David Dean, Ph.D.
Despite all of the hype regarding gene therapy, at present, gene therapy is a dream due to insufficient levels of gene transfer and expression at desired sites. One way to increase gene expression is to target more DNA to the cell nucleus. Since the nucleus is the site of transcription, without the movement of plasmids through the cytoplasm, translocation into the nucleus, and localization to the appropriate subnuclear domain, no gene expression, or "gene therapy" can take place. Ongoing projects in my laboratory are studying the mechanisms of cytoplasmic trafficking of plasmids along the cytoskeleton, plasmid nuclear entry, subnuclear organization, and exploiting what we learn to improve gene therapy. The Dean laboratory has shown that plasmids are able to enter the nucleus in a sequence-specific manner that appears to be mediated by transcription factor binding. They are interested in identifying the proteins required for this activity and the regulation of their nuclear import and are working to expand our repertoire to selectively target expression to any desired cell or tissue. They are also developing methods for extracellular delivery of non-viral vectors in animal models for disease. We have used this approach to prevent and/or cure existing disease in models of acute lung injury and asthma.