Gene Therapy in Cardiology - An Overview

Introduction

Heart disease is frequently linked with abnormalities in electrical function, which may significantly reduce heart function and have fatal results. The current therapeutic choices are successful, but they could be better. Several gene transfer vehicles have been used, with adeno-associated viral gene delivery being the most common option for long-term expression tests and adenoviral gene delivery for short-term proof-of-concept tests. Gene therapy, when combined with advances in creative ideas delivery systems, is believed to be an effective strategy for removing the most painful arrhythmias (irregular heartbeat).

What Is Gene Therapy in Cardiology?

Gene therapy transfers nucleic acids to somatic cells to generate therapeutically useful molecules. It can fix inborn genetic flaws and express gene products to prevent or reverse acquired disorders. It uses a vector system to deliver a specific gene into the target tissue. Gene therapy's general components include the gene transfer vector, the delivery technique, and the transgene.

What Are the Vectors in Gene Therapy?

The vectors in gene therapy are the vehicle that transports the gene of interest into the target tissues. The vector might be either non-viral or viral. Unmodified nucleic acids (DNA or RNA) complicate transfecting cells in vivo. Hence, they are often delivered into target cells using lipid or polymer-based synthetic vehicles. Non-viral vectors consist of naked plasmid DNA, liposome-DNA complexes, polymer-based DNA complexes, deoxycholic acid-conjugated polyethylenimine siRNA combination (PEI-DA or siRNA), miRNA liposome complexes, and oligonucleotides. Viruses are the most widely utilized gene transfer vectors because they carry genetic material more efficiently than non-viral vectors. The most frequent viral vectors for myocardial gene transfer are recombinant adenoviruses, adeno-associated viruses, and lentiviruses. In addition to inserting the transgene into the vector genome, these viral vectors typically contain deletions of important viral genes that render them replication-incompetent, boosting safety. Given the limitations of both viral and non-viral vectors, all currently available vectors must meet the criteria of a perfect gene therapy system.

What Are the Gene Delivery Methods?

• Gene delivery methods for cardiac gene therapy include intramyocardial injection (direct injection into the myocardium), intrapericardial infusion, intracoronary infusion (infusion through one or more heart arteries and veins), and atrial epicardial gene painting. Furthermore, while intravenous perfusion is effective in mice, it does not result in significant cardiac gene transfer in bigger animals using currently available vectors. Gene delivery is the most difficult aspect of successfully translating cardiac gene therapy.

• The intramyocardial injection can be performed using an epicardial or endocardial route. The epicardial injection is usually done directly, either with the chest open or via the closed chest (with echocardiographic guidance), whereas endocardial injection uses a needle-tipped catheter. The primary benefit of this delivery method is its simplicity. The transgene is often highly expressed in the area surrounding the injection site.

• Intracoronary perfusion is less efficient than intramyocardial injection but delivers cardiac genes globally. Methods documented include catheter perfusion of a single coronary artery or vein and simultaneous perfusion of all coronary arteries from the aortic root during cardiopulmonary bypass or aortic cross-clamp. This approach yields a low percentage of transduced myocytes and a low expression level per myocyte. Although coronary flow rate, virus concentration, exposure period, temperature, and microvascular permeability can all be optimized, conditions enabling dense, entire heart gene transfer have yet to be established.

• Intrapericardial infusion is a practical method for delivering viral vectors into rodent hearts. This mode of administration in neonatal mice results in considerable transgene expression in the left ventricles and interventricular septum but only limited expression in the right ventricles. However, intrapericardial infusion is not an effective delivery technique for therapeutic applications in mature animals. Atrial epicardial gene painting differs from intrapericardial infusion in that the vector is delivered directly to the atrial epicardium.

What Are the Treatments for Gene Therapy in Cardiology?

1. Gene Therapy for Coronary Artery Disease: Advancements in pharmacology and revascularization procedures, including gene therapy, have improved long-term survival rates for individuals with coronary artery disease. However, a subset of individuals resistant to traditional treatment has emerged. Despite receiving maximal medical treatment, patients have severe angina pectoris that cannot be treated with percutaneous coronary intervention or coronary artery bypass graft surgery. Therapeutic angiogenesis is an alternate therapy method that is currently being researched. The therapy involves administering genes for angiogenic growth factors to enhance collateral vessel formation.

2. Gene Therapy for Treatment of Heart Failure: New molecular processes underpinning heart failure are being uncovered. These systems are difficult to alter pharmacologically, but they represent new potential targets for gene therapy. The current traditional pharmacological therapy, which focuses on limiting disease development, only modestly raises the ejection fraction, highlighting the need for new therapies. Current gene therapy research targets problems in calcium handling, beta-adrenergic signaling, and heart regeneration using noncoding RNAs that regulate mRNA translation or pluripotent stem cells. These treatments promote cardiac muscle contractility and cytoprotection, induce angiogenesis, or improve stem cell homing to the infarcted myocardium.

3. Gene Therapy for the Treatment of Arrhythmia: Cardiac arrhythmias place a significant cost on the healthcare system. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were found in 43 percent of all sudden death cases studied, but the exact prevalence and incidence are unknown. The primary burden of arrhythmias is exacerbated by the lack of a viable solution for more common arrhythmias, which cause significant morbidity and mortality. There are currently no human clinical trials forarrhythmia gene therapy. Preclinical studies are underway to demonstrate the efficacy and feasibility of gene therapy in treating cardiac arrhythmias.

What Are the Challenges and Problems With Cardiac Gene Therapy?

Although gene therapy may be a promising alternative for treating cardiac arrhythmias, its long-term efficacy and safety have yet to be investigated. Understanding of gene medicine is still in its early stages. Efficient gene transfer under clinically relevant conditions often depends on viruses' employment. Most viral vectors for gene therapies are potentially immunogenic, pro-inflammatory, and difficult to produce at large titers. As the experimental animals differ in species-specific characteristics such as organ size, coronary anatomy, immunology, and physiology, the results of the experiments may not apply to humans.

Conclusion

Gene therapy aims to change a gene or genetic pathway to provide therapeutic value while preventing or reducing disease. Establishing a safe and effective strategy for treating human disease is critical. Important considerations such as tolerance and ease of administration must be communicated to the clinic. Gene therapy for cardiovascular disease has been limited due to vectors and their delivery to the target cell.