PhD Defense by Kalina Paunovska

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  • Date/Time:
    • Wednesday May 6, 2020
      1:00 pm - 3:00 pm
  • Location: REMOTE: BLUE JEANS
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Summary Sentence: An investigation of parameters that influence non-hepatocyte RNA delivery in vivo

Full Summary: No summary paragraph submitted.

Kalina Paunovska

BME PhD Thesis Defense

 

Date: May 6th, 2020

Time: 1:00 PM

Bluejeans: https://bluejeans.com/385189433

 

Committee Members:

 

James E. Dahlman, Ph.D. (Advisor)

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University

 

Andres Garcia, Ph.D.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University

 

Philip J. Santangelo, Ph.D.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University

 

Edward Botchwey, Ph.D.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University

 

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 it a promising way to treat disease. However, clinically relevant delivery of RNA therapeutics to non-hepatocytes in vivo remains challenging. Most LNPs are created by mixing an ionizable lipid with PEG, a phospholipid, and cholesterol, allowing the possibility for 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. However, because LNPs that tend to work in vitro do not necessarily work in vivo, this often leads to a small number of viable candidates. The objective of this thesis is to use high-throughput DNA barcoding to ask fundamental questions about in vivo drug delivery. In particular, this work presents four significant contributions to the field of nucleic acid delivery. First, this work explores in vitro and in vivo LNP delivery in many cell types (e.g. endothelial, macrophage) from many tissues (e.g. heart, lung, bone marrow) and reveals that in vitro LNP delivery is not predictive of in vivo delivery. Second, cholesterol structure – a previously unperturbed LNP component – is found to impact LNP delivery in vivo. Cholesterol variants are naturally trafficked in lipoproteins (e.g. LDL, VLDL) suggesting that LNP targeting can be tuned by using naturally- or synthetically-derived cholesterol variants. Third, LNPs that deliver RNA to non-hepatocytes more efficiently than to hepatocytes are identified. Fourth, manipulating cell metabolism through exogenous administration of a small molecule is found to impact LNP-delivered mRNA translation in vivo. Finally, the potential for related works and new directions worthy of pursuit within the field nucleic acid drug delivery are discussed. Taken together, this work enables understanding and optimization of the factors that influence non-hepatocyte RNA delivery in vivo.   

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Phd Defense
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  • Created By: Tatianna Richardson
  • Workflow Status: Published
  • Created On: Apr 10, 2020 - 11:26am
  • Last Updated: Apr 10, 2020 - 11:26am