Cellular & Cell Therapy
Current treatment for sudden cardiac death (SCD) due to arrhythmias is limited to antiarrhythmic drugs, tissue ablation, and cardiac devices (pacemakers etc.). Despite some success saving patients lives, most current treatment options do not offer a cure. Novel biological therapies, such as gene and cell therapy, can potentially restore normal electrophysiological function and cure SCD. Investigators in the HVRC are using novel molecular and cellular techniques to develop and validate new biological therapies for SCD.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


Cell Therapy for Sudden Cardiac Death Kenneth R. Laurita, Ph.D. (Principal Investigator), Marc S. Penn, M.D., Ph.D. (Co PI, Cleveland Clinic Foundation)

Ischemic heart disease (IHD) results in irreversible damage to the myocardium and is the leading cause of death in the United States. Congestive heart failure (CHF) and sudden cardiac death (SCD) are common devastating consequences of IHD. Recent investigations have focused on restoring hemodynamic function by adding new, healthy cells such as skeletal muscle myoblasts (SKMB) and bone marrow-derived stem cells. Early results are encouraging and indicate hemodynamic improvement; however, the effect cell therapy has on cardiac electrophysiology and SCD is unknown. A major goal of this project is to determine the electrophysiological and arrhythmogenic consequence of cell therapies including SKMB and bone marrow derived mesenchymal stem cells (MSC). To achieve this goal, novel optical mapping techniques and a rat model of IHD will be utilized. Overall, this study will improve our understanding of the electrophysiological and arrhythmic consequence of cell therapy for damaged myocardium associated with MI, and lay important basic groundwork for more extensive science-based clinical trials in this exciting, yet emerging field. The long term goal of this study is to develop a cure for SCD associated with IHD.

 


 

Methods for Improved Gene Transfer
J. Kevin Donahue, MD (Principal Investigator)

Gene therapy has the potential to radically alter treatment of human diseases. The possibility of correcting or even preventing disease at a molecular level caused a large amount of hype to surround the field in the mid to late 90s. Frustration began to mount as gene therapy failed to deliver on the many promises made during the early development of the field. One of the fundamental problems in the field is the inability to deliver the genetic material in an efficient and specific manner. Our lab has focused considerable effort on solving this problem for myocardial gene delivery. The majority of our efforts have been directed at improving methods for virus-mediated gene delivery via the coronary vasculature. By stepwise analysis of the relevant parameters, we increased the efficiency of gene transfer to the cardiac ventricles. Currently, we can reach approximately 80% of cardiac myocytes in the targeted coronary distribution. Using an epicardial method, we have succeeded in transferring genes to all atrial cells except those in the posterior or septal portions of the atria. Ongoing work is aimed at increasing the target area for ventricular gene delivery, and our long term goal is to develop methods for successful gene transfer to all cardiac myocytes in the targeted area. Shown in the figure are regions of significant gene transfer (dark blue, right atrium and apex).


 

Gene Therapy for Cardiac Arrhythmias
J. Kevin Donahue, MD (Principal Investigator)

Cardiac arrhythmias cause extensive morbidity and mortality in the economically developed world. Compounding the problem is a lack of effective therapies. Antiarrhythmic drugs, catheter ablations, and implantable cardiac devices are the available therapies. Unfortunately, drugs have been shown to increase mortality in most clinical trials; ablations are limited to a subset of the problem, and devices are expensive and associated with a number of their own risks. The limitations of current therapies have motivated our development of gene therapies for cardiac arrhythmias. We initially showed the ability to control ventricular response rate to atrial fibrillation, as a proof of concept work that gene therapy could be used for common arrhythmias. More recently, we have investigated the use of gene therapy to treat the atrial fibrillation itself, and to eliminate ventricular tachycardia inducibility in the setting of myocardial infarct scar. Current work in the lab is directed toward a better understanding of these arrhythmias on a molecular level, the choice of genes for treatment of these arrhythmias, and the evaluation of arrhythmia risk before and after gene therapy for these very common arrhythmias.