Nonviral vectors in the new millennium: Delivery barriers in gene transfer

Development of an efficient method for introducing a therapeutic gene into target cells in vivo is the key issue in treating genetic and acquired dise ases by gene therapy. To this end, various nonviral vectors have been desig ned and developed, acid some of them are in clinical trials. The simplest a pproach is naked DNA injection into local tissues or systemic circulation. Physical (gene gun, electroporation) and chemical (cationic lipid or polyme r) approaches have also been utilized to improve the efficiency and target cell specificity of gene transfer by plasmid DNA. After administration, how ever, nonviral vectors encounter many hurdles that result in diminished gen e transfer in target cells. Cationic vectors sometimes attract serum protei ns and blood cells when entering into blood circulation, which results in d ynamic changes in their physicochemical properties. To reach target cells, nonviral vectors should pass through the capillaries, avoid recognition by mononuclear phagocytes, emerge from the blood vessels to the interstitium, and bind to the surface of the target cells. They then need to be internali zed, escape from endosomes, and then find a way to the nucleus, avoiding cy toplasmic degradation. Successful clinical applications of nonviral vectors will rely on a better understanding of barriers in gene transfer and devel opment of vectors that can overcome these barriers.