A tiny piece of genetic material, microRNA-199a, has been used to stimulate cardiac repair in a large mammal, the pig. Delivered through an adeno-associated viral vector, which was injected into myocardial tissue, the microRNA resulted in almost complete recovery from myocardial infarction.
The healing effects were observed at King’s College London and confirmed in 25 pigs. Unfortunately, in most of the pigs, subsequent expression of the microRNA resulted in sudden arrhythmic death, suggesting that microRNA dosage must be carefully controlled.
Nonetheless, the findings are encouraging. They show that microRNAs can succeed where stem cells have failed so far. Rather than introduce dedifferentiated cells, the microRNA approach induces cardiomyocyte dedifferentiation and proliferation, stimulating cardiac repair.
Detailed results appeared May 8 in the journal Nature, in an article titled, “MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs.” The article builds on previous findings that cardiomyocyte proliferation is under the control of the microRNA (miRNA) network.
“In particular, high-throughput screening work revealed that a few human miRNAs, including hsa-miR-199a-3p, can stimulate rodent cardiomyocyte entry into the cell cycle and cardiac regeneration after myocardial infarction in mice,” the article’ authors noted. “We therefore investigated whether these findings could be translated to myocardial infarction in pigs, a clinically relevant large-animal model.”
“One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size,” the authors emphasized. “These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation.”
Lead author Mauro Giacca, a professor in cardiovascular sciences from King’s College London said, “It is a very exciting moment for the field. After so many unsuccessful attempts at regenerating the heart using stem cells, which all have failed so far, for the first time we see real cardiac repair in a large animal.”
This is the first demonstration that cardiac regeneration can be achieved by administering an effective genetic drug that stimulates cardiac regeneration in a large animal, with heart anatomy and physiology like that of humans.
“It will take some time before we can proceed to clinical trials,” explained Giacca.
“We still need to learn how to administer the RNA as a synthetic molecule in large animals and then in patients,” he continued, “but we already know this works well in mice.”