811. ACE-Targeted eNOS and BMPR2 Gene Therapy Attenuates Pulmonary Hypertension in a Chronic Hypoxia Rat Model

Idiopathic pulmonary arterial hypertension is a fatal disease characterized by vascular remodeling and right ventricular failure. Modern vasodilator therapies improve prognosis but ultimately most patients succumb or require heart-lung transplantation. We previously developed targeted adenoviral (Ad) strategies for pulmonary vascular gene delivery based on the use of a bispecific conjugate (Fab-9B9) that targets Ad infection to angiotensin converting enzyme (ACE) expressed on pulmonary vascular endothelium. In the current study we determined whether targeting achieved therapeutic gains when using Ad gene delivery of endothelial nitric oxide synthase (eNOS), then evaluated a more novel approach using targeted delivery of the gene for bone morphogenetic protein receptor type 2, based on the knowledge that mutations in this receptor and defects in BMPR2 signaling account for many of the inherited forms of IPAH. Rats (n=6) were injected with 5|[times]|109 pfu of either irrelevant virus, AdCMVeNOS, AdCMVeNOS+Fab9B9 or saline (PBS), then exposed to 10% oxygen atmosphere for three weeks, then right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (Fulton Index, FI) were determined. A concurrent group of rats maintained in normoxic conditions was used as a control. Hypoxia lead to increased RVSP (42.2|[plusmn]|4.6mmHg), PAP (34.5|[plusmn]|2.8 mmHg) and FI (0.48|[plusmn]|0.02) vs normoxic controls (22.3|[plusmn]|0.8, 19.4|[plusmn]|1.2 and 0.26|[plusmn]|0.01 respectively). AdCMVeNOS attenuated RVSP(33.9|[plusmn]|1.9), PAP(27|[plusmn]|2.3) and FI(0.41|[plusmn]|.03), with a further therapeutic gain seen with Fab-9B9 targeting (RVSP 28.0|[plusmn]|1.8). A separate experiment using irrelevant virus+Fab-9B9, AdCMVBMPR2+Fab-9B9 or PBS showed that BMPR2 gene delivery attenuated the hypoxia-induced increase in RVSP, PAP and FI by 27%, 34% and 50% respectively. Irrelevant Ad alone or with Fab-9B9 had no effect. Thus, the novel findings are that Ad-mediated eNOS delivery attenuates chronic hypoxia-induced PHT, and this effect is improved with targeting. This is also the first demonstration that upregulation of BMPR2 signaling attenuates pulmonary hypertension, suggesting a therapeutic strategy for patients with BMPR2 mutations.