Potential Gene Therapy: Intravenous Administration of Phagocytes Transfected Ex Vivo with FGF4 DNA/Biodegradable Gelatin Complex Promotes Angiogenesis in Animal Model of Myocardial Ischemia/Reperfusion Injury

Conventional gene therapies still require improvement in various respects, such as transfection efficiency for targeting organs or tissues, safety (Li Q et al., 2001; Pfeifer A & Verma IM, 2001; Watson DJ et al., 2002), and so on. For example, transfection of naked plasmid DNA requires the use of a large quantity of DNA because of enzymatic degradation in the human body. Conventional non-viral vectors seem to be inferior to viral ones in efficiency, except for nucleofection (Nishikawa M & Hashida M, 2002; Schakowski F et al., 2004). On the other hand, gene therapy using viral vectors such as adenovirus, retrovirus etc., may induce tissue inflammation (Tomasoni S & Benigni A, 2004), though the efficiency of transfection is often relatively high. Also, the safety of viral transfection remains an issue, because of the risk of toxicity or mutation of viruses (Ferber D, 2001; Isner JM, 2002; Kay MA et al., 2001). Moreover, in vivo gene delivery to localized target tissues usually necessitates an invasive approach; for example, direct gene transfection to cardiomyocytes requires a surgical approach (Losordo DW et al.,1998) or catheterization (Kornowski R et al., 2000; Laitinen M et al., 2000). On the other hand, ex vivo gene transfection is less invasive. However, targeting of specific tissues by intravenous injection is usually inefficient. Macrophages accumulate in ischemic tissues through chemotaxis (Ramsay SC et al., 1992). Therefore, we considered that intravenously administered macrophages might target ischemic tissue in vivo. Tabata, et al. reported that particles of gelatin are phagocytized by macrophages (Tabata Y & Ikada Y, 1987; Tabata Y & Ikada Y, 1988). Gelatin is a natural polymer derived from collagen, and is widely used in pharmaceutical or medical applications, i.e., it is safe and suitable for use in humans (Young S et al., 2005). Further, its isoelectric point (Ip) can be adjusted by modification of its residues, and positively charged gelatin can be impregnated with negatively charged substances (Ikada Y & Tabata Y, 1998),