Project Grant F31AR088385

TARGETING APE1/REF-1 WITH APX3330 IN MUSCULAR DYSTROPHY - PROJECT SUMMARY/ABSTRACT DUCHENNE MUSCULAR DYSTROPHY (DMD) IS A FATAL X-LINKED DISEASE CAUSED BY MUTATIONS IN THE DYSTROPHIN GENE AND HAS NO CURE. LOSS OF DYSTROPHIN INCREASES SUSCEPTIBILITY TO CONTRACTION-INDUCED MUSCLE INJURY, INITIATING AN INFLAMMATORY RESPONSE THAT DRIVES DISEASE PATHOLOGY. RECENT ADVANCES HAVE UNCOVERED A COMPLEX ROLE OF THE IMMUNE SYSTEM IN MUSCULAR DYSTROPHY, REVEALING THAT IMMUNE CELLS CAN BOTH EXACERBATE MUSCLE INJURY THROUGH CYTOTOXIC AND PRO-INFLAMMATORY SIGNALING AND, ALTERNATELY, SECRETE FACTORS THAT SUPPORT MYOGENESIS AND TISSUE REPAIR. HOWEVER, THIS KNOWLEDGE HAS NOT TRANSLATED CLINICALLY. BROAD IMMUNOSUPPRESSION WITH CORTICOSTEROIDS REMAINS THE STANDARD OF CARE, INDISCRIMINATELY SUPPRESSING BOTH BENEFICIAL AND DETRIMENTAL IMMUNE RESPONSES, AND CAUSING SIGNIFICANT ADVERSE EFFECTS, INCLUDING OSTEOPOROSIS AND ADRENAL SUPPRESSION. THERAPIES THAT SELECTIVELY INHIBIT HARMFUL INFLAMMATION WHILE PRESERVING IMMUNE FUNCTIONS ESSENTIAL FOR REPAIR ARE NEEDED. APURINIC/APYRIMIDINIC ENDONUCLEASE 1/REDOX EFFECTOR FACTOR 1 (APE1/REF-1) IS A DUAL-FUNCTION PROTEIN THAT COORDINATES DNA REPAIR AND REDOX-DEPENDENT SIGNALING, AND ITS REDOX ACTIVITY DRIVES PATHOLOGICAL INFLAMMATORY AND OXIDATIVE PATHWAYS. APX3330 SELECTIVELY BLOCKS APE1/REF-1'S REDOX FUNCTION, PROVIDING A TARGETED MEANS TO ATTENUATE THESE PROCESSES. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT INHIBITING APE1/REF-1 REDOX SIGNALING WITH APX3330 REDUCES INFLAMMATION, OXIDATIVE STRESS, AND MUSCLE INJURY IN MUSCULAR DYSTROPHY. AIM 1 WILL DETERMINE WHETHER INHIBITION OF APE1/REF-1 WITH APX3330 REDUCES MUSCLE PATHOLOGY AND IMPROVES MUSCLE FUNCTION IN THE MDX MOUSE MODEL OF DMD. THIS WILL BE TESTED BY ADMINISTERING APX3330 BEFORE OR AFTER THE ACUTE ONSET OF PATHOLOGY TO CAPTURE DISEASE-STAGE SPECIFIC RESPONSES, WITH THE STANDARD OF CARE PREDNISOLONE SERVING AS A CLINICAL BENCHMARK. AIM 2 WILL DETERMINE WHETHER APX3330 ACTS ON MACROPHAGES TO REDUCE MUSCLE INJURY AND PROMOTE MUSCLE REPAIR. IN SITU AND EX VIVO ASSAYS WILL BE USED TO DETERMINE WHETHER APX3330 ALTERS MACROPHAGE CYTOLYTIC AND PRO-MYOGENIC FUNCTIONS, ELUCIDATING A MECHANISM BY WHICH APX3330 MITIGATES PATHOLOGY. TOGETHER, THESE STUDIES ARE EXPECTED TO ESTABLISH APX3330 AS A SAFE, TARGETED THERAPEUTIC STRATEGY TO REDUCE DYSTROPHIC MUSCLE PATHOLOGY. THE PROPOSED FELLOWSHIP WILL DELIVER TARGETED TRAINING CRUCIAL FOR DEVELOPMENT INTO AN INDEPENDENT SCIENTIST FOCUSED ON THE MECHANISMS OF MUSCLE DISEASE AND THE ADVANCEMENT OF NEW THERAPEUTIC APPROACHES. UNDER GUIDED MENTORSHIP, RESEARCH TRAINING WILL FOCUS ON KEY TECHNIQUES FOR STUDYING MUSCLE IMMUNOBIOLOGY, REDOX SIGNALING, AND EVALUATING THERAPEUTICS IN PRECLINICAL MODELS. THIS WORK WILL BE CARRIED OUT WITHIN THE INDIANA CENTER FOR MUSCULOSKELETAL HEALTH (ICMH), A COLLABORATIVE SETTING THAT OFFERS EXPERTISE AND TRAINING IN MUSCLE BIOLOGY AND TRANSLATIONAL MUSCULOSKELETAL RESEARCH. COMBINED WITH STRUCTURED PROFESSIONAL DEVELOPMENT IN SCIENTIFIC COMMUNICATION AND LEADERSHIP, SUPPORT FROM THE ICMH WILL FOSTER THE APPLICANT'S PROGRESSION TOWARD BECOMING AN INDEPENDENT SCIENTIST LEADING A RESEARCH PROGRAM INVESTIGATING THE MECHANISMS UNDERLYING MUSCLE DISEASE.