Project Grant R42HL170898

PRECISION MRI WITH PROTEIN CONTRAST AGENT FOR NONINVASIVE DETECTION OF LUNG FIBROSIS - SUMMARY LUNG DISEASES, SUCH AS INTERSTITIAL LUNG DISEASES, INCLUDING IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND ACUTE VIRAL INFECTION, ARE MAJOR LEADING CAUSES OF DEATH WORLDWIDE. IPF IS CHARACTERIZED BY INCREASED EXTRACELLULAR MATRIX (ECM) DEPOSITION, ESPECIALLY TYPE I COLLAGEN, WITHIN THE LUNG, CAUSING IRREVERSIBLE LUNG DAMAGE. WHILE HIGH-RESOLUTION COMPUTED TOMOGRAPHY (HRCT) IS COMMONLY USED TO DIAGNOSE IPF, THIS METHOD CAN PRODUCE LARGE INTER-OBSERVER VARIATION AND ERROR (UP TO 50%) AND CANNOT DETECT EARLY-STAGE LUNG FIBROSIS DUE TO POOR SOFT TISSUE CONTRAST. A SURGICAL LUNG BIOPSY IS OFTEN REQUIRED TO CONFIRM THE DIAGNOSIS FOR PATIENTS WITH SUSPECTED IPF. HOWEVER, THIS IS VERY RISKY DUE TO COMORBIDITIES AND PHYSICAL IMPAIRMENTS. HRCT AND OTHER AVAILABLE DIAGNOSTIC METHODS PROVIDE LITTLE INFORMATION ABOUT HETEROGENEOUS FIBROSIS RELATED TO DISEASE ACTIVITY, PROGRESSION, AND REGRESSION. THERE IS A PRESSING UNMET MEDICAL NEED TO DEVELOP NONINVASIVE IMAGING METHODOLOGIES AND CONTRAST AGENTS TO DETECT EARLY STAGES OF LUNG FIBROSIS, AND TO STAGE FIBROSIS SEVERITY AND HETEROGENEOUS EXPRESSION OF COLLAGEN. THE MAIN OBJECTIVES OF THIS PHASE II APPLICATION WILL PROVIDE NECESSARY RESULTS FOR TRANSITION TO CLINICAL APPLICATION FOR NON-INVASIVE LONGITUDINAL EARLY DIAGNOSIS AND STAGING OF LUNG FIBROSIS WITH DISEASE ACTIVITY BY PMRI. AIM 1 IS TO ANALYZE TOXICOLOGY AND METAL TOXICITY OF PROCA32.COLLAGEN IN HEALTHY AND LUNG FIBROSIS MICE. WE WILL COMPLETE SINGLE AND REPEATING DOSE STUDIES TO VERIFY THAT INL-101 IS NOT TOXIC USING ESTABLISHED IPF ANIMAL MODELS INCLUDING REVERSIBLE AND IRREVERSIBLE FIBROSIS MODELS. WE WILL ALSO DETERMINE MINIMAL EFFECTIVE DOSE OF INL-101 FOR DETERMINING LUNG FIBROSIS. AIM 2 IS TO EXECUTE THE DESIGNED TOX/PK SAFE PROFILE STUDIES FOR IND APPLICATION AND PREPARE HUMAN IMAGING. WE WILL OPTIMIZE INJECTION ROUTES FOR IN VIVO IMAGING FOR IND APPLICATION. THIS TRANSFORMATIVE PLATFORM AND PROPRIETARY METHODOLOGY WILL HAVE STRONG IMPACT IN IPF PATIENT STRATIFICATION FOR EFFECTIVE TREATMENT AND REDUCTION OF MORTALITY BY DISTINGUISHING IPF PATIENTS WHO ARE EXPERIENCING RAPID PROGRESSION FROM THOSE WHO ARE STABLE BASED ON FEATURES OF REVERSIBLE AND IRREVERSIBLE FIBROSIS.