Researchers have developed a novel adeno-associated virus (AAV) delivery strategy that utilizes mechanical support to enhance the safety and efficacy of cardiac gene transfer. The study, published in Nature Communications, demonstrates that combining the Impella CP device with controlled coronary artery occlusion in a swine model of myocardial infarction significantly improves gene delivery to the heart while minimizing off-target effects.
The research team, led by investigators at the Icahn School of Medicine at Mount Sinai, sought to address the challenges associated with traditional AAV-mediated gene therapy in the heart, which often suffers from inefficient transduction and potential systemic exposure. To overcome these limitations, they employed a strategy involving mechanical circulatory support (MCS) using the Impella CP device, coupled with transient occlusion of coronary arteries and the coronary sinus.
The study involved inducing acute myocardial infarction (MI) in Yorkshire pigs, followed by AAV serotype 6 encoding for luciferase (AAV6.Luc) delivery one week later. Different delivery methods were compared, including antegrade intracoronary infusion with and without MCS, intramyocardial injection, and stop-flow techniques involving coronary artery occlusion. The researchers assessed luciferase expression in cardiac and extracardiac tissues to evaluate the efficiency and specificity of gene transfer.
"Our findings indicate that mechanical support with Impella CP, combined with coronary artery occlusion, significantly enhances AAV delivery to the heart," said the lead author. "This approach not only increases luciferase expression in the myocardium but also reduces the presence of viral genomes in off-target tissues, suggesting improved safety compared to conventional methods."
The results showed that the stop-flow technique, which involved occluding both the coronary artery and coronary sinus during AAV6.Luc infusion, resulted in the highest levels of luciferase expression in the left ventricle. Viral genome quantification revealed that this method also led to a lower viral load in extracardiac tissues such as the liver, lung and kidney, compared to continuous infusion without MCS. Electron microscopy confirmed the presence of gold nanoparticles, used as a tracer, within the cardiac tissue following stop-flow delivery.
Echocardiographic and pressure-volume loop measurements were performed to assess cardiac function and remodeling. The researchers found that the mechanical support strategy did not adversely affect cardiac function and may have contributed to improved hemodynamic parameters in some animals.
The study's findings suggest that mechanical support during cardiac gene transfer can enhance vector delivery, reduce off-target effects, and improve the overall safety profile of AAV-mediated gene therapy. This approach holds promise for treating various cardiovascular diseases, including heart failure and inherited cardiomyopathies. However, the authors acknowledge that further studies are needed to optimize the delivery protocol and evaluate the long-term efficacy and safety of this strategy in larger animal models and, eventually, in human clinical trials.
Implications for Cardiac Gene Therapy
The development of safer and more effective gene therapy strategies is crucial for addressing unmet medical needs in cardiovascular medicine. The current study provides a compelling rationale for further exploring mechanical support as a means to enhance cardiac gene transfer. By improving vector delivery and reducing systemic exposure, this approach has the potential to overcome some of the limitations associated with traditional gene therapy methods and pave the way for new treatments for heart disease.
