mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice

Scientific Reports
Susan Liu-ChenZhaozhong Han

Abstract

Thrombotic thrombocytopenic purpura (TTP) is primarily caused by deficiency of ADAMTS13 within the blood stream due to either genetic defects or presence of inhibitory autoantibodies. Preclinical and clinical studies suggest that enzyme replacement therapy with recombinant human ADAMTS13 protein (rhADAMTS13) is effective and safe in treatment of TTP. However, frequent dosing would be required due to the relatively short half-life of rhADAMTS13 in circulation as well as the presence of inhibitory autoantibodies that collectively result in the poor pharmacological profile of rhADAMTS13. With technical breakthroughs in exploring mRNA as therapeutics, we hypothesized that restoration of ADAMTS13 activity for a prolonged duration of time can be achieved through systemic dosing of mRNA, wherein the dosed mRNA would utilize hepatic cells as bioreactors for continuous production of ADAMTS13. To test this hypothesis, mRNA encoding human ADAMTS13 WT or an ADAMTS13 variant, that had demonstrated resistance to predominant clinical TTP autoantibodies, was formulated in lipid nano-particles for liver-targeted delivery. In both ADAMTS13-sufficient and -deficient mice, a single dose of the formulated mRNAs at 1 mg/kg resulted in expression of ...Continue Reading

References

Aug 16, 2002·Proceedings of the National Academy of Sciences of the United States of America·Koichi KokameYoshihiro Fujimura
May 5, 2006·The New England Journal of Medicine·James N George
Sep 5, 2009·The Journal of Biological Chemistry·Anthony N Vomund, Elaine M Majerus
Jan 27, 2011·The Journal of Clinical Investigation·Junmei ChenJosé A López
Mar 14, 2012·British Journal of Haematology·John ChapinJeffrey Laurence
Aug 13, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Norbert PardiDrew Weissman
Feb 11, 2016·The New England Journal of Medicine·Flora PeyvandiUNKNOWN TITAN Investigators
Jul 6, 2016·Journal of Thrombosis and Thrombolysis·Giulia Berti de MarinisAnna Maria Lombardi
Feb 6, 2017·Journal of Controlled Release : Official Journal of the Controlled Release Society·Maximilian UtzingerChristian Plank
Feb 17, 2017·Proceedings of the National Academy of Sciences of the United States of America·Suvasini RamaswamyInder M Verma
Feb 23, 2017·Cell·Justin M RichnerMichael S Diamond
Mar 4, 2017·Arteriosclerosis, Thrombosis, and Vascular Biology·Sebastien VerhenneKaren Vanhoorelbeke
Feb 14, 2018·Nucleic Acid Therapeutics·Jeremiah D FarelliRomesh R Subramanian
Mar 27, 2018·RNA Biology·Kirtika H AsraniJeffrey M Brown

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Citations

Oct 20, 2018·Cellular and Molecular Life Sciences : CMLS·Thomas SchlakeIngo Jordan
Jul 1, 2019·Biomaterials·Weiyu ZhaoYizhou Dong
Aug 17, 2021·Nature Reviews. Materials·Xucheng HouYizhou Dong
Apr 18, 2020·Molecular Therapy. Methods & Clinical Development·Nishat SultanaLior Zangi

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Methods Mentioned

BETA
glycosylation
transfection
electrophoresis
ELISA
fluorescence resonance
enzyme replacement therapy
Assay

Software Mentioned

GraphPad Prism
GraphPad

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