Prevent the development of heart failure in patients with large myocardial infarcts
Prolifagen’s objective is to prevent development of heart failure in patients with large myocardial infarcts, by inducing regeneration of the heart muscle during the first month after infarct.
Lower vertebrates like zebrafish are able to regenerate injured sections of their hearts due to initiation of proliferation of remaining viable cardiomyocytes (cardiac muscle cells) upon injury. Mammals like mice, pigs and humans have lost this ability and very little, if any, proliferation of cardiomyocytes is noted in adult cardiac tissue after injury. Transient administration of miR302mimic to injured murine hearts has been shown to potently activate cardiomyocyte proliferation and regeneration of cardiac function. (1) (2)
Mir302 is a microRNA involved in cardiac development. It affects several proteins of the Hippo pathway, a pathway known to regulate cardiac development and regeneration (3).
Potent cardiac regeneration in mice (smaller scar size, improved heart function) has been demonstrated by transient systemic administration of miR302(1), as well as by a single cardiac injection of miR302 formulated in shear thinning hydrogel designed to protect RNA and release it over 7-10 days (2).
Prolifagen is currently testing mir302 induction of cardiomyocyte proliferation in a pig model of cardiac regeneration using funds from an NIH Small Business Innovation Research Grant.
(1) Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, Snitow F, Morley M, Li D, Petrenko N, Zhou S, Lu M, Gao E, Koch WJ, Stewart KM, Morrisey EE.
A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice.
Science Translational Medicine 2015: Vol. 7, Issue 279, p. 279
– Ge Tao, Jun Wang and James F. Martin Small RNA: From development to regeneration
Science Translational Medicine 18 Mar 2015: Vol. 7, Issue 279
– Giacca M. RNA mimics as therapeutics for cardiac regeneration: a paradigm shift.
Mol Ther. 2015 Jun;23(6):984-6
(2) Wang LL, Liu Y, Chung JJ, Wang T, Gaffey AC, Lu M, Cavanaugh CA, Zhou S, Kanade R, Atluri P3, Morrisey EE, Burdick JA.
Local and sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischemic injury.
Nat Biomed Eng. 2017; 1:983-992.
– Irene Fernandez-Ruiz A hydrogel–miRNA complex stimulates heart recovery
Nature Reviews Cardiology | Published online 14 Dec 2017; doi:10.1038/nrcardio.2017.210
(3) Leach et al. Hippo Pathway Deficiency Reverses Systolic Heart Failure Post-Infarction
Nature. 2017 October 12; 550(7675): 260–264. doi:10.1038/nature24045