Gene therapy cationic lipids

Massing U. Screening for optimized cationic lipids to improve human gene therapy. New Drugs 2002 4 42-45. 

Particles from cationic lipids may also be useful for antisense therapy of skin disease — a nontoxic increase in the oligonucleotide uptake by cultivated keratinocytes and a sebocyte cell line has been reported [66]. Moreover, cationic dendri-mers also efficiently transfer reporter gene DNA to human keratinocytes cultivated in vitro. In the skin of hairless mice, in vivo transfection was possible with complexes, yet reporter gene expression was localized to perifollicular areas. Transfection, however, failed with the naked plasmid. For prolonged contact, biodegradable membranes coated with dendrimer/DNA complexes were used [67]. This hints at a follicular uptake of these complexes and indicates that gene transfection also may be possible with human skin, which has a thicker stratum comeum compared with mouse skin (eight to ten vs. two to three layers [58]). 

Anwer, K., C. Meaney, G. Kao, N. Hussain, R. Shelvin, R.M. Earls, R Leonard, A. Quezada, A.P. Rolland, and S.M. Sullivan, Cationic lipid-based delivery system for systemic cancer gene therapy. Cancer Gene Ther, 2000. 7(8) 1156-64. 

Kumar, V.V., Singh, R.S., Chaudhuri, A. (2003). Cationic transfection lipids in gene therapy successes, set-backs, challenges and promises. Curr. Med. Chem., 10(14), 1297-1306. 

Zhdanov, R.I., Podobed, O.V., Vlassov, V.V. (2002). Cationic lipid-DNA complexes-lipoplexes-for gene transfer and therapy. Bioelectrochemistry, 58(1), 53-64. 

Maslov, M.A., Syicheva, E.V., Morozova, N.G. and Serebrennikova, G.A. (2000) Cationic amphiphiles of both lipid and non lipid nature in gene therapy. Russian Chem. Bull., 49, 385—401. 

Keywords Cationic lipids Cell delivery Dendrimers Gene therapy... 

Cationic lipids are often combined with neutral and zwitterionic lipids in formulations for gene therapy. The most frequent colipids are cholesterol, DOPE and dioleoylphosphatidylcholine (DOPC) (or other PCs) (Fig. 28). These neutral lipids may play a role in transfection by increasing the level of DNA protection against DNases or facilitating the destabilization of the endosomes [35,103]. The optimum cationic lipid/helper lipid stoichiometry varies for the different cationic lipids, nucleic acids, and cells. 

In this chapter, we provide an overview of our recent efforts to develop a fundamental science base for the design and preparation of optimal lipid-based carriers of DNA and siRNA for gene therapy and gene silencing. We employ synthesis of custom multivalent lipids, synchrotron X-ray diffraction (XRD) techniques, optical and cryo-electron microscopy, as well as biological assays in order to correlate the structures, chemical, and biophysical properties of cationic liposome (CL)-NA complexes to their biological activity and to clarify the interactions between CL-NA complexes and cellular components. Earlier work has been reviewed elsewhere [1-7] and will not be covered exhaustively here. 

Ewert KK, Slack NL, Ahmad A, Evans HM, Lin A, Samuel CE, Safinya CR (2004) Cationic lipid-DNA complexes for gene therapy understanding the relationship between complex structures and gene delivery pathways at the molecular level. Curr Med Chem 11 1241-1253... 

Ewert K, Ahmad A, Evans H, Safinya CR (2005) Cationic lipid-DNA complexes for non-viral gene therapy relating supramolecular structures to cellular pathways. Expert Opin Biol Ther 5 33-53... 

Schwartz, B., Ivanov, M.A., Pitard, B., Escriou, V, Rangara, R., Byk, G., Wils, P., Crouzet, J., and Scherman, D. (1999) Synthetic DNA-compacting peptides derived from human sequence enhance cationic lipid-mediated gene transfer in vitro and in vivo. Gene Therapy 6 282-292. 

A recent study has explored the potential of the ternary complex formed between a poly(p-cyclodextrin) (formed by polycondensation of p-cyclodextrin), a cationic surfactant (dodecyltrimethylammonium chloride), and a polyanion in water, to act as a delivery system for gene therapy,using a combination of viscometric and SANS studies as well as visual observations to determine the macroscopic and microscopic properties of the complexes. In the study, sodium dextran sulfate was used as a substitute for DNA. The potential advantages of the use of such ternary complexes over the more commonly investigated DNA-lipid or polymer complexes (lipoplexes and poly-plexes, respectively) include a high water solubility of the resulting complex (lipoplexes and polyplexes often... 

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