ABSTRACT

Currently, more than 900 clinical protocols have been approved for human gene therapy. However, in many cases no remarkable successes have been reported. In 1995, the Orkin-Motulsky report indicated the importance of vector development in human gene therapy. Numerous vectors have been developed to date. In general, viral vectors are more effective for gene transfer; the problem, however, is safety.1 Unfortunately, in 1999, a young patient died following infusion of an adenoviral vector via the hepatic artery.2 In 2002, two patients with X-linked severe combined immunodeficiency, treated with retroviral vector gene therapy, suffered from leukemia-like symptoms, likely induced by insertional mutagenesis of the retroviral DNA.3 Hemophilia B gene therapy using the adeno-associated virus (AAV) vector looks promising,4 but several potential risks still remain, such as germ line transmission. On the other hand, nonviral vectors have been evaluated for safety, but the limitation of this vector system is inefficient gene transfection.5 Therefore, the current consensus for vector development is that highly efficient and minimally invasive vectors are the most appropriate for human gene therapy. It appears to be very difficult to satisfy both

efficacy and safety. Before developing vector systems, we should analyze the biological barriers to gene transfer and develop methods to solve such difficulties.