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Jared Beyersdorf
BME PhD Defense Presentation
Date:2022-04-11
Time: 3:30 - 5:00 pm
Location / Meeting Link: Georgia Tech, Whitaker Building, Room 1232; Zoom: https://zoom.us/j/93015220967?pwd=a3grRjNiRFB6c0h4K2NneHZ1WXlkQT09 Meeting ID: 930 1522 0967 Passcode: SgaN9a
Committee Members:
Philip Santangelo, PhD (Advisor); Krishnendu Roy, PhD; Wilbur Lam, MD, PhD; James Dahlman, PhD; Joseph Schoeniger, MD/PhD
Title: Development of an mRNA-based Prophylactic for Protection Against Nerve Agent Toxicity
Abstract: Nerve agents are toxic compounds that rapidly lead to cholinergic crisis in humans, leaving little time for medical intervention to prevent death. To overcome limitations with current medical interventions, protein bioscavengers of nerve agents, such as butyrylcholinesterase (BChE), have been developed. BChE circulates naturally in human plasma and binds to nerve agents before they can reach nerve synapses and induce toxicity. However, natural levels are too low to provide significant protection. Recombinant BChE has been shown to be effective in animals and safe in phase I clinical trials, but exceedingly high doses must be administered, which are expensive and difficult to manufacture. As an alternative approach, we developed mRNA-based strategies to prophylactically over express BChE protein for protection against nerve agent toxicity. In Aim 1, we developed an mRNA-based direct expression approach for secretion of tetrameric BChE protein in mice. In Aim 2, we developed an mRNA-based gene activation approach for programmable overexpression of specific endogenous genes in mice. In Aim 3, we utilized direct expression and gene activation approaches to overexpress BChE protein and identified areas for future optimization. The findings from this work can be directly applied to create an mRNA-based prophylactic against nerve agent toxicity and improve current understanding of mRNA-based protein therapies.
