Jared Beyersdorf

BME PhD Thesis Proposal Presentation

Date: February 16th

Time: 4:00 – 5:30 pm (EST)

Link: https://bluejeans.com/4450273439

Advisor:

Philip Santangelo, PhD

BME, Georgia Institute of Technology

Committee Members:

Krishnendu Roy, PhD

BME, Georgia Institute of Technology

Wilbur Lam, MD/PhD

BME, Georgia Institute of Technology

Department of Pediatrics, Emory University

James Dahlman, PhD    

BME, Georgia Institute of Technology

Joseph Schoeniger, MD/PhD

Department of Systems Biology, Sandia National Laboratories

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 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, we will develop mRNA-based strategies to prophylactically overexpress BChE for nerve agent protection. This proposal aims to 1) develop direct mRNA and gene activation approaches to maximize the secretion of functional BCHE protein in human in vitro systems and mouse models, 2) characterize LNP formulations for RNA loading and patterns of transfection in vivo, and 3) utilize an RNA-based prophylactic to protect mice from lethal nerve agent intoxication. By completing these aims, we will provide the first mRNA-based demonstration of nerve agent protection and improve current understanding of mRNA-based protein therapies.