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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Novel Nonviral Vectors Target Cellular Signaling Pathways: Regulated Gene Expression and Reduced Toxicity

Division of Molecular Pharmaceutics, University of North Carolina School of Pharmacy, Chapel Hill, North Carolina (F.L., C.C.C., L.M.S., L.H.); Duke University Medical Center, Durham, North Carolina (X.Y.); and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (L.M.S.)

Advances in cell biology over the last several decades have allowed for a much greater understanding of the regulation of cellular processes. Many of these revelations have provided substantial details regarding the key players in cellular pathways and the role small-molecule ligands may play in controlling their function. Although much progress has been made in these areas, optimization of nonviral gene delivery vectors has not met with similar success. Many of the issues that have plagued the field, such as limited transgene activity, difficulty with specific cell targeting, inflammatory responses, and degradation of the vector, among others, continue to limit the efficacy of these delivery systems. In this study, we investigate several cellular pathways in an effort to develop more efficient nonviral vectors. To increase nuclear uptake of the transgene, we explored the use of nuclear localization sequences (NLS) incorporated into our plasmid. The results indicated that the NLS did significantly increase gene expression under several circumstances in the presence of small-molecule ligands, as indicated by both in vitro and in vivo studies. Furthermore, to decrease inflammatory response to the vectors, additional studies were performed to demonstrate that the incorporation of free anti-inflammatory ligands into liposome formulations does not affect transgene activity but is able to significantly decrease the inflammatory response. Overall, these examples provide hope that free ligand can be used to effectively mediate cellular processes to overcome some of the obstacles limiting the success of gene therapy.

Address correspondence to: Dr. Feng Liu, Division of Molecular Pharmaceutics, University of North Carolina School of Pharmacy, 1318 Kerr Hall, CB 7360, Chapel Hill, NC 27599-7360. E-mail: fliu{at}email.unc.edu