Sponsored Content by OXGENEMay 20 2020
Cardiovascular disease is one of the main causes of death globally. It is responsible for approximately 17.9 million deaths every year, with 80% of these directly linked to stroke and heart attack. These events are triggered by artery blockages such as atherosclerosis which causes tissue ischemia.
Existing treatments for conditions such as these include medications, artery bypass, and angioplasty. Advances in angiogenic gene therapy have begun to indicate that physicians may soon be able to treat heart disease through the stimulation of new vascular tissue growth, focusing this in the areas where it is most needed.
What’s more, gene therapy has exhibited a great deal of promise in the treatment of other types of heart disease, such as congenital heart failure or arrhythmias.
Angiogenesis
Angiogenesis occurs in cases where new blood vessels are formed from previously existing ones. While this process does occur naturally in the body with embryonic development, it is also linked to pathogenic malignancies and other diseases.
Cancers cannot grow to beyond a few millimeters in size without a suitable blood supply, so they will redirect blood from healthy tissues, creating their own vascular pipelines to attract nutrients and oxygen. Researchers have used this mechanism as inspiration in the development of therapeutic angiogenesis.
Judah Folkman is a pioneer in the field of angiogenesis. In the 1970s he outlined tumors’ need for neovascularization, suggesting growth factors that may contribute to the process.
While initially controversial, his work led to an increase of interest in angiogenesis for treatment in both cancer and tissue ischemia.
In the late 1990s and early 2000s, researchers saw successful results from the provocation of angiogenesis in peripheral tissues via gene therapy; first in animals, and then in humans. In more recent years, angiogenesis in ischemic myocardial tissues has seen increased success. However, there are still a number of issues to be addressed.
In simple terms, angiogenesis occurs when endothelial cells are attracted to areas by specific growth factors. These growth factors may include vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF), occurring through two different routes: sprouting or intussusceptive.
Sprouting is the formation of new vessels where none existed previously, while intussusceptive angiogenesis creates new vessel branches through the splitting of existing vessels.
It is possible to artificially induce angiogenesis through the transfection of target tissues via viral or non-viral vectors, using encoding genes like VEGF and FGF, generally expressed during natural angiogenesis.
Modified mRNA (modRNA) and naked plasmid vectors are easy to produce, eliciting low cytotoxic effects on target tissues, but, both have issues with the degree of gene expression, duration of gene expression, or even both.
Viral vectors provide much more efficient gene transfer and expression, but these do pose the risk of triggering moderate to severe immune responses.
A gene therapy vector of choice is the class of recombinant adeno-associated viruses (AAVs), and this virus is increasing in popularity all the time. While somewhat similar to adenoviruses in their capability of transfecting target cells with additional genetic material, these viruses exhibit reduced pathogenicity and an innate affinity for cardiac cells.
The leading disadvantage in the use of AAV vectors and their adenovirus cousins is that a large percentage of the population possesses antibodies that are able to fight against a considerable amount of the commonly studied virus serotypes from previous infections.
A great deal of work has been conducted to improve this, however, through the discovery of new virus serotypes which most people have not yet been infected by, or through the development of novel versions that are able to avoid pre-existing immune responses.
In early 2017, the FDA placed a myocardial gene therapy designed by Taxus Cardium – Generx - on the fast track to a Phase III trial.
Generx utilizes an AAV vector that binds to coxsackie-adenovirus receptors on the surface of cardiac cells. This transfection prompts the expression of FGF, which then stimulates a cascade of different growth factors.
The goal here is the growth of existing vessels, as well as the creation of new capillary systems that help reduce myocardial ischemia. Researchers hope that patients suffering from severe angina, who have tried all other treatment options, will benefit from this new therapy.
Treatment for Other Heart Disease
Arrhythmias and heart failure are two major forms of heart disease that have been targeted by gene therapy research. Early studies showed promise, but there has since been difficulty in proceeding with their development.
One possible avenue for cardiac gene therapy designed for the treatment of arrhythmia lies within the development of biological pacemakers. Electronic pacemakers currently used in patients rely on device implantation which sends electrical signals to the heart, keeping it pumping. While these devices are certainly helpful, they do come with associated risks and limitations.
A 2014 study which was led by Cedars-Sinai Medical Center’s cardiologist Eduardo Marbán was able to successfully induce the creation of biological pacemakers in pigs.
Following the artificial destruction of pacemaking cells in the pigs’ hearts, Marbán introduced a viral vector that carried specific pig genes to stimulate the creation of new pacemaking cells. They did this by reprogramming cardiac muscle cells and within a day, the pigs were exhibiting steady, healthy, heartbeats. This study has not moved to human trials at the current time.
A different line of work, referred to as CUPID, is seeing early success in small-scale clinical trials. This method is attempting to correct a SERCA2a-enzyme activity deficiency within the sarcoplasmic reticulum, responsible for controlling calcium ion flux.
Within this experiment, an AAV virus was used to introduce genes that helped promote the expression of this enzyme. Sadly, larger, Phase II clinical trials displayed no significant positive outcomes from the treatment, so the project was canceled.
Despite the setbacks and slow progress in a number of gene therapy heart treatments, it is hoped that progress in vector and target cell design will continue to advance, moving cardiac gene therapy forward. In fact, Asklepios BioPharmaceutical, Inc. (AskBio) announced that the first patient had been dosed with their AAV-based gene therapy for hashtagcongestive heart failure in a phase 1 hashtagclinical trial in February 2020, suggesting that gene therapies for heart disease really are moving from theoretical possibility to clinical reality.
Acknowledgments
Produced from materials originally authored by Julie Munroe from OXGENE.
About OXGENE
OXGENE™ combines precision engineering and breakthrough science with advanced robotics and bioinformatics to accelerate the rational design, discovery and manufacture of cell and gene therapies across three core areas: gene therapy, gene editing and antibody therapeutics.
Gene therapy: We’re transforming the vision of truly scalable gene therapies into a reality; progressing our industry leading transient gene therapy systems towards alternative technologies for scalable, stable manufacturing solutions.
Gene editing: We have automated gene editing to deliver CRISPR engineered cell lines at unparalleled speed, scale and quality and generate complex disease models in mammalian cells.
Antibody therapeutics: We’re employing a novel proprietary mammalian display technology to discover antibodies against previously intractable membrane proteins.
OXGENE™ works at the edge of impossible in mammalian cell engineering. Our scientific expertise and technology solutions address industry bottlenecks. For more information, please visit www.oxgene.com
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