Several non-coding RNA subpopulations show promise as therapeutic targets in the control of cardiovascular disease, according to Stefanie Dimmeler, who delivered the Louis B. Jaques Plenary Lecture at the ISTH 2015 Congress Thursday.

A small number of phase II trials in this area have been completed, with more clinical trials anticipated. The real excitement about non-coding RNA, however, is driven by preclinical evidence of its role in mediating disease processes, according to Dimmeler, director of the Institute of Cardiovascular Regeneration, University of Frankfort, Germany.

Dimmeler

Stefanie Dimmeler

Outlining the role of a variety of non-coding RNA subpopulations, Dimmeler presented evidence from cell lines, animal models and some human studies linking these molecules to control of angiogenesis, myocyte regeneration and growth of atherosclerosis. She also provided evidence that non-coding RNA is involved in platelet function, suggesting that it might participate in risk of clot formation.

Non-coding RNAs, such as micro RNAs (miRNAs), regulate gene function by inhibiting translation of messenger RNA. The evidence that non-coding RNAs perform important biological functions has been building for some time. Progress in understanding these functions has been accelerated by a growing body of information on miRNAs and the recent characterization of several subpopulations, including long non-coding RNAs (lncRNA) and circular RNAs (circRNAs).

Agents that target miRNA are already demonstrating therapeutic benefit. Dimmeler cited a study that associated miravirsen, an antisense oligonucleotide that sequesters miRNA-122, with a reduction in hepatitis C viral load in a small clinical study (Janssen et al. N Engl J Med 2013;368:1685-94). In cardiovascular disease, studies remain largely confined to animal models, but results are equally encouraging.

For example, an intracoronary injection of antagomir-92A, which inhibits miRNA-92, was found to prevent left ventricular remodeling in a pig model (Bellera et al. J Am Heart Assoc 2014;19;e000946). This finding was consistent with preclinical evidence that mi92-A regulates angiogenesis and vessel patterning, according to Dimmeler, who said that her laboratory recently received funding for clinical development of antagomirs.

Dimmeler spent much of her plenary lecture evaluating the promise of lncRNAs and circRNAs. Although these are at a much earlier stage of investigation, their promise is substantial.

As an example, a series of studies was described evaluating expression of lncRNAs by endothelial cells in response to shear stress. Of these lncRNA molecules, MALAT-1 was among those that were most robustly expressed. In a subsequent study undertaken in an atherosclerosis model, mice fed a high-fat diet developed a greater atheroma burden when MALAT-1 was inhibited.

In another example, she described experimental studies with cZNF292, a circRNA. CircRNAs, of which 7,388 have been identified, are expressed by endothelial cells and platelets. They appear to be among the most stable non-coding RNAs because their closed loop construction is resistant to degradation. Characterization of this type of non-coding RNA is in an early phase.

“At least for cZNF292, we have shown that it regulates endothelial cell function, but I have to say that these are unpublished, preliminary data,” said Dimmeler, adding that gain-of-function studies are needed to provide additional evidence of its biological activity. She noted that evidence suggests that circRNAs interfere with mRNA by interacting with binding proteins “and thereby change their function.”

The major message from Dimmeler’s lecture is that non-coding RNAs are likely to have a major role in mediating vascular disease and therefore are potentially important therapeutic targets. She concluded that this field holds enormous promise.

“Daily we find new RNAs,” Dimmeler said. “The aim is to explore their role in pathological conditions” with the hope of understanding how they can lead to better tools for disease control.

 

By Ted Bosworth |June 25, 2015