Translating Gene Therapy for Lung Injury from the Cell to the ICU
Thursday, February 23, 2017
12:00 pm - 1:00 pm
Fitzpatrick Center Schiciano Auditorium Side B
Daivd Dean, Ph.D., Professor, Pediatrics and Biomedial Engineering, University of Rochester
Abstract:Once DNA enters the cell by any method, a number of barriers must be overcome in order for any transgene expression to occur. We have spent a number of years characterizing the events and mechanisms of plasmid intracellular trafficking with focus on movement through the cytoplasm, into the nucleus, and within the nucleus. We have also investigated whether and how these mechanisms contribute to effective gene transfer and expression. Based on these studies, we have developed several novel approaches to increase gene transfer in vitro and in vivo as well as to confer cell-specificity. These include the use of DNA nuclear targeting sequences to promote nuclear entry of plasmid-DNA complexes, the use of DNA sequences to promote formation of protein-DNA complexes that bind to molecular motors for movement along microtubules, modulation of microtubule post-translational modification to enhance movement of plasmids to the nucleus, and methods for cell entry of the DNA. I will discuss some of these approaches and their exploitation for development of an electroporation-based gene therapy treatment for acute lung injury, a disease with a current mortality of around 30% that kills approximately 75,000 people yearly in the US. This disease results from a number of different stimuli, all of which induce significant inflammation in the lung, breakdown of the alveolar-capillary permeability barrier, accumulation of pulmonary edema, and ultimately reduced gas exchange.