Developing vectors for potent and selective manipulation of cardiac rhythm

Developing vectors for potent and selective manipulation of cardiac rhythm PROJECT SUMMARY Within the cardiac conduction system (CCS), the atrioventricular node (AVN) optimizes the timing of heart contraction and is susceptible to varying degrees of AV block (AVB). The most recent Expert Consensus Statement from the Heart Rhythm Society lists 19 gene mutations that cause AVB, which often requires pacemaker (PM) implantation. Despite the clear efficacy of PMs, alternative treatments, such as targeted AAV gene therapies, could benefit patients that cannot tolerate or do not wish to undergo PM implantation. Recent studies suggest that the burden of genetic predisposition to arrhythmia is much more common than currently appreciated, and mechanistic overlap between genetic and acquired forms of AVB suggest that specific gene targets amenable to gene therapy are likely to exist. However, AAV delivery of therapeutic cargos to the CCS, including the AVN, requires further refinement of existing technology. To address this urgent need, we must accomplish two key objectives: 1) efficient cargo delivery to the AVN and 2) restriction of therapeutic gene expression to the AVN. Based on our preliminary data and the recent published literature, we have developed a feasible approach to address both objectives. The long-term goal of our research program is to devise new therapeutic approaches for cardiac dysrhythmias. The overall objective for this proposal is to develop AAV- based tools to deliver therapeutic cargos to the AVN. Our central hypothesis is that by optimizing AVN uptake of AAV and restricting gene expression to the AVN, we will enable efficient gene therapy for genetic and acquired AVB. The rationale for the proposed research is that once the tools for efficient AVN gene therapy are available, they can be more widely implemented for conduction abnormalities arising elsewhere in the CCS. To test our central hypothesis, we propose the following Specific Aims: 1) Optimize the potency of AAV vectors to efficiently transduce the AVN, 2) Enhance the selectivity of AAV vectors for AVN-specific targeting, and 3) Establish a platform for somatic manipulation of AVN gene expression. Successful completion of the proposed project will create critical gene therapy reagents to potentially cure specific cardiac dysrhythmias. We envision that these new capabilities will enable future extension to arrhythmias related to sinus node and distal conduction system dysfunction.