Improving Gene Therapy Efficacy Using Impella

Abstract

Gene therapy is a promising option for heart failure patients, but there remains a lack of effective delivery mechanisms. The Impella device is a heart pump that can increase coronary flow and pressure, important factors that determines efficacy of gene transduction when using intracoronary delivery. Because it also lends hemodynamic support, the Impella can be coupled with balloon coronary occlusion to increase cardiac vector dwell time. We hypothesized that use of the Impella offers safe and efficient delivery of genes using intracoronary administration of adeno-associated viral (AAV)-6. AAV6 encoding luciferase gene (5.0 × 10E13) was injected into the coronary artery one week after MI induction in Yorkshire pigs. A total of twelve pigs were allocated to one of the following groups: slow antegrade delivery (n=3), slow antegrade delivery with Impella (n=3), delivery during coronary artery occlusion with Impella hemodynamic support (n=3), delivery during coronary artery and sinus occlusions with Impella hemodynamic support (CA + CS, n=3), Four weeks later, tissues were harvested from various heart regions and other organs to assess luciferase expression and viral uptake. Impella support offered safe vector delivery during 1-2 minutes of CA and CS occlusion. Impella + coronary artery block enhanced luciferase expression globally in the heart but not in non-cardiac tissues, such as liver, as compared to injection without coronary artery block. Impella with CA + CS block even further increased luciferase expression by increasing viral uptake, as evidenced by increased vector genome in the tissues detected by PCR. At the infarct border zone, an important area for cardiac gene therapy, CA + CS occlusion led to greater than 300-fold increase in luciferase (p=0.005) compared to viral injection alone. Impella unloading with CA + CS occlusion dramatically improves AAV gene expression in the heart without increasing off-target expression; it is thus a promising method for clinical application of cardiac gene therapy.