We still have a Long Way to go to Effectively Deliver Genes!

Abstract

Gene therapy is emerging as a revolutionary alternative to conventional therapeutic approaches. However, its clinical application is still hampered by the lack of safe and effective gene delivery techniques. Among the plethora of diverse approaches used to ferry nucleic acids into target cells, non-viral vectors represent promising and safer alternatives to viruses and physical techniques. Both cationic lipids and polymers spontaneously wrap and shrink the genetic material in complexes named lipoplexes and polyplexes, respectively, thereby protecting it and shielding its negative charges. The development of non-viral vectors commenced more than two decades ago. Since then, some major classes of interesting molecules have been identified and modified to optimize their properties. However, the way towards the final goal of gene delivery, i.e. protein expression or gene silencing, is filled with obstacles and current non-viral carriers still have concerns about their overall efficiency. We strongly believe that the future of non-viral gene delivery relies on the development of multifunctional vectors specifically tailored with diverse functionalities that act more like viruses. Although these vectors are still a long way from clinical practice they are the ideal platform to effectively shuttle the genetic material to target cells in a safe and controlled way. In this review, after briefly introducing the basis of gene delivery and therapeutic applications we discuss the main polymeric and lipidic vectors utilized for gene delivery, focusing on the strategies adopted to overcome the major weaknesses inherent to their still limited activity, on the way towards ideal multifunctional vectors.

Hydrophobe-substituted bPEI derivatives: boosting transfection on primary vascular cells

“…However, the efficient and safe delivery of nucleic acids to cells is still a key challenge towards the clinical application of gene therapy. Traditional gene delivery techniques used in laboratory are in fact difficult to effectively translate to in vivo [8]. Viral vectors are generally considered to be the most efficient gene delivery systems, but their use is limited by the immune response exerted by the body and other major safety concerns.…”

Influence of Polyplex Formation on the Performance of Star-Shaped Polycationic Transfection Agents for Mammalian Cells

“…Typically, the first task of the non-viral vector is the compaction and electrostatic neutralization of the negatively charged DNA and the field is therefore dominated by natural and (semi-)synthetic polycations and cationic lipids [5][6][7][8]. However, while certainly safer, [9], non-viral delivery of DNA is currently also much less efficient [10] than viral delivery, in particular where non-dividing, primary, or non-adherent cells are concerned. Consequently, the use of non-viral agents is at present largely restricted to cells from mammalian cells lines intended for the recombinant production of biopharmaceuticals.…”

The yin of exofacial protein sulfhydryls and the yang of intracellular glutathione in in vitro transfection with SS14 bioreducible lipoplexes

“…Nonetheless, the inability of gene carriers to fully satisfy the contrary requirements of adequate DNA protection and efficient release is believed to be one of the major impeding factors behind the generally poor effectiveness of cationic lipids. In order to overcome such limitations, the past decade has witnessed tremendous progresses in the development of stimuli-responsive gene delivery vectors able to actively respond to changes in the (micro)environment by altering their properties and behavior [2,3]. Among diverse stimuli, the huge difference in redox potential between the oxidizing extracellular milieu and the reducing cytoplasm makes disulfide bonds unique in biology and in gene delivery systems [4,5].…”