Nusaiba Baker
PhD Proposal Presentation

Date: December 12, 2018
Time: 2 PM
Location: Emerson 401, Emory University Department of Chemistry

Committee Members:
Khalid Salaita, PhD (Emory University, Department of Chemistry) (Advisor)
Andrew Neish, MD (Emory University School of Medicine, Department of Pathology)

Julie Champion, PhD (Georgia Institute of Technology, Chemical and Biomolecular Engineering)

Gabe Kwong, PhD (Georgia Institute of Technology, Biomedical Engineering)

Ed Botchwey, PhD (Georgia Institute of Technology, Biomedical Engineering)

Title: Developing nanoparticle-based immune modifiers for the treatment of Th2-mediated disease: GATA3 inhibitors as therapeutics for asthma and ulcerative colitis

Abstract: Chronic inflammatory diseases, including allergic and autoimmune disorders, have common pathogenic features of immune dysregulation. These disorders present high burdens to patients due to debilitating illness, high costs for medication, and increased risk of mortality. Current treatments, including small molecule inhibitors and steroids, are often administered systemically by injection, thus reducing patient compliance and carrying undesired side effects. As such, identifying novel therapeutics that can be delivered to the site of inflammation is an area of active interest.

A main cause of inflammatory symptoms is the release of cytokines by circulating immune cells, such as the T helper 2 (Th2) subtype of T-cells. This aberrant production of cytokines underlies the inappropriate immune response found in inflammatory disorders. GATA3 is a transcription factor that is a major player in Th2 differentiation and activation and has been found to be upregulated in biopsies and serum from patients with inflammatory diseases. Rodent studies and phase I human trials in asthma showed that targeting GATA3 attenuated the early and late asthmatic response and improvement in airway function. Further, a recent study identified the role of GATA3 in ulcerative colitis (UC), highlighting the potential of novel therapeutics that target this pathway.

Therefore, this proposal aims to suppress GATA3 using a DNA enzyme (Dz) nanoparticle conjugate. This Dz specifically targets and degrades the GATA3 mRNA transcript in the cell cytoplasm, thereby inhibiting gene expression and alleviating inflammatory symptoms. Our lab has shown that conjugating Dzs to a gold nanoparticle significantly improves delivery and cellular uptake. Using an algorithm designed in our lab to optimize Dz sequences, we have created a GATA3 DzNP for the modulation of inflammation in diseases like asthma and ulcerative colitis. Our central hypothesis is that DzNPs are an effective method of regulating intracellular GATA3, leading to reduction of Th2-specific cytokines. Herein, I will investigate nanoparticle-based inhibition of GATA3 via two aims: (1) I will investigate DzNP-mediated GATA3 regulation in a Th2 asthma model. (2) I will establish the efficacy of orally delivered GATA3 DzNP using an alginate hydrogel delivery method in a mouse model of colitis. This technology has broad applications, as DzNP technology can be modified and applied to numerous aberrant disease signals. This work opens the door to targeting additional targets and signals within the immune system and provides enhanced insight to the role of key players in inflammatory disease.