ABSTRACT
Clinical gene therapy has been largely dominated by viral approaches to gene delivery. As natural gene carriers, viruses have demonstrated success in limited gene delivery applications, most notably in the treatment of severe combined immunodeficiency. However, to date, viral systems are still haunted by difficulties in host immunogenicity, safety, manufacturing, and scale-up. Synthetic delivery systems have the potential to overcome these problems (materials that are not peptidebased are generally not recognized by the adaptive immune system, and large-scale chemical
synthesis is routine in many industries) but have their own issues to address; e.g., toxicity, efficiency, and in vivo stability. It is clear that viruses exploit a variety of methodologies to deliver nucleic acids effectively, and complexity is certainly one key to their high transduction efficiency. Many viral proteins work together to overcome barriers to reaching the cell nucleus, and a mutation in one protein can significantly impair successful cell infection. Similarly, it is becoming obvious that nonviral delivery systems need to incorporate multiple functionalities or components to be efficacious in vivo.1 It is important in the design of nonviral systems that these functionalities are included in a synthetically straightforward manner. Otherwise, the advantages in manufacturing and scalability are lost. The objective of our research is to develop a self-assembling, polymeric delivery system for in vitro, ex vivo, and in vivo gene delivery applications.
