Nonviral Gene Therapy: The Promise of Genes as Pharmaceutical Products

Although most research on gene therapy has focused on the use of recombinant viruses to deliver genes to cells in vivo, progress also has been made toward developing nonviral, pharmaceutical formulations of genes for in vivo human therapy. Various methods for nonviral gene therapy have been proposed. Some approaches are aimed at developing “artificial viruses” that attempt to mimic the process of viral infection using synthetic materials. Others apply the theory and methods of advanced, particulate drug delivery to deliver DNA to select somatic targets. These approaches employ DNA complexes containing lipid, protein, peptide, or polymeric carriers as well as ligands capable of targeting the DNA complex to cell-surface receptors on the target cell and ligands for directing the intracellular trafficking of DNA to the nucleus. Nonviral systems have been used to deliver genes to the lung, liver, endothelium, epithelium, and tumor cells and have been shown to be generally safe. More than a dozen clinical trials are currently underway using nonviral systems for disease indications including cystic fibrosis and cancer. Future advances in nonviral systems will be based on an emerging appreciation of the biological constraints on the fate and function of DNA within the body and within the cell. The promise of nonviral gene therapy is that therapeutic products can be developed that exploit the therapeutic potential of genes, but resemble conventional pharmaceutical products in terms of their composition, characterization, safety, and clinical application. Diverse methods for nonviral gene therapy are being developed based on principles of advanced drug delivery. Preclinical studies, and more than a dozen clinical studies currently underway, confirm the potential of nonviral methods for in vivo gene therapy and illustrate approaches for developing effective clinical products.