Abstract 9178: Cell-Based Prostacyclin Gene Therapy Prevents Pulmonary Arterial Hypertension
Objectives: Intravenous prostacyclin is approved for the treatment of pulmonary arterial hypertension (PAH). However, it has limitations of a short half-life, the permanent placement of an intravenous catheter and substantial annual cost. We hypothesized that cell-based prostacyclin gene therapy may provide sustained therapeutic effects without the aforementioned limitations.
Methods and Results: Since prostacyclin is produced from arachidonic acid by the enzymes cyclooxygenase (COX) and prostacyclin synthase (PGIS), we generated a vector expressing COX isoform 1 (COX1) and PGIS fusion protein that is capable of producing prostacyclin from arachidonic acid. Endothelium-like progenitor cells (ELPCs) from syngenetic Fisher 344 rats were transfected with COX1-PGIS expressing vector and lentivirus expressing nuclear localized red fluorescent protein (nuRFP). The engineered ELPCs expressing COX1-PGIS and nuRFP were tested in a monocrotaline (MCT) induced rat PAH model. Twenty-five days after cell transplantation, 48% of transplanted ELPCs resided in the lungs. MCT induced an increase in right ventricular systolic pressure (RVSP) compared to normal controls (51.9 ±2.2 mmHg vs. 26.3 ± 1.5 mmHg, p<0.01). The increase in RVSP was significantly attenuated by treatment with ELPCs alone (40.9 ±1.6 mmHg, p<0.01) or with ELPCs engineered to express the COX1-PGIS transgene (35.9 ±1.6 mmHg, p<0.01). Engineered ELPCs were significantly more effective than ELPCs alone in preventing the increase in RVSP (p<0.05). Right ventricle hypertrophy (right ventricle vs. left ventricle plus septum weight ratio) was reduced by treatment with ELPCs (28.8±0.8% vs. 36.5±3.1%, p<0.01) or engineered ELPCs (30.5±0.9% vs. 36.5±3.1%, p<0.01). Lung vessel thickness index increase (reflecting intima thickening and medial smooth muscle hypertrophy) was attenuated by treatment with engineered ELPCs (78.1±3.1% vs. 90.1±4.1%, p<0.05).
Conclusions: COX1-PGIS expressing ELPCs prevented MCT-induced PAH and showed enhanced efficacy over ELPCs alone. The one time cell delivery offered sustained therapeutic efficacy for at least 25 days, which may provide a promising option for patients with PAH.
- © 2011 by American Heart Association, Inc.