Inhibition of Galectin-3 for Therapy of Remodeling After Myocardial Infarction

PROJECT SUMMARY ABSTRACT The overall goal of this project is to develop a human protein that is an inhibitor of galectin as a biologic to aid in the prevention and treatment of harmful remodeling after myocardial infarction MI heart attack and thereby improve cardiac function and reduce mortality from subsequent heart failure MI is the most common cause of cardiac morbidity and mortality in the Western world The incidence in the United States is new attacks and recurrent attacks annually approximately one every seconds Fibrosis is triggered by the physiological response to injury or infection and leads to the deposition of extracellular matrix and for mation of new connective tissue Excessive or dysregulated fibrosis from insults can dramatically reduce the functioning of the heart and other organs In the heart excessive interstitial fibrosis reduces contractility elas ticity and distensibility exacerbating processes that lead to heart failure Although there are therapeutic agents currently used after MI that are efficacious such as the mineralocorticoid receptor antagonists MRAs angiotensin converting enzyme ACE inhibitors and angiotensin II receptor blockers ARBs and that have shown anti fibrotic effects in animal studies the health burden from MI remains significant Fibrosis is regulated by a number of inflammatory cytokines and growth factors and galectin has recently been implicated as a major and novel mediator of organ fibrosis Increased serum levels of galectin have been approved in the United States and the European Union as prognostic indicators of risk of death from progressive heart failure supporting the hypothesis that galectin is a target for drug development Based on its mechanism of action and structure the protein is a unique inhibitor of galectin with properties that convey therapeutic advantage Our preliminary studies in a rat ischemia reperfusion I R injury model of MI showed very promising efficacy The Specific Aims for this Fast Track Phase I II project are the following Phase I Aim is to determine efficacy of Gal C therapy in animal models Determine antifibrotic potential of Gal C in the context of greater injury caused by permanent ligation of the coronary artery and evaluate efficacy of Gal C therapy relative to ARB and antifibrotic control drugs in a rat I R MI model Phase II Aim is to better understand efficacy of Gal C therapy in animal models Determine efficacy and optimal dosage of Gal C in rat I R MI determine efficacy of Gal C in comparison to a MRA and in combination with an ARB in rat I R MI model and determine efficacy of Gal C in miniswine I R model of MI Aim is to develop GLP GMP production methods and a formulation for Gal C Aim is to perform pharmacokinetic studies and acute subacute toxicology in rodents Achievement of these aims is expected to position MandalMed to complete pre clinical development in the near term and to subsequently file an Investigational New Drug IND application PROJECT NARRATIVE The overall goal of this project is to develop a protein inhibitor of galectin termed galectin C as a biologic to prevent and treat harmful remodeling after myocardial infarction and thereby improve cardiac function and reduce mortality from subsequent heart failure Myocardial infarction is the most common cause of cardiac morbidity and mortality in the western world The annual incidence in the United States is new attacks and recurrent attacks Because current standard practice of minimizing time from onset of myocardial infarction to re opening of the blocked artery has greatly reduced the incidence of death from acute myocardial infarction heart failure subsequent to myocardial infarction has become the main mortality associated with coronary events