Pharmacokinetic Study of Viral Vectors for Gene Therapy: Progress and Challenges

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Gene therapy may be described as the use of genes as medicines to treat disease, or, more precisely, as the delivery of nucleic acids by means of vectors to patients for some therapeutic purpose (Thanou, M. et al., 2007). The major goal of gene therapy is to introduce a functional gene into a target cell and restore protein production that is absent or deficient due to a genetic disorder (Neeltje, A. et al., 2003). This approach is a potentially powerful method for the treatment of diseases for which classical pharmacotherapy is unavailable or not easily applicable. Gene therapy is a therapeutic modality with enormous promise, which is also considered to have failed to deliver much of therapeutic significance in spite of all the apparent clinical interest. Clinical trial activity in gene therapy began in 1989, peaked in 1999, and is now currently declining (Thanou, M. et al., 2007). This decline was marked by some clinical trial problems, including a death from toxic liver shock during an adenovirus-based clinical trial in 1999 (Marshall, E., 2000), the anomalous appearance of a transgene in the gonads during adeno-associated virus-based preclinical trials in 2001 (Arruda, V. R. et al., 2001), signs of hypertension in lipofection clinical trials in 2005 (Pro-1) (MacLachlan, I. et al., 1999), and the development of leukemia in retrovirus-based clinical trials for ex vivo treatment of X-linked severe combined immunedeficiency (X-linked SCID) (Cavazzana-Calvo, M. et al., 2004; Gaspar, H. B., & Thrasher, A. J., 2005). Lessons from those frustrated results suggest that more basic research is required in gene therapy study, including mechanism of diseases and features of viral vectors. In order to modify a specific cell type or tissue, the therapeutic gene must be efficiently delivered to the cell, so that it will express at the appropriate level for a sufficient duration. Thus, identifying the ideal means of carriage for viral gene therapy is the key rate-limiting step in the development of most promising gene therapy strategies. In spite of long-term and extensive efforts to develop in vivo gene delivery systems, little achievements have been reported, especially as far as clinical applications are concerned. Apparently, the development of gene delivery systems will be one of the most critical issues for the success of in vivo gene therapy. Over the years, two broad approaches have been used to deliver therapeutic genes to cells, viral vectors and non-viral vectors. These two kinds of vectors are different as regard to