GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 273Gene Ther Mol Biol Vol 7, 273-289, 2003Advances in cationic lipid-mediated gene deliveryReview ArticleBenjamin Martin 1 , Abderrahim Aissaoui 2 , Matthieu Sainlos 1 , Noufissa Oudrhiri 2 ,Michelle Hauchecorne 2 , Jean-Pierre Vigneron 1 , Jean-Marie Lehn 1 and PierreLehn 2*1Laboratoire de Chimie des Interactions Moléculaires, CNRS UPR 285, Collège-de-France, 11 Place Marcelin Berthelot,75005 Paris, France.2INSERM U458, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France__________________________________________________________________________________*Correspondence: Pierre Lehn, INSERM U458, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France. Phone:33(0)140031932, Fax: 33(0)140031903, E-mail: lehn@idf.inserm.frKey words: gene therapy, gene delivery, transfection, cationic lipid, synthetic vector, lipoplexAbbreviations: N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethyl ammonium chloride, (DOTMA); dioctadecylamido-glycylspermine,(DOGS); 3‚-[_N-(N’,N’-dimethylaminoethyl)carbamoyl]-cholesterol, (DC-Chol); dioleoyl phosphatidylethanolamine, (DOPE);dimethyldioctadecyl ammonium bromide, (DDAB); 1,2-dioleoyloxy-3-[trimethylammonio]-propane, (DOTAP); N 1 -[2-((1S)-1-[3-aminopropyl)amino]-4-[di(3aminopropyl)amino]butylcarboxamido)ethyl]-3,4-di(oleyloxybenzamide), (MVL5); 3β–[6’-kanamycincarbamoyl]cholesterol,(KanaChol); bis-guanidinium-spermidine-cholesterol, (BGSC); bis-guanidinium-tren-cholesterol, (BGTC); 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide, (DMRIE); N’-octadecylsperminecarboxamide hydrofluoroacetate,(C 18 Sper 3+ ); O-(2R-1,2-di-O-(1 Z, 9 Z-octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate, (BCAT); 1,2-dioleoyl-sn-glycero-3-succinyl-2-hydroxyethyl disulfide ornithine, (DOGSDSO); cholesteryl hemidithiodiglycolyl tris(aminoethyl)amine, (CHDTAEA);gamma-interferon-inducible lysosomal thiol reductase, (GILT); small-angle x-ray scattering, (SAXS); dioleoyl phosphatidylcholine,(DOPC); polyethylenimine, (PEI); nuclear pore complexes, (NPCs); glucocorticoid receptors, (GRs); peptide nucleic acid, (PNA);polyethyleneglycol, (PEG)Received: 3 November 2003; Accepted: 1 December 2003; electronically published: December 2003SummaryOver previous years, problems associated with virus-mediated gene delivery have stimulated the synthesis andbiological evaluation of non-viral vectors as a possible alternative for gene therapy applications. Of the various nonviralvectors, cationic lipids have come forward as effective gene delivery agents, although it is clear that theirtransfection efficiency must be increased in order for them to become of real therapeutic value. This can beachieved by overcoming both the intracellular and extracellular barriers they encounter while conveying thetransgene towards the nucleus of the target cells. The purpose of this review is to highlight the advances made todate in facing these challenges by paying particular attention to the design of the cationic lipid itself and thecomplexes (termed lipoplexes) formed on interacting with DNA. Because the structures of all three parts of acationic lipid – the cationic headgroup, the hydrophobic moiety and the connecting linker – are importantdeterminants of transfection efficiency, each will be considered here in turn, with special attention focused on recentstudies including our own work. In addition, the stability of the lipoplex in the extracellular medium and thefeatures of its intracellular trafficking towards the cell nucleus will be assessed from both chemical and biologicalviewpoints. In conclusion, the future will probably see the development of sophisticated modular self-assemblinggene delivery systems incorporating various functional elements to face the various biological barriers encountered.Such vectors can be envisaged as ‘virus-like’ systems which share the levels of gene delivery efficiency of their viralcounterparts, but coupled with the safety of purpose-made organic molecules.I. IntroductionThe use of genes as medicines remains both acaptivating goal and a formidable challenge. By deliberateintroduction of either a functional gene or a sequencecapable of interfering with the functioning of a cellulargene, a wide variety of diseases of inherited and acquiredorigin are open to treatment in a most fundamental sense(Mulligan, 1993; Anderson, 1998). Those working in thefield of gene delivery have much to learn from viruseswhich achieve efficient levels of gene transductioncommensurate both with their need to deliver their geneticmaterial into host cells for the purpose of reproduction and273