Cardiovascular Diseases

Cardiovascular diseases (malfunctioning of the heart and the blood vessels) are on the rise in the developing world, mainly due to sedentary behaviors, diet choices, longer lifespans and the unique stresses that arise from modern lifestyles. Nearly a third of Americans suffer from some form of chronic cardiovascular disease. Gene and cell therapies are now being developed to address chronic cardiovascular conditions such as congestive heart failure, cardiomyopathy, peripheral vascular disease, arrhythmias, as well as acute cardiac events such as heart attacks and critical limb ischemia (CLI). One major obstacle to the field remains the recruitment of sufficient numbers of cardiovascular disease patients to derive meaningful results from placebo-controlled clinical trials.

Stem cells isolated from the patient's own bone marrow (or mobilized leukapheresis) have been used as autologous cell therapy in clinical trials to treat heart attacks and CLI, with mixed results. It is difficult to isolate sufficient numbers of the right types of stem cells from the patient, to maintain their stemness during clinical manufacturing while expanding their numbers, and to administer them back to the patient in a way that improves their function by getting more cells to engraft in the right niches in the body.

Viral vectors such as AAV (adeno-associated virus) and LV (lentivirus) have been used to deliver beneficial genes, including angiogenic growth factors such as VEGF, factors to address heart failure such as SERCA2a to restore calcium function and SDF-1 to activate local stem cells. For arrhythmias, sodium channel, connexin, and adenylyl cyclase genes have been delivered in preclinical small mammal models to improve signal conduction. Delivering sufficient amounts of gene therapy to a large area of heart muscle remains a challenge and the target of considerable innovation in delivery technologies.

Gene therapy is also being deployed to address inherited congenital cardiovascular diseases present at birth. For example, Pompe disease, also known as glycogen storage disease type II (GSDII) is a congenital disease that results from the absence or deficiency of the key enzyme GAA (acid alpha-glucosidase), involved in energy storage via branched sugars in many tissues. Discovered in 1932 by a Dutch pathologist in a 7 month old infant who had died of unexplained heart failure, Pompe disease is the first in a diverse group of over 50 lysosomal storage diseases. Newborn babies who have mutations in GAA often have muscle weakness, including weakness of the heart muscle and of the muscles that are critical for breathing, such as the diaphragm. These babies often succumb early in life to heart or respiratory failure. A gene therapy trial that uses an AAV vector to deliver a functioning GAA gene to restore function has shown promise in preclinical studies.

In addition to offering novel treatments for cardiovascular diseases, gene and cell therapies allow us to better understand how heart muscle and endothelial (vessel wall) cells interact with one another in health and disease. By identifying key signals and molecular markers in patients enrolled in clinical trials, we may gain a much better understanding of how to use gene and cell therapy to promote healing. Insights gained with these approaches can in turn be used to develop new therapies.

22nd Annual Meeting
April 29 – May 2 | Washington D.C.