Gene Transfer Restores Regenerative Power to Circulating Angiogenic Cells
St. Michael’s Hospital ♦ University of Toronto
Published in Molecular Therapy, April 26, 2011
An interesting new approach to autologous cell therapy for patients with coronary artery disease uses gene transfer to enhance the regenerative activity of circulating angiogenic cells (CACs). These rare cells circulate freely throughout human vasculature, and are of interest to researchers because of their ability to promote the formation of new blood vessels and contribute to endogenous vascular repair. The regenerative capacity of these cells is impaired in humans that have cardiovascular disease, however, limiting their use as a therapeutic tool for this patient group.
Noting that the regenerative activity of CACs is linked to the availability of nitric oxide (NO), researchers at St. Michael’s Hospital and the University of Toronto hypothesized that up-regulation of the gene encoding endothelial NO synthase (eNOS) could remedy the problem. This enzyme, typically found in the vasculature, is responsible for endogenous NO production. To test their theory, researchers used a virus to transduce a construct containing the eNOS gene directly into CACs from patients with coronary artery disease; first they looked at the results in vitro. The modified CACs were able to contribute to angiogenic tube formation when grown in the petri dish along with umbilical vein endothelial cells.
A look at the capabilities of transduced CACs in vivo confirmed the in vitro findings. Transduction of the eNOS gene restored the ability of CACs to improve ischemic hind limb perfusion in an animal model. These data support the notion that CACs may prospectively be used to help repair vasculature in patients with coronary artery disease. In this treatment paradigm, CACs would be removed from patients, isolated in the lab, transduced with the eNOS gene, and then injected back into the patient for tissue regeneration.
Ex Vivo Lung Perfusion Determines Viability of High-Risk Donor Lungs
Toronto Lung Transplant Program ♦ Published in NEJM, April 14, 2011
A large majority of donor lung transplants fail to meet the criteria for lung transplantation. A combination of the damage that occurs following brain death, and the injury that occurs to lung tissue in the ICU, renders them unsuitable for medical use. When using sub-optimal donor lungs, graft dysfunction is prevalent, leading to acute lung injury that occurs within the 72 hours following transplantation.
Normothermic ex vivo lung perfusion (EVLP) was developed by a group of researchers in Toronto to increase the percentage of donor lungs that can be used for transplantation. This biotechnology allows for the perfusion of lungs at body temperature in an ex vivo circuit that attempts to mimic normal physiological conditions. EVLP lasts for roughly 4 hours, and provides a means to quantitatively assess the function of donor lungs prior to transplantation. In this clinical study, funded by Vitrolife, researchers assessed the feasability of transplanting high-risk donor lungs into patients following EVLP.
During the clinical study a total of 136 donor lungs were transplanted. Of these, 23 were classified as high-risk and underwent EVLP prior to transplantation, while the remainder made up the control group. The primary endpoint of the study was graft dysfunction after 72 hours; secondary endpoints included 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the hospital ICU. No significant differences were observed in any of the secondary endpoints between treatments. The incidence of graft dysfunction in patients who received high-risk donor lungs prepared with EVLP was only half of that observed in patients receiving donor lungs considered to be “standard” by clinicians (15% and 30% respectively). These results indicate that EVLP does a better job selecting donor lungs for transplantation.