VIRAL GENE TRANSFER TO MODIFY CARDIAC EXCITABILITY

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DESCRIPTION (adapted from the applicant's abstract): The long term goal of this project is to demonstrate whether gene therapy represents a plausible approach to treat arrhythmia. The applicant notes that advances in gene transfer strategies now allow the modification of the electrophysiological substrates using recombinant viral vectors encoding ion channels. The applicant proposes to establish the feasibility of this approach by creating recombinant adenoviruses encoding: 1) the HERG potassium channel which underlies the rapidly activating component of the delayed rectifier current, IKr, and mutant forms of this channel that exist in the chromosome 7-linked form of the long QT syndrome; and 2) the KvLQT1 and minK potassium channel subunits that form the slowly activating component of the delayed rectifier channel IKs, and a mutant form of minK that has dominant negative effects on IKs expression. The central hypothesis to be tested is that over-expression of the wild-type channels will have an antiarrhythmic influence in cultured heart cells and that knock out of the current carried by these channels will lengthen the action potential and facilitate the development of arrhythmogenic afterdepolarizations. In isolated cardiac myocytes, the applicant predicts that these constructs will alter the net current during the plateau and repolarization phases and, thereby, modulate the contour of the action potential. The applicant further expects that cells and hearts overexpressing IKr or IKs will be less likely to develop afterdepolarizations and triggered arrhythmias after exposure to Bay K8644 or ouabain. In contrast, cells and heart in which either current has been reduced by dominant negative suppression upon exposure to mutant channels/subunits are expected to have more unstable rhythms. The primary focus of this work will be to address basic questions regarding optimization of adenovirus-mediated potassium channel expression in vitro and in vivo and modulation of the action potential and electrophysiologic substrate.