In vivo endocrine secretion of prostacyclin following expression of a Cox-1/PGIS fusion protein in the salivary glands of rats via non-viral gene therapy

Pulmonary arterial hypertension is a progressive disease that culminates in right heart failure and death. Prostacyclin(PGI2) and its derivatives are effective treatments for PAH when administered as continuous parenteral infusions. This treatment paradigm requires medical sophistication, and patients are at risk for complications from an indewelling catheter; drug interruptions may result in rebound pulmonary hypertension and death. We hypothesized that the salivary gland can be repurposed into an endogenous production site for circulating PGI2 through the expression of a fusion protein embodying cyclooxygenase-1(Cox1) and prostacyclin synthase(PGIS) domains. We utilized ultrasound-assisted gene transfer (UAGT), a non-viral gene transfer strategy that achieves robust gene transfer to the salivary gland. We initially found that Cox1-PGIS expression in livers of mice using an Adenoviral vector dramatically increased circulating PGI2 relative to untreated rats or rats treated with PGIS alone. We then utiliz...