Vascular gene therapy is an exciting frontier in the treatment of atherosclerotic cardiovascular disease. To date, methods of imaging vascular gene therapy have not been explored. Cardiovascular MR imaging, with its prominent advantages of high-resolution images of the vessel wall and multiple diagnostic evaluations of organ function and morphology as well as multiple image planes with no risk of ionizing radiation, is a unique imaging modality by which to monitor and control vascular gene therapy. In this project, we will explore a new methodology of intravascular MR-based vascular gene therapy through three novel techniques: 1) using our loopless MR antenna as a unique endovascular RF-heating source to enhance vascular gene transfection; 2) using our intravascular MR-guided interventional technique to precisely guide vascular gene delivery; and 3) creating contrast-enhanced intravascular high-resolution MR imaging of the gene/heat-targeted vessel wall to monitor vascular gene therapy. These technical developments will be first tested in vitro using cell phantoms and human cadaveric arteries, and then validated in vivo in domestic pigs and Yucatan minipigs with atherosclerotic stenoses of the iliac arteries. We will use a third-generation lentiviral vector as the primary vascular gene delivery vector in our in vitro and in vivo investigations. In addition, we will compare the role of the lentivirus with that of other viraVnon-viral vectors, such as adenovirus and liposome as well as plasmid DNA, in the MR/RF-heating enhancement of vascular gene transfer. We firmly believe that the success of this project will open up new avenues for the future global comprehensive management of cardiovascular ischemic disorders using MR-based modalities, i.e., using pre- and post-operative MR angiography and functional MR imaging to validate the success of intravascular MR-based interventions and gene therapy in a single setting, in an MR scanner. This should also facilitate clinical acceptance and therefore more extensive clinical use of MR methods to improve tbe diagnosis and management of cardiovascular disorders.
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