A NOVEL ANTI-INFLAMMATORYAND ANTI-OXIDANT THERAPY FOR TREATING NON-HEALING DIABETIC FOOT ULCERS - SUMMARY DELAYED OR IMPAIRED WOUND HEALING IS A SERIOUS COMPLICATION OF DIABETES, OFTEN LEADING TO LOWER LIMB AMPUTATIONS. BY 2050, 1 IN 3 AMERICANS WILL DEVELOP DIABETES, AND UP TO 34% OF DIABETIC PATIENTS WILL DEVELOP A DIABETIC FOOT ULCER (DFU) IN THEIR LIFETIME. CURRENT TREATMENTS FOR DFUS INCLUDE DEBRIDEMENT, INFECTION CONTROL, MAINTAINING A MOIST WOUND ENVIRONMENT, AND PRESSURE OFFLOADING. DESPITE THESE INTERVENTIONS, A LARGE NUMBER OF DFUS FAIL TO HEAL AND ARE ASSOCIATED WITH A COST THAT EXCEEDS $31 BILLION ANNUALLY. CHRONIC INFLAMMATION AND INCREASED OXIDATIVE STRESS HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF THE DIABETIC WOUND HEALING IMPAIRMENT. WE HAVE DESIGNED AND TESTED A NEW THERAPEUTIC THAT SYNERGISTICALLY TARGETS BOTH INFLAMMATION AND OXIDATIVE STRESS USING NOVEL CERIUM OXIDE NANOPARTICLES (CNP), WHICH POSSESS REACTIVE OXYGEN SPECIES (ROS) SCAVENGING PROPERTIES, CONJUGATED WITH AN ANTI-INFLAMMATORY MICRORNA MIMIC (MIR146A) THAT IS DEFICIENT IN DIABETIC WOUNDS AND INHIBITS THE ACTIVATION OF NFΚB-INDUCED PRO-INFLAMMATORY RESPONSE. IMPORTANTLY, OUR NOVEL PATENTED CONJUGATE CNP-MIR146A EFFICIENTLY DELIVERS MIR146A INTO THE WOUND TO REDUCE INFLAMMATION AND ROS, AND ACCELERATE WOUND HEALING. WE HAVE DEVELOPED A CNP-MIR146A SPECIFICALLY FORMULATED FOR INTRADERMAL INJECTION (CTX-001) FOR THE TREATMENT OF DFUS. OUR PRELIMINARY STUDIES DEMONSTRATE THAT A ONE-TIME INTRADERMAL ADMINISTRATION OF CTX-001 TO FULL-THICKNESS WOUNDS FULLY CORRECTS THE WOUND HEALING IMPAIRMENT IN DIABETIC MICE AND ELICITS A SIGNIFICANT 25% IMPROVEMENT IN WOUNDS IN DIABETIC PIGS, ESSENTIALLY BY NORMALIZATION OF INFLAMMATION AND OXIDATIVE STRESS. REPEATED WEEKLY ADMINISTRATION CAN CORRECT THE DIABETIC WOUND HEALING IMPAIRMENT, SIMILAR TO HEALING IN NON- DIABETIC WOUNDS. FOLLOWING A PRE-IND MEETING WITH THE FDA AND HAVING COMPLETED A PILOT BULK DRUG SUBSTANCE CGMP MANUFACTURING OF CTX-001, THE OBJECTIVE OF THIS DIRECT TO PHASE II APPLICATION BY CERIA THERAPEUTICS (CERIA) IS TO COMPLETE CGMP-GRADE MANUFACTURING AND ANALYSIS OF CTX-001 DRUG PRODUCT (SPECIFIC AIM 1) TO FULFILL IND-ENABLING STUDIES. SPECIFIC AIM 2 WILL CONFIRM THE PRECLINICAL EFFICACY OF CTX-001 IN DIABETIC (DB/DB) MICE AND A PORCINE MODEL OF DIABETIC WOUND HEALING; WE WILL ASSESS THE ROLE OF INFECTION ON THE EFFICACY OF CTX-001 IN MICE, AND OPTIMIZE THE DOSE AND FREQUENCY OF ADMINISTRATION OF CTX-001 TO ENHANCE EFFICACY IN THE CORRECTION OF THE IMPAIRED HEALING IN DIABETIC PIGS. IN SPECIFIC AIM 3, WE WILL CARRY OUT A DOSE-RANGE FINDING ACUTE TOXICITY STUDY OF CTX-001 IN BOTH RATS AND MINIPIGS, FOLLOWED BY IND-ENABLING REPEAT DOSE TOXICOLOGY STUDIES. IN VITRO GENOTOXICITY STUDIES AND AN IRRITATION/SENSITIZATION STUDY IN GUINEA PIGS WILL COMPLETE SAFETY STUDIES IN PREPARATION FOR FIRST-IN-HUMAN CLINICAL TRIALS WITH OUR LEAD PRODUCT.