Science and TechnologyA 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 1,000,000 heart attacks every year1. 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 infarction2-3.
JaanBiotherapeutics L.L.C. (JBT) has developed adeno associated viral constructs (JBT-miR2) that express the inhibitors to the four microRNA 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. In addition to viral delivery of the microRNA inhibitor sequences, we have also developed and tested both the safety and efficacy of synthetic oligonucleotide inhibitors (JN-101) in mice with a heart attack4. Our next stage of development is to test both viral and non-viral therapeutics in large animals models of IHD.
In addition we have developed another viral delivered microRNA activator, JN-210, that is being developed for the treatment of hypertrophic cardiomyopathy, the single largest cause of sudden cardiac death in young adults5.
- Salim S. Virani, Alvaro Alonso, Emelia J. Benjamin, Marcio S. Bittencourt, Clifton W. Callaway, April P. Carson, Alanna M. Chamberlain, Alexander R. Chang, Susan Cheng, Francesca N. Delling, Luc Djousse, Mitchell S.V. Elkind, Jane F. Ferguson, Myriam Fornage, Sadiya S. Khan, Brett M. Kissela, Kristen L. Knutson, Tak W. Kwan, Daniel T. Lackland, Tené T. Lewis et al. Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation. 2020;141:e139–e596
- In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Aguirre A, Montserrat N, Zacchigna S, Nivet E, Hishida T, Krause MN, Kurian L, Ocampo A, Vazquez-Ferrer E, Rodriguez-Esteban C, Kumar S, Moresco JJ, Yates JR 3rd, Campistol JM, Sancho-Martinez I, Giacca M, Izpisua Belmonte JC. Cell Stem Cell. 2014 Nov 6;15(5):589-604. doi: 10.1016/j.stem.2014.10.003. Epub 2014 Nov 6. PMID: 25517466
- Heart regeneration: a tale of cell reprogramming. Aguirre A, Sancho-Martinez I, Izpisua Belmonte JC. Circ Res. 2013 Oct 25;113(10):1109-11. doi: 10.1161/CIRCRESAHA.113.302519. PMID: 24158574
- Healing the heart by manipulating microRNAs. https://www.nature.com/articles/d43747-020-00562-x
- MicroRNA-133 controls cardiac hypertrophy.Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Høydal M, Autore C, Russo MA, Dorn GW 2nd, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G. Nat Med. 2007 May;13(5):613-8. doi: 10.1038/nm1582. Epub 2007 Apr 29. PMID: 17468766