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CBE Seminar: Jacob Elmer

Assistant Professor, Chemical Engineering, Villanova University
Thursday, March 22, 2018, 11:30 am
130 CBEC
151 W Woodruff Ave
Columbus, OH 43210

Overcoming Host Cell Defenses Against Gene Therapy

 

Abstract

Gene therapy could potentially cure many different genetic disorders (e.g. hemophilia, immunodeficiency, cancer, et al.), however, many of the clinical trials involving gene therapy have ultimately failed.  This lack of success may be due to one of the many host cell defense mechanisms that originally evolved to protect the cell from foreign viral genes.  Indeed, after DNA is delivered to target cells, it can be bound by cytosolic “DNA sensors” which trigger a kinase signaling cascade that ultimately leads to the translocation of transcription factors and the subsequent activation of several genes that may silence the foreign gene, halt protein expression inside the cell, or induce apoptosis.  In addition, even if the foreign gene evades these defenses and reaches the nucleus, it may still be silenced by epigenetic mechanisms.  In this seminar, several strategies to overcome these defenses will be discussed.   For example, we have identified several different components of these defense pathways (e.g. kinases and transcription factors) that are activated by the delivery of plasmid DNA to cells in vitro.  Inhibition of these enzymes with small molecule inhibitors dramatically increase the magnitude of transgene expression by up to 30-fold (with negligible effects on cell viability).  Alternatively, transgene expression may also be restored by inserting binding motifs for pioneering transcription factors (e.g. NF-Y or CTCF) that prevent epigenetic silencing of the transgene.  Altogether, these results show that eukaryotic cells have formidable defense mechanisms that must be considered when designing effective gene therapy treatments.

Bio

Dr. Elmer began his career by earning dual degrees in Chemical Engineering and Biological Sciences from the Missouri University of Science & Technology (formerly University of Missouri – Rolla) in 2007.  He then earned his Ph.D. from Ohio State University under the guidance of Dr. Andre F. Palmer in 2011 by completing a dissertation that focused on using recombinant and invertebrate hemoglobins as novel blood substitutes.  As a postdoc, he investigated multiple strategies to increase the efficiency of gene therapy treatments in the lab of Dr. Kaushal Rege at Arizona State University.  Dr. Elmer in currently continuing his gene therapy research as an Assistant Professor at Villanova University.  His research mainly focuses on elucidating and manipulating host cell (e.g. T cell) defenses that are activated by the foreign DNA used in gene therapy.

 

 

 

Tags: Seminar