Gene Therapy for Heart Failure Essay
Advances in regenerative medicine go hand in hand with new perspectives and insights into potential treatments for heart disease.
After a decade of per-clinical and early Phase 1 and 2 clinical studies, gene therapy is now emerging as a genuine therapeutic option with the potential to alter the manner in which cardiologists manage heart disease (1).Gene Therapy for Heart Failure Essay
This article focuses on the progression of cardiovascular gene therapy and the continuing need to find less invasive and more cost-effective treatment options, with a specific focus on stable angina due to coronary artery disease, which may likely be the first indication served by cardiovascular gene therapy.Gene Therapy for Heart Failure Essay
Medical and surgical advances in cardiovascular intervention and treatment in the past 30 years have been monumental. Millions of lives have been improved and often saved. Despite this progress, cardiovascular disease is still the leading cause of death in the industrialized world. Globally, some 16 million people die each year of cardiovascular disease. In the United States alone, 12.4 million people have coronary artery disease. Among these, 7.3 million people aged 20 and older have had a heart attack and 1.5 million will have a new or recurrent heart attack this year.
Coronary artery disease is the leading cause of death in the US, accounting for approximately 460,000 deaths annually. Once thought of as a men’s health issue, heart disease is quickly being recognized as the silent killer of women. Compared to 46,000 deaths per year from breast cancer, 250,000 women die each year of coronary artery disease. Approximately five million people in the US have congestive heart failure (CHF) and 300,000 of them will die this year (2).
Recognizing these facts, it is clear that despite the rapid advances in cardiovascular therapy over the past 30 years, present therapies are still inadequate to treat the most prevalent and debilitating disease of our time. The grim statistics, however, may be about to change. The completion of the Human Genome Project has uncovered a new range of genes and genomic information that has begun to advance the field of regenerative medicine and revolutionize the cardiovascular gene therapy industry. The demand for cardiac-specific therapy, not directed merely at the symptoms, but at the correction of the underlying altered physiology that creates disease, is increasing every day (3).
Gene therapy for cardiovascular disease is aimed at providing a non-surgical alternative that will target the disease at its physiological roots and take advantage of nature’s own mechanisms as therapeutic approaches. The advancement of cardiovascular gene therapy into large-scale clinical trials and potential regulatory approval could offer a much desired solution to this unmet medical need for a large patient population worldwide. Gene Therapy for Heart Failure Essay
Regenerative medicine goes hand-in-hand with the androgenic healing process and with it, cardiovascular gene therapy. Iatrogenesis is the term used to describe the body’s natural ability to grow new blood vessels to sustain healthy tissue. A central premise of regenerative medicine is the stimulation of the body’s cells to create new cells, which can lead to the growth of tissues, organs and even systems. The cardiovascular system is one of these.
Reduced blood flow to the heart muscle (ischemia) causes injury to the heart muscle cells and stimulates the release of ischemic injury signals. In response to these signals in the heart, the human body’s natural angiogenic healing process is initiated and there is a natural attempt to grow new blood vessels to restore blood flow to the ischemic tissue. Unfortunately, this response is usually inadequate to keep up with the progressive nature of coronary artery disease, and ultimately progressive areas of the heart muscle are left without enough blood supply to accommodate increased stress or exercise.
Gene therapy for heart failure hit another bump on the road to clinical translation with the announcement by Celladon that its lead product Mydicar’adeno-associated viral vector 1 (AAV1)-expressing sarcoplasmic reticulum calcium ATPase (SERCA2a)’had failed in the phase IIb CUPID2 trial.1
SERCA2a’s role in heart failure was validated in the 1990s but proved to be an elusive target for therapeutic intervention using traditional drug discovery methods. It is well established that SERCA2a, which is critical to calcium homeostasis in the myocardium, is downregulated in failing heart, making it an important target for therapy. Mydicar represents enzyme-replacement gene therapy that aims to increase the content of this calcium transporter in cardiomyocytes. All primary, secondary, and exploratory efficacy end points were negative in this phase IIb trial, which was unexpected following the encouraging findings in phases I and IIa.Gene Therapy for Heart Failure Essay2
The results send gene therapy for heart failure on a familiar path back to the bench, and the field must now strive to understand and overcome the factors contributing to this late-stage failure.
Why did Mydicar fail?Gene Therapy for Heart Failure Essay The usual causes of failure at such a stage include a suboptimal vector dose, an inefficient vector and expression cassette, insufficient duration of gene expression, and/or inefficient gene delivery. An AAV1 vector delivered at the applied dose (1013 vg) has been shown to transduce cardiomyocyte in the preclinical setting, and the cytomegalovirus promoter–driven expression cassette is fairly strong in cardiomyocytes. No data are available on the duration of gene expression in the study, but in other human trials AAV has consistently expressed over several weeks or months. Therefore, these factors are less likely to be responsible for the failure. The most likely reason for the poor outcome is inefficient gene delivery into the fairly large myocardial tissue mass after a single intracoronary injection. Most AAVs bind avidly to the heparan sulfate–rich glycocalyx glycoprotein polysaccharide present on the vascular endothelium, and AAV does not pass efficiently through the intact endothelium into the myocardium.3
In addition, rapid blood flow in the coronary arteries quickly removes vector from the heart. At this time, the most efficient delivery method into the myocardium appears to be direct intramyocardial injection. Retrograde injection via the coronary sinus may also be an efficient method of delivery, but it is a much more difficult procedure and less practical for standard clinical therapy. In the CUPID2 trial, intracoronary delivery was probably chosen partly because it is a relatively easy procedure to apply in the clinic.
It has also been suggested that the very sick patient population contributed to the poor outcome and that some toxic mechanisms in the microenvironment of the failing heart might have inactivated SERCA2a via posttranslational modifications such as oxidation or acetylation. However, only severe heart failure patients would eventually be eligible for gene therapy and as such any intended therapy should be effective under these conditions.Gene Therapy for Heart Failure Essay Celladon had initially announced that they would examine patient subgroups that might have benefited from the therapy, but apparently this has not been successful. While further research is clearly warranted to explore the potential of SERCA2a in the treatment of heart failure, to most investigators in the field, the CUPID2 trial represents just another example of failed gene delivery into the large myocardium.