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New targets for pulmonary hypertension: gene and stem cell therapy

Gene and stem cell therapy has evoked considerable interest in the pulmonary hypertension (PH) community. Choosing the targets, the vectors and the mode of delivery are under investigation. A number of animal models have demonstrated potential and have led to the first human gene therapy trial based on endothelial progenitor cells (EPCs) overexpressing nitric oxide synthase (eNOS) currently underway in Canada (1,2). A number of potential targets for gene therapy have already been explored including bone morphogenetic protein receptor type 2 (BMPR2), the gene responsible for the familial form of PAH. Targeted delivery of adenoviral vectors containing the BMPR2 gene to the pulmonary vascular endothelium of rats reduced cell proliferation and the pulmonary hypertensive response to chronic hypoxia (3), although overexpression of BMPR2 was not effective in the monocrotoline rat model of PAH (4). Other reports have successfully used survivin (5), the human Kv 1.5 channel (6,7) vascular endothelial growth factor (8) and adrenomedullin (9) to inhibit or reverse PH in animals. Mechanisms for delivery of vector have included the traditional inhalation of adenovirus as well as a number of novel approaches. Umbilical cord bloodderived EPCs have a phagocytosing action that can allow non-viral, gene transfer into EPCs (9) and then intravenous administration to target the lung vasculature. Transposons harbouring the eNOS gene, a non-viral method of gene delivery, proved beneficial in an animal model of PH (10). Direct gene transfer into skeletal muscle (11) and into the liver (12,13) have both proved effective in modulating pulmonary vascular responses downstream in the lung. And finally, skeletal muscle overproducing prostacyclin has direct effects on the lung vasculature and conceptually could prove a novel replacement for an indwelling Hickman and chronic infusion pump, as currently used in PH. The right heart is another potential site for gene therapy as it ultimately fails in response to the elevated pulmonary vascular resistance (14). Cellular cardiomyoplasty using cell transplantation to prompt cardiac repair is a potential new avenue (15) while vectors based on recombinant adeno-associated virus are emerging as promising gene transfer vehicles for cadiac muscle (16).