Endothelial siRNA delivery in nonhuman primates using ionizable low–molecular weight polymeric nanoparticles
Name
eaar8409.full.pdf
Description
Published version
Size
2.24 MB
Format
Adobe PDF
Checksum (MD5)
a9f09453af2fa744e7a4f6179804e0fb
Author(s)
Khan, Omar Fizal
Doloff, Joshua C
Tsosie, Jonathan
Bakthavatchalu, Vasudevan
Bodi Winn, Caroline M
Haupt, Jennifer
Jamiel, Morgan
Langer, Robert S
Anderson, Daniel Griffith
Kowalski, Piotr S
Date Issued
June 2018
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Khan, Omar F. et al. "Endothelial siRNA delivery in nonhuman primates using ionizable low–molecular weight polymeric nanoparticles." Science Advances 4, 6 (June 2018): eaar8409 © 2018 The Authors
Version
Final published version
Abstract
Dysfunctional endothelial cells contribute to the pathophysiology of many diseases, including vascular disease, stroke, hypertension, atherosclerosis, organ failure, diabetes, retinopathy, and cancer. Toward the goal of creating a new RNA-based therapy to correct aberrant endothelial cell gene expression in humans, efficient gene silencing in the endothelium of nonhuman primates was achieved by delivering small interfering RNA (siRNA) with 7C1, a low–molecular weight, ionizable polymer that forms nanoparticles. After a single intravenous administration of 1 mg of siRNA per kilogram of animal, 7C1 nanoparticles delivering Tie2 siRNA caused Tie2 mRNA levels to decrease by approximately 80% in the endothelium of the lung. Significant decreases in Tie2 mRNA were also found in the heart, retina, kidney, pancreas, and bone. Blood chemistry and liver function analysis before and after treatment all showed protein and enzyme concentrations within the normal reference ranges. Furthermore, after controlling for siRNA-specific effects, no significant increases in inflammatory cytokine concentrations were found in the serum. Similarly, no gross lesions or significant underlying pathologies were observed after histological examination of nonhuman primate tissues. This study is the first demonstration of endothelial gene silencing in multiple nonhuman primate organs using systemically administered siRNA nanoparticles and highlights the potential of this approach for the treatment of disease in humans.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/SCIADV.AAR8409
