CAREER: Manipulating the Innate Immune Response to Improve Gene Therapy

Villanova University, Villanova PA

Investigators

Abstract

PI: Elmer, Jacob Proposal No: 1651837 The goal of this project is to improve gene therapy by identifying and modifying the genes involved in the immune response to extraneous DNA in several cancer cell lines. Such an approach is expected to enhance gene delivery by inhibiting the target genes with both small molecule inhibitors and inhibitor proteins. A somatic cell's first line of defense against viral infection is the innate immune response (IIR) consisting of several enzymes and receptors that actively seek out pathogenic molecules within the cell. Activation of the IIR by cytoplasmic DNA can then induces inflammation, inhibits protein translation, and even cause the host cell to self-destruct. While all of these reactions defend the cell from viruses, they can significantly hinder gene therapy. Indeed, most gene therapy treatments deliver therapeutic DNA to the cytoplasm, where it unintentionally activates the IIR. The goal of this project is to improve gene therapy by addressing this problem. We will begin by identifying the exact proteins and genes involved in the innate immune response to cytoplasmic DNA in a variety of cancer cell lines. Gene delivery will then be enhanced by inhibiting those genes/proteins with small molecule inhibitors and/or viral inhibitor proteins. As an alternative to inhibition of the IIR, transgene expression will be increased by using promoters that are known to be activated by the IIR. Altogether, these experiments will simultaneously improve gene therapy and increase our understanding of the innate immune response to cytoplasmic DNA. In addition, this project will also include a series of year-round outreach activities that will directly benefit the community. For example, the PI will organize an outreach program that enables underrepresented high school students to perform gene delivery and biochemical engineering experiments at Villanova. The PI will also create a summer research experience program for high school teachers that allows them to perform gene therapy experiments in the PI?s lab and then share those experiences with their classes in the fall semester. Finally, each of the experiments conducted in this project will also be recorded and used to create educational/training videos.