Optimization of Gene Delivery in Rodent Hearts

Gwathmey, Judith

Abstract

In this proposal, the applicants plan to optimize gene delivery by adenoviral vectors in-vivo in rodent models, which have become widely available through recombinant technology (knock-out and transgenic mice). To achieve these goals, the applicants have developed a catheter based method of gene delivery which they will test to enhance gene transduction in the whole heart in a homogeneous fashion. In Phase I of this project, the applicants will individually vary five different parameters of gene delivery to increase the efficiency of myocyte transduction: 1. temperature at which the adenovirus is delivered to the heart; 2. the exposure time of the heart to the adenovirus; 3. the concentration of adenovirus used; 4. the coronary perfusion rate at which the adenovirus is delivered; and 5. the type of medium in which the adenovirus has been dissolved. In Phase 2, the applicants propose to test the mode of delivery in knock-out and transgenic animals with cardiovascular disease. Specific adenoviruses encoding for genes that are relevant and important to the heart will be delivered to the heart and tested for improvement in function. The long term goal is to make the technology available to individual investigators, biotechnology companies, and the pharmaceutical industry requiring a model system to transduce whole hearts with specific genes. Another long term goal is to perform pre-clinical research and development by applying this mode of delivery to test treatments for a variety of myocardial disorders such as cardiomyopathy, ventricular arrhythmias, and coronary artery diseases. In addition, the applicants anticipate that this delivery method can be applied to a variety of tissues and organs and, hence, applicable to various other disease states.