Cardiovascular disease is a leading cause of death worldwide, killing approximately 17.5 million people annually. Of these, 80% are directly related to heart attack and stroke. These events are brought on by artery blockages, such as atherosclerosis, causing tissue ischemia. Current treatments for these conditions include artery bypass, medications, and angioplasty. However, advances in angiogenic gene therapy suggest that physicians might soon be able to treat heart disease by stimulating the growth of new vascular tissue where it is most needed. Furthermore, gene therapy shows promise for treating other types of heart disease, such as arrhythmias or congenital heart failure.
Angiogenesis occurs when new blood vessels are formed from previously existing ones. This process occurs naturally in the body beginning with embryonic development, but it is also associated with pathogenic malignancies and certain other diseases. Cancers are unable to grow beyond more than a few millimeters in size without an adequate blood supply. Thus, they redirect blood from healthy tissues by creating their own vascular pipelines to draw in oxygen and nutrients. Researchers used this mechanism as inspiration to develop therapeutic angiogenesis.
Judah Folkman, a pioneer in the field of angiogenesis, described in the 1970’s the need by tumors for neovascularization, and suggested growth factors that may be contributors to the process. Although controversial at first, his work led to an explosion of interest in the topic of angiogenesis, both for treatment in cancer and tissue ischemia. By the late 1990’s and early 2000’s, researchers were seeing success in provoking angiogenesis in peripheral tissues using gene therapy in animals, and then humans. In recent years, angiogenesis in ischemic myocardial tissues is seeing increased success, but there are still significant kinks to work out.
Put simply, angiogenesis occurs when endothelial cells are attracted to areas by specific growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). It can occur through two different routes: sprouting or intussusceptive. Sprouting is the formation of new vessels where there were previously none, while intussusceptive angiogenesis creates new vessel branches by the splitting of existing vessels. Angiogenesis can be artificially induced by the transfection of target tissues by a viral or non-viral vectors encoding genes such as VEGF and FGF that are expressed during natural angiogenesis.
Naked plasmid and modified mRNA (modRNA) vectors are easily produced and elicit low cytotoxic effects on target tissues. However, both of these have problems with duration of gene expression, degree of gene expression, or both. Viral vectors offer much higher efficiency of gene transfer and expression; however, they pose the risk of provoking moderate to severe immune responses. A virus that is gaining popularity as a gene therapy vector of choice is the class of recombinant adeno-associated viruses (AAVs). While similar to adenoviruses in their ability to transfect target cells with more genetic material, they have decreased pathogenicity and an inherent affinity for cardiac cells. The primary disadvantage to using AAV vectors, along with their adenovirus cousins, is that significant portion of the population possess antibodies against many of the commonly studied virus serotypes from previous infections. A substantial amount of work how now been conducted to improve this by discovering new virus serotypes that most people have not been infected by, or developing novel versions that avoid the pre-existing immune response.
Recently, in early 2017, the FDA put a myocardial gene therapy designed by Taxus Cardium, called Generx, on the fast track to a Phase III trial. Generx uses a AAV vector which binds to coxsackie-adenovirus receptors on the surface of cardiac cells. This transfection causes the expression of FGF, which then stimulates a cascade of other growth factors. The goal is growth of existing vessels, and creation of new capillary systems to reduce myocardial ischemia. Researchers are hoping that those suffering from severe angina and have exhausted all other treatment options will benefit from this new therapy.
Two other significant forms of heart disease that have been targeted by gene therapy research are arrhythmias and heart failure. While early studies showed promise, there have been difficulties in progressing with their development. One possibility for cardiac gene therapy for the treatment of arrhythmia is the development of biological pacemakers. Electronic pacemakers that are currently used in patients require a device implantation that sends electrical signals to the heart to keep it pumping. Helpful as they are, they come with risks and limitations to patients. A 2014 study led by Cedars-Sinai Medical Center cardiologist Eduardo Marbán was successful in inducing the creation of biological pacemakers in pigs. After artificially destroying pacemaking cells in the pigs’ hearts, Marbán introduced a viral vector carrying pig genes that stimulated creation of new pacemaking cells by reprogramming cardiac muscle cells. Within a day, the pigs exhibited steady, healthy, heartbeats. This study has not yet moved to human trials.
A separate line of work, referred to as CUPID, saw success in small, early clinical trials. This approach attempted to correct a SERCA2a-enzyme activity deficiency in the sarcoplasmic reticulum, which is responsible for controlling calcium ion flux. An AAV virus was used to introduce genes to help promote expression of this enzyme. Unfortunately, the larger phase 2 clinical trials saw no significant positive outcomes from the treatment, and the project was dropped. Despite these setback and slow advances in many gene therapy heart treatments, there is a hopeful attitude that progress in vector and target cell design will continue to move cardiac gene therapy forward.
By Julie Monroe