The enormous potential of RNA-based therapies was presented by Prof. Dr. med. Stefanie Dimmeler from the Institute of Cardiovascular Regeneration in Frankfurt am Main during the 62nd Annual GTH Meeting in Vienna.
After introducing topics such as the functionalities of different groups of non-coding RNAs, the growing market for related drugs, and the first successfully developed drugs in this field, Dr. Dimmeler addressed a key topic of interest: The development of a miRNA-92 blocker for better control of wound healing and angiogenesis in cardiovascular diseases.
miR-92a regulates angiogenesis and vascular structuring by inhibiting vessel growth. In the case of overexpression, it can considerably interfere with the development of a healthy vascular structure. In order to support the formation of new blood vessels, Prof. Dimmeler and team developed a miR-92a blocker, the AntimiR-92a.
In experiments on mice, AntagomiR 92a and LNA 92a were first tested, where it was found that both have an inhibitory effect on miR-92a expression. However, the effect of the LNA-92a variant was considerably better. Already in 2009 Dimmeler et. al. showed that AntagomiR can significantly improve angiogenesis and even muscle growth in the mice’s infarct damaged heart (1).
In 2013, a positive effect on the functional recovery of ischemic tissue in pigs was demonstrated by the inhibition of miR-92a. The high-dose anterograde administration of LNA-92a was shown to be the best experimental set-up in terms of both the suppression of micro-RNA and clinical findings (2).
The administration of LNA-92a led to reduced coronary heart attack incidence, improved general and local heart function, reduced inflammation and increased neovascularization. While all application types of LNA-92a showed significant improvements throughout the control group, the best results were observed through intracoronary administration.
In 2014, the study results were supported by a Spanish-led study in pigs under the direction of N. Bellera, in which the administration of a single injection of microencapsulated AntagomiR-92a resulted in significantly reduced septal dyskinesia and thus an improvement in cardiac contraction (3).
Further positive results of miR-92a blockers were found in acute myocardial infarction and ischemia in mice. A positive influence on vascular and arterial protection was also observed. However, fears that AntagomiR-92a might accelerate tumor growth have not been confirmed.
A study published in 2017 by Lucas et al. showed that the newly developed miR-92a blocker AntimiR-92a in mice significantly improved wound healing (4). By 2013, Penzkofer et al. had already found resistance to a high-fat diet in miR-92a-/- mice, where a weight increase between 6-14.5 weeks of age (-24±4% vs. WT; p<0.01) was observed (5).
Through funding from the German Federal Ministry of Education and Research, these academic results could be converted into lead structures in pre-clinical studies and were confirmed toxicologically in rats. Various LNA-based AntimiRs were created for this purpose, whose therapeutic effect lies between 0.03 mg/kg i. c. in pigs and between 0.5 and 2.5 mg/kg i. c. in mice. The test was carried out with doses of 3,10 and 30 mg/kg i. c.
Side effects included transient hyperemia, increased ALT and increased microalbumin levels in some animals urine samples. All these side effects occurred only in the 30mg/kg group. Furthermore, minimal amounts of erythrocytes and leukocytes were found in the urine. All these effects disappeared after discontinuation of the therapy. There were no treatment-related microscopic findings.
According to Dr. Dimmeler, this paves the way for clinical studies, and interested industry cooperation partners have already been found for providing financial support towards these clinical studies.
Plenary Session: RNA therapeutics for cardiovascular disease 21 February 2018 GTH Vienna, Austria