Understanding barriers to in vivo gene delivery and developing nonviral vectors for more efficient gene delivery

Gene therapy has the potential to cure many debilitating diseases that arise from a genetic origin, from cancer to Alzheimer's disease to hemophilia. For this potential to be fully realized, an efficient delivery vector must be developed to ensure the facile delivery of genes to target cells in vivo. However, many barriers to delivery exist, and these must be surmounted by a successful delivery vehicle. The goal of this dissertation is to describe previously undefined extracellular barriers to polyplex-mediated gene delivery and the design of a novel gene delivery vehicle that is able to overcome all delivery barriers and successfully deliver genes in vivo. An understanding of the barriers to gene delivery in vivo will enable rational design of gene delivery vectors that can overcome these delivery barriers to mediate more effective gene delivery in vivo. In the second chapter of this dissertation, the evidence for extracellular barriers to polyplex-mediated gene delivery is presented and the implications for in vivo gene delivery are discussed. In Chapters 3 and 4, a copolymerization strategy is employed to generate bioactive peptide-containing copolymers designed to overcome not only the newly defined extracellular barriers, but the familiar intracellular barriers as well. The modular polymeric delivery system developed in this work holds great potential to overcome many of the limitations currently plaguing nonviral gene delivery vehicles.