A University of Alberta research team has discovered important new information they hope will lead to more effective treatments for pulmonary arterial hypertension (PAH)--a deadly form of high blood pressure in the pulmonary arteries caused by uncontrolled cell growth. Therapies are currently limited for a disease that can lead to heart failure and death within a few years.
The researchers have shown that Survivin, a protein almost exclusively expressed in cancer, is also heavily expressed in both human and animal lung arteries with PAH. Survivin is an inhibitor of apoptosis--or programmed cell death--which promotes cancer by suppressing the body's ability to limit excessive cell growth.
Armed with this new information and using animal models, the researchers developed a nebulized and inhaled gene therapy to deliver an inactive Survivin-mutant via a virus--known in science as a "dominant negative construct"--effectively inhibiting endogenous Survivin. The therapy reversed PAH in rats and improved their heart function and their survival, thus holding out some promising avenues of treatment for human PAH. The team members believe that as in cancer, Survivin drives excessive cell growth in the PAH lung blood vessels.
"The most intriguing aspect," explains principal researcher Evangelos Michelakis, "is we've shown for the first time that this cancer protein is also expressed within the blood vessels of the lung in patients suffering with PAH, but not in normal human blood vessels, making survivin a very attractive target for selective intervention.
"This makes the proliferation of lung blood vessels in this disease a 'form of cancer' or a form of neoplasia to be more precise, first proposed by Drs. Voelkel and Tuder from the University of Colorado. We've demonstrated for the first time that, like cancer, apoptosis is suppressed in the lung blood vessel wall in this disease."
"Our biggest challenge in treating PAH is the fact we don't know what makes the cells in the lung blood vessel wall grow excessively," says the University of Alberta cardiology professor and Canada Research Chair holder. "And therapies also have to target the lung blood vessels and spare the normal cells in the rest of the body."
The paper is entitled Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. It's published in the June issue of The Journal of Clinical Investigation. In an accompanying editorial entitled Lessons learned from cancer may help in the treatment of pulmonary hypertension, written by French researcher Serge Adnot, the journal stated: "These findings raise important issues regarding the role of survivin in the pathogenesis of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies."
Other authors include: Sean McMurtry, Pulmonary Hypertension Program; Stephen Archer, Canada Research Chair in Translational Cardiovascular Research; Dario Altieri, Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School; Sebastien Bonnet, Alois Haromy, Gwyneth Harry and Sandra Bonnet, the Vascular Biology Group and Pulmonary Hypertension Program; and Lakshmi Puttagunta, Department of Laboratory Medicine and Pathology, U of A.
The latest research builds on previous work by the group, published a few months ago in Circulation Research, showing that an orally available drug, Dichloroacetate, selectively enhances apoptosis in PAH and thus reverses PAH, prolonging the survival of rats. Because this oral therapy has already been tried in humans with congenital mitochondrial diseases, the team is initiating a clinical trial in human PAH. Similarly, newer drugs that inhibit Survivin, currently in trials in oncology, might also be directly applicable to PAH patients, Dr. Michelakis explains.
The researchers are supported by the Canadian Institutes of Health Research and Canada Research Chair Program, the Alberta Heart and Stroke Foundation, the Alberta Heritage Foundation for Medical Research, the Canadian Institutes of Health Research, the National Institutes of Health, and the Alberta Cardiovascular and Stroke Research Centre (ABACUS). Dr. McMurtry is supported by the University's clinician investigator program and TORCH, a CIHR-sponsored multidisciplinary training program in cardiovascular disease, and a training grant from Bristol-Myers Squibb Company.