Circular versus Linear DNA for Gene Delivery: Application towards The Genetic Complementation of Fabry Disease

Gene delivery is typically carried out using cDNA plasmids which generally result in transgene overexpression, leading to cytotoxicity and cell death. To achieve regulated transgene expression for long-term safety, BACs comprising full-length GLA gDNA were developed for the genetic complementation of Fabry disease in this study. Transfection of human Fabry cell models showed that circular BACs conferred superior transfection efficiency than their linear counterparts, while the native regulatory elements resided within the BACs conferred more physiologically relevant GLA complementation than cDNA plasmid. This is the first study establishing GLA gDNA BACs that potentially mitigate the disease progression in Fabry patients.