Gene therapy is the insertion of functional DNA into cells or tissues to replace defective genes that are responsible for genetic disorders. In order to enable the gene insertion also known as transfection, a vector is required to carry the genes to the nucleus of the right target cells. In the past, viral vectors have been used to promote this transfection process. However, due to safety reasons, non-viral systems such as chemical vectors are required. 

The collaboration between Patrick Midoux, at Centre National de la Recherche Scientifique, Orléans and Jean-Jacques Yaouanc, at Université de Bretagne Occidentale, Brest, resulted in the development of novel neutral lipophosphoramides. Such neutral lipids are shown to significantly improve the transfection efficiencies of cationic lipids. 

Yaouanc and Midoux's helper lipids contain an imidazole moiety that forms the polar head of the amphiphile. When the neutral lipids are combined with cationic lipids and DNA, tiny bubbles called cationic liposomes are formed. This is due to the electrostatic complexes between the DNA and the vectors. At pH below 6.0, imidazole protonation occurs in the acidic compartment of the cell (e.g.endosome) which induces fusion of liposomes and endosomes. This favours the liberation of foreign DNA to the cytosol. 'This work also underlines the fact that the structural similarities between cationic lipids and helper lipids give the synergic effects required to produce high transfection efficiencies,' says Midoux. 

The next step will consist of evaluating the benefit of these new helper lipids for in vivo transfection assays. 'Establishment of a structure-activity relationship will contribute to the synthesis of new compounds with high membrane desatbilisation efficiency for cytosolic delivery of DNA,' adds Midoux. 

Kathleen Too