Gene Therapy for Coronary Artery Disease

Coronary artery disease (CAD) is a widespread and severe cardiovascular disorder affecting millions of people globally. It arises due to the narrowing or blockage of the coronary arteries, crucial vessels that supply blood and oxygen to the heart muscle. Major risk factors for CAD encompass high blood pressure, high cholesterol, smoking, diabetes, obesity, and family history. CAD symptoms vary based on the severity and location of artery damage, often including chest pain, shortness of breath, fatigue, palpitations, and arrhythmias. If left untreated, CAD can lead to grave complications such as heart attacks, heart failure, strokes, and even death. Current CAD treatments primarily focus on restoring blood flow to the heart and preventing further damage. However, these treatments have their limitations and drawbacks. Moreover, they fail to address the underlying causes of CAD, such as genetic defects or environmental factors. Hence, there exists a compelling need for innovative and promising approaches in CAD treatment, ones that can surpass the limitations of current therapies and offer more efficient and enduring benefits. One such revolutionary approach is gene therapy, a technique involving the delivery of therapeutic genes to specific cells or tissues to modify their function or expression. Gene therapy holds the potential to treat CAD by targeting the genes and pathways intricately involved in the disease's pathogenesis and progression. For instance, gene therapy can enhance angiogenesis, the process of forming new blood vessels, thereby improving blood flow to the heart. Additionally, it can reduce apoptosis, the programmed cell death that occurs in CAD-affected tissues, or modulate inflammation, the body's immune response in the ischemic heart.

Fig.1 Physiologic Pathways Related to Genetic Loci Associated with Coronary Artery Disease (Khera AV, 2017)

Features of Gene Therapy for CAD

Gene therapy for CAD encompasses three pivotal features: the target genes, the benefits, and the administration process. The target genes play a crucial role in influencing vascular and cardiac functions in CAD. These genes, including angiogenic, anti-apoptotic, or anti-inflammatory factors, modulate various biological processes involved in the pathogenesis and progression of CAD. Such processes encompass angiogenesis, apoptosis, inflammation, oxidative stress, endothelial dysfunction, and myocardial remodeling. The benefits derived from gene therapy for CAD are manifold. They focus on enhancing blood flow, reducing ischemia, and improving cardiac function. This is achieved through mechanisms like inducing angiogenesis, inhibiting apoptosis, or modulating inflammation. These therapeutic benefits enhance perfusion and oxygenation in the ischemic myocardium, preserve viability and contractility of cardiac tissues, and mitigate inflammatory cytokines and leukocytes that exacerbate vascular and cardiac damage. In the administration of gene therapy for CAD, the delivery method of the gene vector to target cells or tissues is pivotal. Routes such as intracoronary, intramyocardial, or systemic delivery are employed. Each route offers varying levels of concentration, specificity, stability, and duration of gene expression in the target area. The optimal administration method depends on factors such as vector type, target gene, target tissue, and desired effect. Striking a balance between safety and efficacy is imperative when determining the optimal administration approach for gene therapy in CAD.

Research or Clinical Progress of Gene Therapy for CAD

Gene therapy for CAD has undergone extensive investigation in both preclinical and clinical settings. Preclinical studies have employed diverse animal models, including mice, rats, pigs, and more, to assess the safety and efficacy of various gene vectors, target genes, and administration routes. These studies have demonstrated the potential of gene therapy to induce angiogenesis, inhibit apoptosis, modulate inflammation, and enhance cardiac function in the ischemic heart. However, preclinical research has also unveiled some challenges and limitations, such as issues with low transfection efficiency, transient gene expression, immune responses, toxicity concerns, and off-target effects. Clinical trials have further explored the feasibility and applicability of gene therapy for CAD in human patients. Some of the most prominent trials include the VEGF-2 trial, the AGENT trials, and the CUPID trials. The VEGF-2 trial, as the pioneering phase I trial of gene therapy for CAD, utilized an adenoviral vector to deliver the VEGF-2 gene to the ischemic myocardium through intracoronary injection. While the trial confirmed the safety and tolerability of gene therapy, it did not yield improvements in blood flow or angina symptoms. The AGENT trials, comprising phase II and III trials, employed a non-viral vector to deliver the FGF-1 gene to the ischemic myocardium via intracoronary or intramyocardial injection. These trials demonstrated the safety and feasibility of gene therapy but did not significantly impact exercise capacity or the patients' quality of life. In contrast, the CUPID trials, consisting of phase II and III trials, utilized an AAV vector to deliver the SERCA2a gene to the failing myocardium via intracoronary injection. Remarkably, these trials revealed that gene therapy was not only safe but also effective in improving cardiac function and enhancing patient survival.

Table 1. Examples of Gene Therapy Trials for CAD

Clinical trials have showcased the potential and promise of gene therapy for CAD. However, they have also faced challenges like low gene expression, variable responses, ethical concerns, and regulatory obstacles. Hence, additional research and development are essential to optimize gene therapy for CAD and translate it into clinical practice.

References

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