Abstract 14156: Airway Gene Delivery of Serca2a Ameliorates Chronic Pulmonary Hypertension in a Large Animal Preclinical Model

Abstract

Downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in Ca2+ homeostasis, endothelial dysfunction, and transition of pulmonary artery smooth muscle cells from a contractile to a proliferative phenotype. To assess the feasibility and benefits of sustained pulmonary vascular SERCA2a gene transfer, we created a model of chronic post-capillary PH in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was hemodynamically confirmed, and animals were randomized to intratracheal administration of adeno-associated virus type 1 (AAV1) carrying the human SERCA2a gene (n=10, AAV1.SERCA2a group) or Saline (n=10). Transduction efficacy after intratracheal delivery of AAV1 was confirmed by β-galactosidase detection in the distal pulmonary vasculature and significant overexpression of SERCA2a protein at the distal airway and small pulmonary arteries. Two months after gene delivery, disease progression was prevented in AAV1.SERCA2a treated animals as assessed by mean pulmonary pressure (29[5] vs 54[20] mmHg, p=0.027, Figure) and pulmonary vascular resistance index (3.2[2.2] vs 10.3[7.1] Wood units*m2, p=0.020) along with decreased small vessel remodeling in the AAV1.SERCA2a group (p<0.05). RV ejection fraction (61[7] vs 50[7] % units, p=0.014) was preserved and improvement of RV end-diastolic pressure-volume relationship (0.12[0.08] vs 0.28[0.07] mmHg/ml, p=0.08) in AAV1.SERCA2a treated pigs versus Saline. In conclusion, airway-based delivery of AAV vectors to the pulmonary arteries is feasible, efficient, and safe in a clinically relevant chronic PH model. Selective vascular SERCA2a overexpression results in beneficial effects on pulmonary hemodynamics and RV performance, and may offer therapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases.