Future Directions and Clinical Perspective

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Summary

Future Directions

MiRNA manipulation in animal models has been demonstrated as a potential therapeutic approach. A first clinical trial used miravirsen, an antagomiR of miR-122, on patients with chronic hepatitis C infection (HCV).⁶⁷ In this Phase IIa multicentre trial the use of miravirsen was shown to safe and effective in 36 patients: 5 weekly injections resulted in a dose-dependent reduction of HCV RNA levels for 14 weeks without evidence of viral resistance. A follow-up study on their patient cohort could confirm the safety and effectivity of miravirsen.⁶⁸ Furthermore, upcoming clinical trials targeting miRNAs have been announced in the context of kidney fibrosis and coronary artery disease.^69,70

These initial data and upcoming trials in humans are promising and justify further evaluation of miRNA therapeutics in AF, too. Based on the available data and suggested mechanisms of atrial fibrosis by miRNA action one focus could be the prevention or inhibition of progression of atrial fibrosis by targeting extracellular matrix-relevant miRNAs (e.g. miR-21 or miR-29b).

However, several challenges remain including more detailed evaluation of underlying pathophysiological mechanisms, chemical optimisation of miRNA agents or refinement of drug delivery. Furthermore, miRNAs might also serve as diagnostic biomarkers for AF as shown in our study on miR-29b. We demonstrated a significant downregulation of miR-29b in the plasma of patients with persistent AF that was further aggravated in patients with AF and concomitant congestive heart failure.⁵⁴ In case miRNAs could provide a representative biomarker for the existing structural changes or the predominant underlying pathophysiological mechanism this information could guide the choice of therapy in the individual patient.

In summary, progress in miRNA research has opened a window for establishing a new potential therapeutic intervention in the context of translational medicine. The future will show whether miRNAs can help to close the translational gap between underlying causes and specific treatment, which is currently thought to be one major problem in AF disease management.⁷¹

Clinical Perspective

• MicroRNAs are mediators of electrical and structural remodelling leading to AF.
• MicroRNA-related mechanisms can be targeted in vivo by antagomiRs, locked nucleic acids, miRNA-ponges/ erasers, miR-masks (inhibiting miRNA effects) or miR mimics (enhancing miRNA effects).
• A first clinical phase IIa trial using an antagomiR for treatment of hepatitis C demonstrated it to be safe and effective for treatment of human patients.
• Upcoming clinical trials will be targeting miRNAs in the context of kidney fibrosis and coronary artery disease.
• Targeting miRNAs in patients might be a novel therapeutic option for treatment of AF.