We recently found a constitutively active mutant of
natriuretic peptide receptor 2 (caNPR2; V883M), which synthesizes larger amounts of cyclic
guanosine monophosphate (cGMP) intracellularly without any
ligand stimulation than existing drugs. The aim of this study was to investigate the
therapeutic effects of gene transduction using caNPR2 for
pulmonary arterial hypertension (PAH). In vitro gene transduction into human pulmonary arterial smooth muscle cells using Sendai virus (SeV) vectors carrying caNPR2 induced 10,000-fold increases in the synthesis of cGMP without
ligand stimulation, and the proliferation of caNPR2-expressing cells was significantly attenuated. The PAH model rats generated by
hypoxia and the administration of
SU5416 were then treated with SeV vectors through a direct injection into the left pulmonary artery. Right ventricular systolic pressure was significantly decreased 2 weeks after the treatment, while systemic blood pressure remained unchanged. Histological analyses revealed that the medial wall thickness and occlusion rate of pulmonary arterioles were significantly improved in caNPR2-treated lungs. Neither the systemic integration of virus vectors nor side effects were observed. The massive stimulation of cGMP synthesis by gene therapy with caNPR2 was safe and effective in a PAH rat model and, thus, has potential as a novel
therapy for patients with severe progressive PAH.