Primary pulmonary hypertension is a uniformly fatal disease of young and middle aged people; there is little understanding of the pathogenesis and no specific therapy. The principal pharmacologic therapy in current use is chronic constant intravenous infusion of the vasodilator prostanoid, prostacyclin. This therapy is effective, but requires maintenance of an intravenous catheter and continuous intravenous infusion; the only alternative is lung transplantation. The investigators showed some time ago that it is possible to transfect the lungs with the arachidonate cyclooxygenase (COX) gene and achieve selective increases in prostacyclin and PGE2 prostanoids which are potentially therapeutic for pulmonary hypertension. Studies supported by this phase I grant have documented that aerosol delivery of the COX gene as a plasmid-cationic liposome complex can decrease pulmonary vascular reactivity significantly in an animal model which is anatomically and physiologically similar to humans with no adverse effects on lung function. The investigators hypothesize that aerosol delivery of the COX gene in an expression plasmid complexed with cationic liposomes will prevent development and/or progression of the physiologic and pathologic changes of chronic pulmonary hypertension. The investigators further speculate that this therapy will prove superior to any current therapy for the treatment of patients with primary pulmonary hypertension and may provide a new therapeutic modality for treatment of a much larger group of patients with secondary pulmonary hypertension. In this Phase II application, the PI will determine: 1) effects of repeated administration of the COX gene in a plasmid-cationic liposome complex by aerosol on lung function, 2) prostanoid generation and pulmonary vascular reactivity in unanesthetized sheep; 3) determine whether administration of the COX gene by aerosol in a plasmid-liposome complex will prevent development or progression of sustained pulmonary hypertension and pulmonary vascular remodeling in a well-characterized chronic air embolization model of sustained pulmonary hypertension in sheep; and 4) increase the efficiency of aerosol delivery of plasmid-cationic liposome complexes by using newer generation aerosol delivery devices and improved liposome-DNA formulations.
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