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Kalina Paunovska
PhD Proposal Presentation
Date: February 4th, 2018
Time: 2:00 PM
Location: IBB Suddath Seminar Room (1128)
Committee Members:
Advisor: James E. Dahlman, Ph.D. Wallace H. Coulter Department of Biomedical Engineering
Andres Garcia, Ph.D. George W. Woodruff School of Mechanical Engineering
Philip J. Santangelo, Ph.D. Wallace H. Coulter Department of Biomedical Engineering
Edward Botchwey, Ph.D. Wallace H. Coulter Department of Biomedical Engineering
Julie Champion, Ph.D. Department of Chemical and Biomolecular Engineering, Georgia Institute of Technology
Title: An investigation of parameters that influence non-hepatocyte RNA delivery in vivo
Abstract: Lipid nanoparticle (LNP)-mediated nucleic acid delivery can regulate the expression of any gene, making this approach a promising way to treat disease. However, clinically relevant delivery of RNA therapies to non-hepatocytes in vivo remains challenging.Most LNPs are created by mixing an ionizable lipid with PEG, a phospholipid, and cholesterol, making it possible to create thousands of chemically distinct LNPs. These nanoparticles are typically screened in vitro in easily expandable cell lines, yet these cell culture conditions are not representative of in vivo tissue microenvironments. LNPs that deliver their payload (e.g. DNA, RNA) successfully in vitro are then validated in vivo. This leads to a small number of viable candidates as particles that tend to work in vitro do not necessarily work in vivo.The objective of this proposal is to use high-throughput DNA barcoding to ask fundamental questions about in vivo drug delivery. In particular, we will make 4 significant contributions to the field of nucleic acid delivery. First, we will test whether in vitro LNP delivery is predictive of in vivoLNP delivery. We will test this effect in many cell types (i.e. endothelial, macrophage) from many tissues (i.e. heart, lung, bone marrow). Second, we will investigate whether cholesterol structure – a previously unperturbed LNP component – can impact LNP delivery in vivo. Cholesterol variants are naturally trafficked in lipoproteins (i.e. LDL, VLDL) suggesting that LNP targeting can be tuned by using naturally- or synthetically-derived cholesterol variants. Third, we will identify LNPs that deliver RNA to non-hepatocytes more efficiently than to hepatocytes. Fourth, we will develop and optimize a novel functional LNP screening platform that is independent of the cell type being targeted or the mouse model being used. This will allow us to perform screens and LNP validation studies in transgenic mice so that we can understand the impact of particular genes on LNP trafficking and nucleic acid delivery. Taken together, this work will enable both the understanding and optimization of factors that influence non-hepatocyte RNA delivery in vivo.
