Presentation description

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the world and is a major risk factor for subsequent heart failure and stroke which are the two leading causes of death. A key feature of AF is the development of fibrotic remodeling exclusively in the atria, yet current technology only allows for non-specific targeting of fibroblasts in both atrial and ventricular chambers hampering mechanistic investigations. Therefore, we hypothesize that atrial fibroblasts (Afb) have a uniquely expressed gene profile that will allow for the development of a novel AAV9 platform to confer Afb-specific transduction in the heart. To address this, primary cardiac Afb were subjected to a cumulative panel of phenotyping assays or mRNA-sequencing for differential gene expression analysis which confirmed that they are unique cell populations with distinct functional phenotypes. Transcriptome analysis identified three prioritized lead candidate genes which were exclusively expressed in Afb and were further validated via qRT-PCR. Finally, in silico analysis of the promoter region of the three targets of interest further prioritized a single target for future analysis, Adh1. In conclusion, Afb are a distinct population of cardiac-resident fibroblasts and we have identified a lead candidate gene target for a potential future promoter-directed AAV9 to target this cell population, in vivo. Future studies will assess the specificity and efficacy of this targeting approach using tandem fluorescent reporter mice in the hopes that this will lead to a potential viable AAV9-vector as a gene therapy for AF.