BMPRII-driven treatment response in heritable and idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare and severe disease, characterized by a pre-capillary pulmonary arteriopathy resulting in increased pulmonary vascular resistance, right ventricular hypertrophy and progressive right heart failure. PAH may be idiopathic (IPAH), heritable (HPAH), or associated with other diseases. Germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are detected in HPAH and in IPAH cases. BMPR2 mutation carriers usually display more severe pulmonary hypertension than non-carriers. Impaired BMPRII signaling is observed in HPAH, IPAH and in experimental models of pulmonary hypertension. It is involved in hyperproliferation of pre-capillary pulmonary arterial smooth muscle cells, which results in remodeling and obstruction of pre-capillary pulmonary arteries. Impaired BMPR2 signaling may also result in loss of pulmonary endothelium integrity and impaired angiogenesis, potentially contributing to distal pulmonary obstruction. The pharmacological therapies currently used to treat PAH, including endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), a guanylate cyclase stimulator (sGC), and prostacyclin (PGI2) analogs, mainly target smooth muscle proliferation. Considering that BMPRII-driven loss of endothelium integrity and impaired angiogenesis could play a role in the pathogenesis of PAH and that PAH-specific drugs such as PGI2 can induce BMPRII signaling, we hypothesized that BMPRII-mediated effects of PAH-specific drugs could contribute to preserve endothelium integrity and maintained angiogenesis. Despite the development of numerous therapies, PAH remains a devastating condition. Current guidelines advocate starting with monotherapy, to escalate to sequential combined therapy and to finally opt for lung transplantation in case of inadequate clinical response. However, upfront combination therapy targeting different pathways may be beneficial and early diagnosis of PAH with early therapeutic intervention may result in better long-term outcomes. Knowing that i) PAH-specific therapies are quite expensive, ii) guidelines not always applicable, iii) each patient differently responds to treatment and iv) there is no current mean to predict response to specific PAH-therapies, we propose developing tools which could assist to define an optimal treatment, in combination with BMPR2 genetic screening, to further improve the long-term outcome of PAH. We consequently aim to first investigate in vitro the effects of impaired BMPRII signaling on angiogenesis and integrity of PAECs knocked-down for BMPR2 or overexpressing BMPR2 mutants, using lentiviral vectors. Therefore, we propose to study the in vitro effects of PAH-specific drugs on angiogenesis and integrity of monolayer of PAECs (knocked-down for BMPR2 or overexpressing a BMPR2 mutant). Finally, we would like to investigate BMPRII-mediated effects of PAH-specific drugs, alone or in combination, on angiogenesis and integrity of PAECs isolated from PAH patients, at the time of diagnosis, using a recently developed technique allowing PAEC isolation from the catheter used for right heart catheterization, the gold standard examination to firmly diagnose PAH. The purpose would be to implement a tool that could assist predicting response to PAH-specific treatment by establishing a drug profile response, corresponding to each newly diagnosed patient, in order to adopt an optimal therapy. This tool may also display potential interest towards pharmaceutical companies, especially in pre-clinical studies of newly developed drugs as an alternative to animal models, reducing time to results and costs before starting Phase I/"in human first" studies.status: publishe