Review articleCardiac gene therapy: Recent advances and future directions
Graphical abstract
Introduction
Cardiovascular disease (CVD) is still a substantial cause of death throughout the world and 20% of people who are diagnosed with heart failure die within a year [1]. It is reported in 2010, more than 2150 Americans die due to cardiovascular disease each day accounting for an average of one death in 40 s and coronary heart disease is responsible for one in every 6 deaths [2]. The most common origins of heart failure are high blood pressure, diabetes, and coronary artery disease, all of which are becoming more prevalent in modern society. These diseases are more common in the elderly aging population and the number is gradually increasing worldwide. The cost for the treatment of CVD is comparatively much higher than any disease group. In 2010, the total direct and indirect cost of CVD and stroke in the United States is estimated to be $315.4 billion [2].
Human left ventricle has 2 to 4 billion cardiomyocytes. Disorders of cardiac overload such as hypertension or valvular heart disease kill cardiomyocytes slowly over many years. Along with these, aging is also associated with the loss of around 20 million cardiomyocytes per year in the absence of a diagnosed heart disease [3]. An acute event like myocardial infarction (MI) can cause massive damage to the heart that is not fully repairable. It is estimated that 25% of cardiomyocytes in the left ventricle can be wiped out in a few hours by MI [3]. This injury permanently scars the heart and currently there are no available pharmaceutical or medical devices to prevent this damage and initiate repair and regeneration of the damaged tissue. Heart transplantation typically provides the best patient outcome but there are not nearly enough donors to meet the demand.
Recently, gene therapy has become a promising approach to treat and heal damaged cardiovascular tissue and able to return the heart from nonfunctional to a functional state. As a result, the need for heart transplantation will decrease and subsequently reduce the mortality. The basic concept of gene therapy is to deliver functional genetic material such as therapeutic pDNA, siRNA to human cells, tissues, or organs to provide therapeutic functions for the purpose of preventing or treating disease, or to fix a genetic defect [4]. It can be accomplished in various ways including overexpression of a target molecule, adjustment of the target's intracellular transporting routes through introduction of decoy molecules, loss of function methods using dominant negative molecules or by introduction of RNA interference. It can also be accomplished by correction of damaging gene mutations/deletions at the genome or primary mRNA levels, or by introducing genetically altered donor cells [5]. Gene therapy has the potential to specifically modify the mechanisms of disease whereas pharmaceuticals typically treat the symptoms and require long-term administration. As our understanding of the mechanisms and pathways involved in CVD increases, more targets for cardiac gene therapy can be identified and new treatments can be designed.
Generally, two types of carriers such as viral and non-viral carriers are used in gene therapy [6]. But, an efficient and safe gene delivery vector is remained undiscovered for successful gene therapy application. Gene transfer efficacy is typically limited by insufficient delivery to the target tissue, negative immune response to the treatment and loss of therapeutic effect over time [7]. To overcome such limitations, various gene delivery approaches are being explored. The review will consider applications of viral and non-viral carriers to highlight their potential for incorporating gene therapy into the treatment of cardiovascular disease. The limitations of gene therapy will also be discussed along with the emerging techniques to overcome those limitations.
Section snippets
Current therapeutic approaches
In heart failure, the heart fails to meet the metabolic demand of the body. In an attempt to adapt to the stressful conditions, there is activation of the renin angiotensin and β-adrenergic system followed by remodeling of the heart [1]. As a result, the adrenergic activation increases the Protein Kinase A (PKA), Ca2 + Calmodulin-Dependent Protein Kinase II, and diastolic Ca2 + levels. This also disrupts Phosphoinositol 3 kinase (PI3K/AKT) signaling and thus, leads to several negative
Strategies for repairing the damaged heart using gene therapy
There are typically three elements necessary for a successful gene therapy. They include an appropriate therapeutic gene to be expressed, a packaging system that will contain and deliver the genetic material, and a delivery method that can efficiently transduce the desired amount of cardiac cells [1]. Choosing the gene to be expressed is the most difficult part because cases of heart disease vary widely in their cause and severity. There are several strategies that can be used in gene therapy
Gene delivery: barriers and uptake mechanisms
Before exploring the various methods and carriers to deliver genes inside the cardiac tissue, it is important to understand the critical barriers and uptake mechanisms that influence the delivery process. Typically, following an in vivo administration, the gene delivery systems are met with several physiological barriers. These can be broadly classified as extracellular and intracellular barriers for delivery of genes to target cells as shown in Fig. 1.
The common extracellular barriers include
Gene delivery: methods and carriers
Once optimized, gene of interest can be delivered directly into the heart or into the circulation by various gene delivery methods [54]. Direct intramuscular (IM) injection is the most commonly used route and delivers high concentration of naked genes or carriers to a local area. Specialized catheters can be used to directly deliver a dose of naked gene or vector into a specific coronary artery but there will inevitably be some leakage into the systemic circulation. While the possibility of
Current clinical status of cardiac gene therapies
Several trials are currently recruiting patients for gene therapies targeting the cardiovascular system (summarized in Table 1). The targets thus far include SERCA2a, Adenylyl cyclase class type 6 and VEGF. The very first clinical trial of a gene therapy targeting SERCA2a occurred in 2007 and involved 9 patients with advanced heart failure receiving a lone intracoronary infusion of AAV1/SERCA2a [88]. It was a multicenter trial designed to evaluate the biological effects and safety profile of
Conclusions and future directions
In summary, we have discussed available genetic targets in cardiovascular diseases and currently used gene delivery approaches. A brief look into clinical trials in this area is provided giving researchers guidance to rationally develop therapies. Vital considerations for researchers to ensure a successful cardiac gene therapy include careful analysis of mass of cardiomyocytes, duration of gene expression, size of gene and tolerability of carriers/vectors. Depending on the disease, the mass of
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work is supported by the Start-up funds from the Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh to Shilpa Sant, PhD. Authors thank Drs. Vinayak Sant, Manjulata Singh and Kishor Sarkar for critical reading of this manuscript.
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