SERCA2a gene therapy ameliorates pulmonary hypertension in a pig model: comparison of different delivery methods and therapeutic effect

Background: Sarcoplasmatic reticulum Ca++ ATPase (SERCA2a) is downregulated in the pulmonary vasculature of pulmonary hypertension (PH) patients. SERCA2a gene therapy seems a promising alternative for treating PH. The best gene delivery method has to be defined. Objective: a) compare two different airway delivery methods: bronchoscopic vs intratracheal sprayer, b) efficacy/safety of bronchoscopic delivered AAV1-SERCA2a Gene Therapy for treating PH. Methods and Results: Initially adeno-associated virus serotype1 (AAV1) encoding for reporter genes (luciferase, GFP) was injected in healthy pigs using a spray catheter inserted in a flexible bronchoscope or an intratracheal sprayer. Bronchoscopic delivery showed a denser distribution in the distal airways. We hypothesized that high concentrations of AAV1-SERCA2a would ameliorate PH. PH was induced in Yorkshire pigs (n=12) by pulmonary vein banding. 2 months after surgery the animals were randomized in 2 groups: treatment (injected with AAV1-SERCA2a) and saline. The animals were observed for 2 more months. 6 pigs reached the end timepoint. Mean PA pressure was ameliorated in the treatment vs saline injected animals (25.7 ± 5.8 vs 36.3 ± 3.0 mmHg, p Conclusion: Gene delivery using a bronchoscope is an efficient method for PH gene therapy. AAV1SERCA2 gene therapy using this delivery method ameliorates PH in a large animal model.