| Cardiovascular disease (CVD) is the nation's number one killer. Several pharmacotherapies exist to combat CVD however its incidence and mortality rates continue to rise. Alternative treatment options must be explored in order to provide hope for the future treatment of this disease. Gene therapy has been suggested as one such alternative option.; Gene therapy involves the transfer of therapeutic nucleic acid into diseased cell types. The vector for such gene transfer is of major consideration when approaching any disorder. Viral vectors based on HIV-1 are an up and coming class of gene transfer vehicles first utilized in 1996 and already finding their way into human clinical trials. However the HIV-1 vectors, or lentiviral vectors, are poorly characterized in almost every major organ of the CV system. Lentiviral vectors possess many of the characteristics required for effective gene therapy for CVD including the ability to accommodate large payloads of nucleic acid, transduce non-dividing cells, direct long-term transgene expression, and evoke a miniscule immune response. However, many challenges face lentiviral vectors including questions about their safety for use in humans and technical hurdles concerning their large-scale preparation. The primary goal of this study was to further develop the lentiviral vector system and characterize its efficacy in the CV system and its ability to prevent CVD.; Novel methods were developed for the production and concentration of the vector allowing for reproducible large-scale production. Upon delivery to neonatal rats, the lentiviral vector transduced every major target organ of the rat cardiovascular system including the heart, liver, brain, kidney, and adrenal gland. The optimal vector dose was determined, and additional studies using an angiotensin II type 2 receptor transgene illustrated the ability of the vector to prevent the development of hypertrophy in a spontaneous model of hypertension in the rat.; The methodology of lentiviral vector preparation was improved and its effectiveness in the CV system illustrated. Initial results using a therapeutic transgene show promise for the future study of cardiac hypertrophy. The findings here help to lay the foundation for future use of the lentiviral vector in the study and possible therapy of CVD. |
