10:20 AM - 11:50 AM
[I-S10-05] 基礎研究からみた肺動脈性肺高血圧治療における新たな知見
Pulmonary arterial hypertension (PAH) is a devastating disease with a 5-year estimated survival rate of around 70% for patients with childhood-onset PAH. At present, multiple drug therapies are clinically available and mainly target three pathways: the nitric oxide (NO) to cyclic guanosine monophosphate (cGMP) pathway; endothelin 1 pathway; and prostanoid pathway. All these medications have been confirmed to relax pulmonary vascular tone and improve the outcomes of PAH patients. However, some patients are resistant to these medications and require lung transplantation. Therefore, a novel therapeutic strategy for severe PAH is strongly needed. Various studies have identified several possible therapeutic targets such as genetic/epigenetic, vasoactive, inflammation, vascular remodeling, metabolic, neurohormonal, and cell-based therapeutic targets. In line with these insights, we have investigated the possibility of gene therapy in the sugen PAH rat model using patients derived gain-of function mutant in the natriuretic peptide receptor 2 (NPR2) gene, which synthesizes larger amounts of cGMP intracellularly without any ligand stimulation than existing drugs. We also have conducted in silico screening for the small molecule with the ability to increase cGMP levels comparable to the mutant NPR2 by using homology modelling and in silico virtual docking with small molecules of the ZINC database. In this presentation, we will present the results from our in vitro, in vivo, in silico studies, along with several insights from recent basic studies.