Gene delivery nonviral systems

Tomlinson, E., and Rolland, A.P., Controllable gene therapy pharmaceutics of nonviral gene delivery systems, Journal of Controlled Release, 1995, 39, 357-372. 

Anchordoquy, TJ. 1999. Nonviral gene delivery systems, Part 1 Physical stability. Biop harm 12 42-48. 

This section will describe the features and clinical applications for each gene delivery system. The description will start with a common feature of both viral and nonviral gene delivery systems, the expression cassette for the therapeutic protein. 

TABLE 15.2. Key features of viral and nonviral gene delivery systems... 

Nonviral vector systems are usually either composed of a plasmid based expression cassette alone ( naked DNA), or are prepared with a synthetic amphipathic DNA-complexing agent (84, 88). Gene delivery systems based on nonviral vectors mainly comprise cationic liposomes, DNA-polymer-protein complexes, and mechanic administration of naked DNA. An idealized/optimized multifunctional nonviral gene delivery system is depicted in Figure 13.4. 

Several major barriers need to be overcome for the development of nonviral gene delivery systems into true therapeutic products for use in humans. These barriers fall into three classes manufacturing, formulation, and stability (extracellular barriers and intracellular barriers) (85). Cationic lipids and cationic polymers self-assemble with DNA to form small particles that are suitable for cellular uptake. At the therapeutic doses positively charged particles readily aggregate as their concentration increases, and are quickly precipitated above their critical flocculation concentration. 

FIGURE 13.4 An optimized/ideal multifunctional nonviral gene delivery system. 

Lin, A.J., Slack, N.L., Ahmad, A., Koltover, I., George, C.X., Samuel, C.E. and Safinya, C.R. (2000) Structure-function studies of lipid-DNA nonviral gene delivery systems. J. Drug Target., 8, 13-27. 

Byk, G., Wetzer, B., Frederic, M., Dubertret, C., Pitard, B., Jaslin, G. etal. (2000) Reduction-sensitive lipopolyamines as a novel nonviral gene delivery system for modulated release of DNA with improved transgene expression. J. Med. Chem., 43,4377M387. 

Koping-Hoggard M, Tubulekas I, Guan H, Edwards K, Nilsson M, Varum KM, Artursson P (2001) Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo. Gene Ther 8 1108-1121... 

Safinya CR, Koltover I (1999) Self assembled structures of lipid-DNA nonviral gene delivery systems from synchrotron X-ray diffraction. In Huang L, Hung M-C, Wagner E (eds) Nonviral vectors for gene therapy. Academic, San Diego... 

Reduction-sensitive lipopolyamines as a novel nonviral gene delivery system for modulated release of DNA with improved transgene expression. J Med Chem 43 4377-4387... 

The transfection efficiency with the gene delivery system by sonoporation mechanism using BLs and US was higher than conventional lipofection method with Lipofectin and Lipofectamine 2000. Therefore, it is expected that this system might be an effective nonviral gene delivery system. 

Uduehi AN, Stammberger U, Frese S, Schmid RA. Efficiency of nonviral gene delivery systems to rat lungs. Eur J Cardiothorac Surg 2001, 20, 159-163. 

The prerequisites of successful HGT include therapeutically suitable genes (with a proven role in pathophysiology of the disease either by its lack, mutation, or overexpression), appropriate gene delivery systems (e.g., viral and nonviral vectors), proof of principle of efficacy and safety in appropriate preclinical models, and suitable manufacturing and analytical processes to provide well-defined HGT products for clinical investigations. 

Comparison of Viral vs. NonViral Gene Delivery Systems 1150... 

COMPARISON OF VIRAL VS. NONVIRAL GENE DELIVERY SYSTEMS... 

Of the many nonlipidic polycation gene delivery systems developed in the past decades, poly(L-lysine) (PLL) was the hrst polycation used for nonviral gene delivery [34]. Among a vast number of other positively charged polymers, polyethyleni-mine (PEI) has been widely used for nonviral transfection in vitro and in vivo and has an advantage over other polycations in that it combines strong DNA condensation capacity with an intrinsic endosomolytic activity [35-38]. 

The elements of a nonviral gene delivery system include a gene coding for the therapeutic gene, a plasmid-based expression system, and a synthetic delivery system. 

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