Guanidinium-cholesterol cationic lipids: novel reagents for gene transfection and perspectives for gene therapy

Artificial self-assembling systems are at present widely investigated as an alternative approach to recombinant viruses for gene transfer studies and gene therapy applications. Among these synthetic vectors, cationic lipids are particularly attractive as it is possible to design and synthesize a great variety of reagents. Several amine-carrying cationic lipids have been shown to be efficient for gene transfection; moreover, some reagents (DC Chol:DOPE, DOTAP...) have even already been used in clinical trials. Over the last years, we have developed a novel class of cationic lipids : cholesterol derivatives characterized by polar head groups containing guanidinium functions. Such reagents combine the membrane compatible features of the cholesterol subunit and the favorable features of the guanidinium groups for DNA binding. We herein intend to summarize our work showing that these novel cationic lipids are efficient for gene transfection in vitro (into various mammalian cell lines and primary human airway cells) and also in vivo (into the mouse airway epithelium). These studies confirm the potential of cationic lipids for human gene therapy, namely lung-directed gene therapy for Cystic Fibrosis. Most importantly, our work also provides the basis for the design of improved artificial gene delivery systems. Thus, in this forward-looking review, we will also discuss some of the remaining problems that need to be resolved in order to develop improved synthetic vectors for nonviral gene delivery.