Abstract
Top of pageAbstract Primary pulmonary hypertension is a life threatening disease characterized by increased pulmonary vascular resistance. This results in right ventricle (RV) hypertrophy, dilation, and potential RV failure due to increased right ventricular afterload. Current treatment strategies involve the use of various pulmonary vasodilators, including intravenous administration of prostacyclin (PGI2) which improves symptoms, morbidity and mortality of patients. The goal of this project is to develop a clinically relevant gene therapy treatment strategy for patients with primary pulmonary hypertension. Preliminary studies have involved the characterization of a monocrotaline (MCT)-induced rat model of pulmonary hypertension (PH) to be used for evaluation of recombinant adeno-associated viral (rAAV) vector-mediated correction. Using this model, we can recapitulate many of the PH-associated symptoms such as; endothelial cell damage and pulmonary vascular injury, after a single MCT injection. Pulmonary artery pressure was significantly different between the 60 mg/kg test group and the PBS control group (0.44 |[plusmn]| 0.1 mmHg vs 0.22 |[plusmn]| 0.04 mmHg; p=0.0006). The right ventricle weight per body weight also differed between the two groups (0.727 |[plusmn]| 0.1 vs 0.605 |[plusmn]| 0.087). Using a single injection of MCT to induce PH, we currently are assessing intratracheal delivery of rAAV serotype 5 vectors expressing the prostacyclin synthase gene to produce sufficient levels of prostacyclin for prevention of PH. Four week after intratracheal delivery of 3 |[times]| 1011 P rAAV5-hPGIS, a single 60 mg/kg dose of MCT was administered. Currently the animals are being weighed weekly and will have MRI images, echocardiograms and pulmonary artery pressures measured by catheterization to evaluate the success of treatment. Preliminary data of MRI images suggest no RV enlargement at seven weeks post gene delivery and three weeks post induction of PH. Long term over expression of PGIS using AAV has the potential to be a useful treatment strategy in PH.
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