LAUSR

A disappointing number of new therapies for pulmonary hypertension (PH) have been successfully translated to the clinic. Adeno-associated viral (AAV) gene therapy has the potential to treat the underlying pathology of PH, but the challenge remains in efficient and safe delivery. The aims of this study were i) to test the efficacy of endo-bronchial aerosolization delivery for AAV1-mediated sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) gene therapy in a PH pig model and ii) to identify the most efficient airway administration modality for in-lung gene therapy in PH. We hypothesized that delivery to the distal bronchi increases lung viral uptake and avoids virus loss in off-target compartments. In part one of the study, PH was induced in pigs by surgically banding the pulmonary veins. Two months post-surgery, 1x1013 viral genomes (vg) of AAV1.SERCA2a or saline was endo-bronchially aerosolized using a bronchoscope. Two months after aerosolization, high vg copies were detected in the lungs, accompanied by functional and morphometrical amelioration of PH. In part two of the study, we directly compared the endo-bronchial aerosolization gene delivery to the intra-tracheal aerosolization in PH pigs. Endo-bronchial delivery demonstrated higher viral expression (6,719 ± 927 vs 1,444 ± 402 vg copy/100ng DNA, p=0.0017), suggesting this delivery modality is a promising method for clinical AAV gene therapy for PH.