Science and Technology
A new class of therapies to treat cardiovascular diseases
Ischemic heart disease (IHD) is the single largest cause of death worldwide. In the United States of America alone, there are over 525,000 known heart attacks and 225,000 events are not reported1. Limitation of blood flow to the heart causes ischemia and irreversible death of the myocardial cells resulting in irreversible heart damage, progressive myocardial remodeling, reduced heart function and heart failure. The size of a myocardial infarct is directly correlated with a decrease of heart function, the risk of developing heart failure and mortality. Infarct size may be significantly decreased with prompt reperfusion after the first symptoms, either by thrombolytic treatment or by percutaneous intervention. Indeed, restoration of arterial perfusion with thrombolytic and antiplatelet therapy during percutaneous coronary intervention (PCI) is the most commonly performed invasive therapeutic cardiac procedure in the management of IHD. The decline in myocardial infarction (MI) acute mortality, achieved with primary PCI, has augmented the prevalence of HF among survivors, because of the development of substantial scarring despite reperfusion strategies. A major problem is that human adult cardiac myocytes fail to elicit an endogenous regenerative response after a MI, and there are no adjunctive pharmacological treatments that can be administered in conjunction with reperfusion injury to regenerate heart muscle at the time of or following an MI.
Establishment of a therapy that promotes endogenous cardiac myocyte regeneration in the ischemic heart to reduce infarct size offers a potential treatment of IHD, reducing morbidity and mortality. Inhibition of a specific combination of four mircroRNAs are critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish and the sequences and target proteins are evolutionarily conserved in humans. In vivo manipulation of this molecular machinery using adeno associated viral delivery of inhibitors of the four microRNAs in mice with permanent left anterior descending (LAD) coronary artery ligation results in a reduction of infarct size, scarring and increases heart function up to 90 days following the infarction2. Jaan Biotherapeutics L.L.C. (JBT) has developed adeno associated viral constructs that expresses the four microRNA inhibitor sequences. Uniquely, injections of this virus directly into the myocardium reduce infarct size in our experimental murine model of IHD and constitute an ideal and innovative approach for regeneration of human cardiac myocytes adjunct with reperfusion therapy.
- Mozaffarian D, Benjamin EJ, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2015 update: a report from the American Heart Association Circulation. 2015;131(4):e29-322.
- Aguirre A, Montserrat N, et al. In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell. 2014;15(5):589-604.