What has long been thought of as “junk” in the human genome is actually a trove of potential therapeutic targets, according to Stefanie Dimmeler, PhD, who delivered the Paul Dudley White International Lecture on Tuesday.
Dimmeler, who is professor and director of the Institute of Cardiovascular Regeneration at the University of Frankfurt in Germany, said most of the RNAs coded within the genome play key roles in epigenetic regulation, transcriptional regulation, epithelial activity, atherosclerosis and much more.
“Humans have a very small number of genes, only about 23,000,” she said. “About 3 percent of our DNA is transcribed into proteins and about 80 percent is transcribed into RNA. These noncoding RNAs appear to exert very precise controlling functions throughout the cardiovascular system and the rest of the body.”
There are two basic types of noncoding RNAs. Small noncoding RNA have fewer than 200 nucleotides and are widely known as microRNAs (miRNAs). Long noncoding RNAs (lncRNAs) have more than 200 nucleotides.
There are more lncRNAs known than miRNAs — 30,000 compared to 2,000 — but more is known about miRNAs, Dimmeler said.
Most miRNAs are involved in translational repression and degradation of messenger RNA (mRNA), she explained. A single miRNA can target hundreds of mRNAs to exert broad effects on cell death, fibrosis, epicardial repair, angiogenesis, cardiomyocyte proliferation, cardiac reprogramming, endothelial function and more.
One of the most-studied miRNA, miR-92a, regulates angiogenesis and vessel patterning, but its biologic effects are far broader. Inhibiting miR-92a enhances neovascularization and recovery after ischemia, enhances tissue recovery after myocardial infarction and improves cardiac function after acute myocardial infarction.
In one study, inhibiting miR-92a reduced infarct size, improved global and regional cardiac function, reduced inflammation and augmented neovascularization, Dimmeler reported.
“Delivery is important,” she said. “Intracoronary delivery via catheter appears to be more effective than intravenous delivery, with a 6.4-fold improved recovery for the intracoronary route.”
Other studies show broad cardiovascular effects of miR-92a inhibition, with beneficial changes to endothelial cells, fibroblasts, cardiomyocytes and other cell types. About 50 targets for miR-92a inhibition have already been identified in different cardiovascular cells, Dimmeler said.
In addition to enhancing recovery from acute MI, miR-92a shows dramatic benefits in reducing hind limb ischemia, vasoprotection, protection against atherosclerosis and protection against metabolic syndrome while on a high-fat diet. All of these benefits accrue without any increase in tumor growth, Dimmeler said, suggesting a potential therapeutic role.
Preclinical studies have shown good efficacy at improving recovery following acute myocardial infarction with no liver or kidney toxicity up to a dose of 10 mg, and no treatment-related microscopic findings. The first in-human trials are slated to begin in late 2017.
“Work so far suggests that we need to work on improved delivery methods,” Dimmeler said. “We have been looking at nanoparticle delivery, local delivery using a variety of devices, aptamers, vectors, light activation and ligands to stimulate receptor-mediated uptake.”
Work in lncRNA is less advanced. Several lncRNA, including MALAT 1, have been linked to different stages in cardiovascular development from the pluripotent stem cell stage to differentiation into cardiac cell types. MALAT 1 is also present and active in mature organs. In endothelial cells, for example, the expression of MALAT 1 is regulated by hypoxia and laminar flow to modulate endothelial cell function and vessel growth.
MALAT 1 also inhibits vascular inflammation, Dimmeler said. In mice, MALAT 1 can reduce the burden of atherosclerotic lesions and enhance the outcome of bone marrow transplantation. In humans, normal arteries have higher levels of MALAT 1 compared to atherosclerotic plaques and long-term survivors following bone marrow transplantation have higher levels of MALAT 1 compared to individuals who die sooner after transplantation.
How MALAT 1 and other lncRNAs function is not known, Dimmeler said. lncRNAs may function as sponges to hold and attract
miRNAs to focus their activity in specific areas. Or lncRNAs may enhance miRNA stability to lengthen dwell time to improve function.
“We hope that by understanding the involvement of noncoding RNAs in cardiovascular disease, we may be able to target them to regulate cell function and treat cardiovascular and other diseases,” Dimmeler said.