM 1.1) DEMONSTRATING THAT PFKFB3 TARGETING (DEPLETION) RESTORES Β-CELL FUNCTION, GLUCOSE TOLERANCE, AND INSULIN SENSITIVITY, (AIM 1.2) DETERMINING THE COMPARATIVE EFFICACY OF PFKFB3 INHIBITORS TO STABLY CONTROL GLYCEMIA ALONE AND TOGETHER WITH METFORMIN VS. METFORMIN ALONE, (AIM 1.3) ESTABLISHING THE DURABILITY OF PFKFB3 INHIBITOR TREATMENT; AND BY (AIM 2.1) DESIGNING NEW COMPOSITION ENTITIES (NCE) FOR PFKFB3 INHIBITION, AND (AIM 2.2) PERFORMING SIMULATION OF MOLECULAR DYNAMICS ON SELECT NCE CANDIDATES. IN ADDITION TO THE POTENTIAL TO SIGNIFICANTLY ADVANCE THE CURRENT UNDERSTANDING OF THE UNDERLYING MECHANISM OF ACTION OF T2D, IF SUCCESSFUL, THIS STUDY WILL LEAD TO NOVEL, PATENTABLE, FIRST-IN-CLASS PFKFB3 INHIBITOR THERAPEUTIC CANDIDATES THAT TARGET THE UNDERLYING MECHANISM OF T2D. THIS TREATMENT HAS POTENTIAL TO NOT ONLY ALTER DISEASE TRAJECTORY IN THE SHORT TERM, BUT ALSO TO BE CURATIVE IN THE LONG TERM VIA ISLET ENRICHMENT WITH FUNCTIONAL Β-CELLS.

METANOIA COMMUNITY DEVELOPMENT CORPORATION PROPOSES TO UTILIZE THIS GRANT TO LAUNCH AN EARLY CHILDHOOD EDUCATION CENTER FOR STUDENTS FROM 6 WEEKS OLD TO 5 YEARS OLD.

PURPOSE: TO SUPPORT A CULTURAL PLACEKEEPING AND PLANNING PROJECT IN NORTH CHARLESTON, SOUTH CAROLINA.