Proteolytic Imaging of Remodeling Myocardium

DESCRIPTIONprovided by applicantProteolytic Imaging of Remodeling Myocardium Abstract Heart attacksi emyocardial infarction or MIoccur in more thanmillion patients annuallyAdvances in interventional and pharmacological therapies have dramatically improved survival following the initial MIand patients are often surviving acute MI with more extensive myocardial injuryConsequentlythe number of patients with previous MI continues to increase and as a result put in jeopardy millions of patients for development of heart failure an adverse outcome associated with extensive myocardial injury post MIIn these patients with a previous MIdespite optimal standard of carea scar can form in the portion of the heart musclemyocardiumthat was injured from the MIFormation of a myocardial scar following MI is associated with a malignant remodeling process with respect to changes in the structure and shape of the MI regioninfarct expansionwhich is due to activation of enzymes that degrade key structures of the MI regiontermed matrix metalloproteinasesMMPsThis adverse remodeling after MI can lead to increased morbidity and mortality in these patientsThe development of new pharmacologicaltherapeutic approaches to target this process has been hampered by our ability to visualize and measure MMP activity in the heart of patients post MIThe technology to be advanced in this application directly addresses this unmet medical need by developing a unique MMP targeted imaging agent that can be used in the clinical context of post MI remodeling in patientsand thus move the entire field forward in terms of risk stratification and the evaluation of new therapiesThis fast track technology transfer application is intended to move forward the MMP imaging technology by finalizing the formulation and validation of this approach in a clinically relevant preclinical large animal model of MI and then perform first in man safety and preliminary proof of concept studiesThese studies will be undertaken in two phasesPhase Istandardize the synthesis and formulation of the radiolabeled MMP targeted imaging agent and perform initial toxicity studies in rodentsPhase IIperform in vivo serial MMP imaging and validate quantitative image analysis tools in an established preclinical large animal model of post MI remodelingPerform initial safetybiodistributionand dosimetry studies in normal volunteersand preliminary feasibility and proof of concept studies in patients post MI through an Exploratory IND pathwaydemonstrating that this technology would be highly relevant to identifying patients at increased risk for heart failur and as a companion diagnostic for the purposes of testing new drugs for reducing adverse postMI remodeling