FUNCTIONAL AND TARGETING POLYMERIC GENE CARRIERS

University Of Utah, Salt Lake City UT

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the Applicant's Abstract): In this application, the investigators propose to design two new polymeric gene carriers. The first carrier is a dendrimer polymer consisting of polyethylene glycol (PEG) and poly(L-lysine) PLL (PEG-b-PLL) that is water-soluble and non-toxic. It forms self-assembling complexes with plasmid DNA. The second carrier is PEG grafted PLL conjugated with an artery wall-targeting moiety (targeting molecule-PEG-g-PLL). The targeting moiety consists of a peptide or protein (apoB-100) ligand in low-density lipoprotein (LDL). To enhance the efficiency of plasmid DNA transfection, the investigators will also incorporate an endosomal disrupting peptide (EDP) and a nuclear localization signal (NLS) peptide to the dendrimers, respectively. After optimization in systemic studies, these two novel gene carrier systems will be further evaluated in two well characterized cardiovascular disease models (ischemic heart disease (IHD) and angioplasty induced restenosis) with four currently most potent therapeutic genes (VEGF, FGF-2 for IHD, and eNOS, truncated TGF-beta receptor II (TTbetaR-II) for restenosis). Although naked DNA plasmids encoding VEGF and FGF-2 have shown to be therapeutically effective by direct myocardium injection, naked DNA is by no means an efficient mode of gene delivery. The past failures in cardiovascular disease gene therapy are due to a lack of appropriate gene transfer carriers. The investigators believe that the proposed gene carriers are superior to naked DNA and other carriers such as liposomes in delivering the gene of interest to artery wall cells and the myocardium. For the study of restenosis gene therapy, the use of a local gene delivery device applied to vascular wall of an animal model is proposed. For prevention of restenosis formation, a porcine coronary artery injury model will be selected to evaluate the effectiveness of our new gene carriers, the therapeutic genes, and the gene delivery catheters on prevention of restenosis formation. This project is designed so that our new gene carriers and their proper administration can be adapted for clinical use. These studies will provide important information, not only for further successful treatment and prevention of human IHD and restenosis, but also for the use of gene therapy in other disease states.