Delivery of Macromolecular Therapeutics: Tackling a Billion Year Old Barrier
Presenter: Steven Dowdy (UCSD School of Medicine)
Date: December 17, 2019
All macromolecular therapeutics, including ASOs, siRNAs, peptides, proteins, CRISPR, mRNA and non-viral DNA vectors, are taken up into cells by endocytosis. However, <1% to none of the endocytosed therapeutic cargo escapes into the cytoplasm and nucleus of the cell. Thus, for all macromolecular therapeutics, endosomal escape remains the rate-limiting delivery step that prevents their effective use to treat cancer, pandemic influenza, and other diseases. Our research is focused on addressing this problem by developing new chemistry to synthesize novel universal endosomal escape domains (uEEDs) with the goal of enhancing endosomal escape of macromolecular therapeutics by 10- to 100-fold in the absence of toxicity.
Recording of the webinar: Click play to view
- Overcoming cellular barriers for RNA therapeutics.
Nat Biotechnol. 2017 Mar;35(3):222-229.
- The chemical evolution of oligonucleotide therapies of clinical utility.
Khvorova A, Watts JK.
Nat Biotechnol. 2017 Mar;35(3):238-248.
- Intracellular Trafficking and Endosomal Release of Oligonucleotides: What We Know and What We Don’t.
Nucleic Acid Ther. 2018 Jun;28(3):166-177.
- RNA Therapeutics (Almost) Comes of Age: Targeting, Delivery and Endosomal Escape.
Dowdy SF, Levy M.
Nucleic Acid Ther. 2018 Jun;28(3):107-108.
- and this special issue of Nucleic Acid Therapeutics:
Relevant Dowdy Lab Research:
- Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications.
Meade BR, Gogoi K, Hamil AS, Palm-Apergi C, van den Berg A, Hagopian JC, Springer AD, Eguchi A, Kacsinta AD, Dowdy CF, Presente A, Lönn P, Kaulich M, Yoshioka N, Gros E, Cui XS, Dowdy SF.
Nat Biotechnol. 2014 Dec;32(12):1256-61.
- Enhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics.
Lönn P, Kacsinta AD, Cui XS, Hamil AS, Kaulich M, Gogoi K, Dowdy SF.
Sci Rep. 2016 Sep 8;6:32301.
- Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase.
Huggins IJ, Medina CA, Springer AD, van den Berg A, Jadhav S, Cui X, Dowdy SF.
Molecules. 2019 Sep 10;24(18). pii: E3287.
Dr. Dowdy is a cancer biologist, specializing in RNAi therapeutics and G1 cell cycle control. He received his PhD in Molecular Genetics from UC Irvine with Eric Stanbridge (1990) working on tumor suppressor genes and performed his postdoctoral fellowship with Bob Weinberg at MIT working on the biochemistry of the Rb tumor suppressor gene (1990-1994). From 1994-2001, He was an Assistant Professor at Washington University School of Medicine. In 2001, He moved his lab to UCSD School of Medicine, where he is a Professor in the Dept. of Cellular & Molecular Medicine. He was a Howard Hughes Medical Institute Investigator for 18 years (1994-2012). Dr. Dowdy’s lab developed the synthesis of RNAi triggers containing neutral, bioreversible phosphotriester groups to increase stability and deliverability. He serves/has served on Science Advisory Boards for biotechs, pharmas and non-profit institutes. He is currently a co-founder and Board Director of Solstice Biologics, an RNAi biotech.