KOMM: MicroRNAs for risk assessment and treatment of venous thromboembolism

Venous thromboembolism (VTE) is a common disease, which affects around 1.1 million individuals in Europe each year, with 540,000 VTE-related deaths. The individual suffering and economic burden caused by VTE are tremendous, and the disease has become a major challenge to public health and health care systems. Today, anticoagulants are the only drugs available for effective prevention and treatment of VTE. However, severe bleeding is a feared side-effect (affects 3-4% of patients per year), and anticoagulants should therefore only be given to those at particularly high VTE risk in order to achieve a positive benefit-to-harm ratio for treatment. At the Thrombosis Research Center (TREC), we have discovered two microRNAs (miRs) that are associated with risk of VTE. Targeted intervention with these miRs has the potential to effectively prevent VTE without serious side-effects. In the proposed project, we (i) performed a validation study to confirm the association between these miRs and VTE in an external population, (ii) performed randomized controlled intervention studies in mice to test the efficacy and safety of the miRs on the risks of VTE and bleeding, and (iii) tested the functional properties of these miRs to reveal their mechanistic role in venous thrombus formation (may reveal new drug targets). The validation study showed that both miRs were associated with VTE, but the association was substantially stronger for one of the miRs (miR-A). Accordingly, the intervention studies showed that mice treated with miR-A had significantly fewer and smaller thrombi compared with untreated mice. The mice treated with miR-A had somewhat prolonged bleeding time. There was no effect of the other miR (miR-B) on the incidence and size of thrombi. Plasma proteomic and RNA sequencing of liver biopsy samples from the mice treated with miR-A were analyzed and interpreted. In vitro studies on target cells and target genes were conduced and revealed regulation of genes involved in intracellular signalling.

I dette prosjektet har vi vist at plasmanivået av miR-A er inverst assosiert med risikoen for framtidig utvikling av VTE. I en dyremodell har vi vist at administrasjon av miR-A gir redusert forekomst og størrelse på venøs blodpropp. Eksperimentelle studier har vist at miR-A uttrykkes i monocytter, leverceller og endotel og regulerer genuttrykket av proteiner som er involvert i intracellulær signalering. Våre funn kan tyde på at miR-A kan forutsi risiko for framtidig VTE og at behandling med miR-A reduserer risikoen for VTE.