ABSTRACT Over 3 million people in the United States currently suffer from heart failure caused by a myocardial infarction (MI) and more than 600,000 survivable MIs occur each year. These troubling statistics amount to an economic burden of over $30 billion annually. Current clinical treatments for MI include coronary stents and bypass surgeries to overcome the blocked artery and pharmacologic prescription to lessen the workload of the injured heart. Unfortunately these treatments do little to alter the tissue remodeling process initiated after coronary artery occlusion, and progression to heart failure is common. Matrix metalloproteinases (MMPs) are a class of tissue degrading enzymes that contribute to adverse tissue remodeling post MI. While systemic administration of MMP inhibitors has shown beneficial effects in preclinical animal models, this approach was limited in patients due to off target effects of the inhibitors. To overcome these limitations we have recently reported the local delivery of an inhibitor to MMPs (TIMP-3) to the infarct using injectable hydrogels. The injectable hydrogels were designed to dose TIMP-3 release in proportion to MMP activity within the myocardium in order to address concerns of MMP expression heterogeneities in patients post MI. This novel delivery technology significantly attenuated adverse LV remodeling in a preclinical, large animal model of MI, which was published in the journal Nature Materials. In addition, the technology has been protected by an issued patent and several additional patent applications have been filed. Further, Prohibix, LLC was founded by the inventors to commercialize the technology. The objective of the proposed work is to further develop the bioresponsive hydrogel technology into a translatable catheter delivered product, with the overall goal of attenuating the progression towards heart failure in MI patients. First, we will develop a formulation that can be safely passed through a clinically available and validated catheter. Second, we will demonstrate that the formulation can be reliably injected into the myocardium via a percutaneous catheterization. Completion of this proposal will lay the groundwork for safety and efficacy studies of the catheter deliver hydrogels as a follow-up Phase II investigation. Further, this work will strengthen interest from industry partners as it opens the therapy to treating a large and growing patient population who suffer an MI.

R41HL140645

2018-08-15

2020-07-14