Research Project
8597803
DESCRIPTION (provided by applicant): The wound-healing response of the human body to injuries involves induction of fibrosis, which is a dynamic scarring process. When fibrosis occurs in internal organs, it is indisputably a major cause of morbidity and mortality worldwide. The overall goal of the proposed research is to develop an inhibitor of galectin-3 as a drug that will limit excess fibrosis and adverse remodeling of the heart after myocardial infarction (heart attack) and, thereby, improve patient outcomes and reduce mortality. In the Phase I project, we will test the feasibility of using a dominant-negative galectin-3 inhibitor, termed galectin-3C (Ga-3C), to limit adverse remodeling and improve cardiac function after myocardial infarction (MI). MI is the most common cause of cardiac morbidity and mortality in the western world, and is responsible for 1 in 6 deaths (~400,000) in the US per year. Galectin- 3 is one of the galectin family of lectins that has homologous carbohydrate recognition domains and characteristic affinity for ¿-galactosides. There are compelling in vitro and animal data showing that galectin-3 is critical for organ fibrosis and specifically fibrosis in the heart. In humans, plasma levels of galectin-3 are approved by the US FDA and in Europe as a biomarker for risk of mortality in those with chronic heart failure (www.galectin-3.com) that is independent of severity of heart failure or renal dysfunction. The Phase I Specific Aims are as follows: 1. To determine the effect of Gal-3C on the TGF- ¿1-induced differentiation of primary cardiac fibroblasts to myofibroblasts and on their resulting collagen secretion. 2. To determine an effective dose of Gal-3C to reduce fibrosis in a rat ischemia/reperfusion model of MI. Subaim 2A. We will perform an initial dose-range finding study using osmotic pumps to deliver Gal-3C to rats after surgical induction of MI. Levels of collagen in the heart wil be analyzed as the main endpoint. Subaim 2B. We will test two different doses of Gal-3C administered over days 1-7 post-MI to determine its effect on 1 month post-MI cardiac function. 3. To determine if immediate or delayed treatment with Gal-3C leads to better cardiac function. Subaim 3A. We will assay serum collected at different times from the rats in Subaim 2B to establish the time-course of galectin-3 appearance, to determine the time window for Gal-3C delivery. Subaim 3B. We will repeat the Gal-3C delivery experiment from Aim 2 with delayed treatment timing based on what we learn in Subaim 3A. In Phase II, we plan to test a sustained-release form or a Gal-3C construct with a longer circulating half-life, conduct studies to refine post-MI treatment in animal models, and focus on toxicology, pharmacokinetics, and GMP production towards filing an IND application with the FDA and initiation of Phase I human clinical trials.
