Novel Regenerative Therapy for Myocardial Infarction
Principal Investigator: Andrew R Mendelsohn
Abstract: DESCRIPTION (provided by applicant): A Novel Regenerative Therapy for Myocardial Infarction Myocardial infarction (MI) is an acute public health problem killing one third of the 1.5 million Americans afflicted annually. Almost all MIs are caused by rupture of coronary atherosclerotic plaques with superimposed coronary thrombosis resulting in ischemia. Patients with MI usually present with signs and symptoms of crushing chest pressure, diaphoresis, malignant ventricular arrhythmias, heart failure (HF), or shock. MI may also manifest as sudden cardiac death. Although rapid treatment and cardiac catheterization has led to improved outcomes, most patients suffer some ischemic damage to the heart that results in cardiomyocyte death. Severe damage leads to impaired cardiac function, arrhythmias, and often progression to heart failure. There is a great need to repair severe cardiac damage. Regenerative stem cell-based therapies are a promising approach in development. However, adult stem cell therapy with bone-marrow-derived stem cells to date has only resulted in about 3% average gain in LV function over 13 clinical trials (Martin-Rendon et al. 2008). Stem cell therapy suffers from numerous problems, the most important of which is that few adult stem cells from hematopoetic or mesenchymal sources differentiate into viable cardiomyocyes to replace damaged cells. Most of the therapeutic effect is due to improved circulation from neovascularization. Even if exogenous cardiomyocytes could be obtained in great numbers and programmed to survive, it is unclear that they would correctly integrate into heart tissue. Recently, it has been observed in paradigm-breaking work that mammalian hearts contain endogenous adult mononucleated cardiomyocytes that can be stimulated to re-enter the cell cycle, divide and redifferentiate when exposed to neuregulin-1 beta-1 (NRG1b1), an EGF family growth factor that activates ErbB4 (Bersell et al. 2009). Mice treated with NRG1b1 had permanently improved myocardial function, smaller infarct scar size, and attenuated myocardial hypertrophy. Prior work has shown that NRG1b1 effectively treated ischemic, dilated, and viral cardiomyopathies in mouse, rat and dog model systems. NRG1b1 also [maintains cardiomyocyte function and] protects cardiomyocytes from cell death by rapid activation of PI3K, eNOS and protein kinase G and increased diastolic calcium levels (Brero et al. 2010). [These additional functions contribute to NRG1's ability to repair damaged cardiac tissue.] Previously, we developed a long-acting NRG1b1-Fc fusion protein as a potential therapeutic. However, because neuregulins may cause undesirable side-effects, we propose to construct bifunctional fusion proteins that target NRG1b1 to damaged heart cells through an antibody domain. To achieve this goal we utilize a novel proprietary protein heterodimerization strategy "polyprotein heterodimerization" (PPH). The targeted Ab will reduce or eliminate potential unwanted effects to make NRG1b1-based therapeutics practical. We expect that this new regenerative therapy will help restore heart function post-MI. PUBLIC HEALTH RELEVANCE: We are developing a new regenerative therapy for the treatment of myocardial infarction (heart attacks). A new drug will stimulate the heart to repair itself.
Funding Period: 2011-08-01 - 2013-07-31
more information: NIH RePORT