OR02
Aerosolized gene and oligonucleotide therapy targeting microRNA-224 ameliorates pulmonary hypertension by orchestrating the BMP pathway
O Bikou(1,2) C Swarts(3) M Bisserier(2) P Avramopoulos(5) E Kohlbrenner(2) R Hajjar(4) S Engelhardt(5) L Hadri(2) S Bonnet(6) Y Sassi(3)
1:Ludwig-Maximilians-Universitat München; 2:Icahn School of Medicine at Mount Sinai, NY, USA; 3:Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia, USA; 4:Gene and Cell Therapy Institute, Massachusetts General Brigham, Boston, USA; 5:Technische Universität München; 6:Université Laval, Québec, QC, Canada
Pulmonary arterial hypertension (PAH) is a severe vascular disease that leads to right heart failure and death. Currently there is no cure for PAH. We identified microRNA (miR)-224 as a lung enriched miR and in silico approaches predicted miR-224 among the miRs that target PAH related genes. In this study we aimed to investigate the role of miR-224 in pulmonary vascular remodeling and to test the therapeutic effect of miR-224 gene- and oligonucleotide therapies in PAH.
We found pulmonary miR-224 levels to be increased in PH-diseased lungs and in PH human pulmonary artery smooth muscle cells (hPASMCs). In vitro studies revealed that miR-224 is necessary to induce hPASMCs proliferation.
We next tested the therapeutic effect of miR-224 inhibition using three different PAH animal models in mice and rats. In a first approach, we intra-tracheally aerosolized an AAV1-Tough Decoy-miR-224 (AAV1-TuD-224) to PH diseased mice. AAV-Control-treated mice displayed all the hallmarks of PAH, whereas AAV1-TuD-224-treated mice displayed a marked and significant decrease in those parameters. Next, we intra-tracheally aerosolized a chemically modified antisense oligonucleotide specific for miR-224 (LNA-224) to PH diseased mice and rats. LNA-224 significantly suppressed PAH. We finally delivered LNA-224 to monocrotaline-treated rats and found that miR-224 inhibition improves survival and ameliorates PAH. Mechanistically, we found that miR-224 represses BMP signaling by directly targeting four pathway factors.
Our data suggest that miR-224 plays a pivotal role in pulmonary vascular remodeling by targeting the BMP pathway. Aerosolized gene and oligonucleotide therapy targeting miR-224 may have therapeutic value for PAH.