From Traditional Pharmacological Towards Nucleic Acid-based Therapies for Cardiovascular Diseases

Ulf Landmesser; Wolfgang Poller; Sotirios Tsimikas; Patrick Most; Francesco Paneni; Thomas F. Lüscher


Eur Heart J. 2020;41(40):3884-3899. 

In This Article

MicroRNA-modulating Therapeutics in Cardiovascular Disease

MicroRNAs (miRNAs)—defined as small non-coding RNAs of ~22 nucleotides—are potent post-transcriptional regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs.[58] Recognition of specific gene transcripts by miRNAs is due to complementarities between positions 2–8 of miRNA 5′-end with the 3′-untranslated region of target mRNAs. However, a single miRNA may regulate multiple genes, and its targeting may induce significant changes of the transcriptional landscape, with impact on cell phenotype.[101] Mature miRNA sequences are short and highly conserved across different mammalian species.[102] These features make miRNAs a promising therapeutic target to treat a wide panel of diseases, including CVD. Two approaches are currently employed to modulate miRNAs levels: (i) synthetic double-stranded miRNAs or viral vector-based overexpression; (ii) chemically modified anti-miR oligonucleotides.[102] Gain and loss-of-function studies in experimental models of hindlimb ischaemia have shown that reprogramming specific miRNAs, namely miR-92a, miR-21, and miR-29b, may heavily modify transcriptional networks regulating angiogenic responses, myocyte growth, fibrosis, and hypertrophy.[103] Intravenous administration of a specific antagomir targeting miR-92a, a member of the miR-17/92 cluster orchestrating angiogenic genes (integrin α5), restores blood vessel growth leading to functional improvement of the ischaemic limb and myocardium in mice.[104] In vivo inhibition of miR-21, a master regulator of MAP kinase signalling, attenuated cardiomyocyte hypertrophy and interstitial fibrosis, thus preventing transaortic constriction (TAC)-induced cardiac dysfunction.[105] Along the same line, deletion of miR-29 in cardiac myocytes prevented TAC-induced cardiac fibrosis in mice.[106]

Clinical Application of miRNAs Therapeutics

Many miRNA-based therapeutics are currently in preclinical development, and a growing number is reaching clinical trials. In a human phase 2 study, administration of a locked nucleic acid directed against miR-122 (Miravirsen), a miR targeting the hepatitis C virus RNA, showed dose-dependent antiviral activity when given as a 4-week monotherapy.[107] Moreover, a double-stranded miRNA mimic of miR-34, MRX34, reduced tumour progression in patients with refractory advanced solid tumours.[108] MiRagen therapeutics, a clinical-stage biopharmaceutical company, has recently established partnerships with pharmaceutical industry (i.e. Santaris Pharma, Servier) to develop miRNA-based therapeutics with potential application in CVD. A phase I clinical trial (NCT03603431) will test the effects of local intradermal injection of MRG-110,[109] an oligonucleotide inhibitor of miR-92a, on angiogenic response and wound healing in healthy volunteers with excisional wounds.[109] Given the pro-angiogenic effects of miR-92a inhibition, this trial will set the stage for phase 2 clinical trials testing the therapeutic potential of MRG-110 in patients with ischaemic cardiomyopathy and heart failure and/or peripheral artery disease. Another trial which started patient recruitment in July 2018 will test the effect of the miR-29 mimic Remlarsen (MRG-201) in preventing or reducing keloid formation in subjects with a history of keloid scars (NCT03601052).[110,111] The results of this trial, which are expected in April 2020, are eagerly awaited as they will pave the way to investigate the effects of Remlarsen on extracellular matrix remodelling and myocardial fibrosis in patients with heart failure. The lack of effective anti-fibrotic therapies in CV patients confers high impact to these studies. Regulus therapeutics is also developing miRNA therapeutics with potential applications in CVD such as anti-miR-21, anti-miR-155, and anti-miR-33 for the treatment of fibrotic diseases, inflammation and cardiometabolic disorders, respectively.[112]

Open Issues

The expansion of effective delivery approaches, especially to the heart and the vasculature, is a primary requirement for the use of miRNAs therapeutics in CV patients.[112] The prevention of undesirable 'off-target effects' also represents a relevant issue as miRNAs usually target multiple genes. Ongoing and upcoming clinical trials will provide invaluable information on the pharmacodynamics, safety and efficacy of miRNAs therapeutics in patients with CVD.