Gene Therapy of Liver Disease with Lentiviral Vectors Preclinical Studies in Models of Crigler-Najjar Disease and Hepatitis C

The main theme of this thesis is the application of lentiviral vectors for the treatment of congenital and acquired liver disease. Gene therapy represents a relatively new and promising therapeutic tool with possible applications in a broad spectrum of medical disciplines. The underlying principle of gene therapy is based on the introduction of genetic material into living cells to achieve a therapeutic biological effect. Consequently, gene therapy focuses on treating the cause of disease rather than the symptoms. The first part of this introduction will review the current options and developments in the field of liver directed gene therapy (1.1). Next we will review the most widely used viral vector systems (1.2). HIV-1 derived lentiviral vectors are among the most efficient gene therapy vectors that are currently available. The capacity of lentiviral vectors to stably integrate into the target cell genome of non-dividing cells is one of the main distinguishing features of this vector system. Clinical trials that involve the ex vivo transduction and retransplantation of autologous CD4+ T-cells or hematopoietic stem cells have been initiated [1-3]. In preclinical experiments, lentiviral vectors efficiently transduce differentiated liver parenchymal cells in vivo [4, 5]. Other major targets, such as the central nervous system and the airways are also under intense investigation [6, 7]. In the third part of this introduction, we will introduce this relatively new vector system that plays a central role in our studies (1.3). To learn how a dangerous pathogen such as HIV-1 was transformed into an efficient and safe gene transfer vehicle, the HIV-1 genome and virion composition and the viral lifecycle will be reviewed. Furthermore, we will discuss the lentiviral vector production procedure and transduction process. Finally, the scope of the thesis is outlined by introducing each chapter (1.4).