mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice
| Autor: | Susan Liu-Chen, Lei Cheng, Zhaozhong Han, Brendan Connolly, Romesh R. Subramanian |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Thrombotic thrombocytopenic purpura lcsh:Medicine ADAMTS13 Protein Pharmacology Article law.invention 03 medical and health sciences Mice law hemic and lymphatic diseases medicine Animals Humans RNA Messenger lcsh:Science Autoantibodies Mice Knockout Messenger RNA Drug Carriers Multidisciplinary Purpura Thrombotic Thrombocytopenic business.industry HEK 293 cells lcsh:R Autoantibody Enzyme replacement therapy Genetic Therapy medicine.disease Lipids ADAMTS13 030104 developmental biology HEK293 Cells Liver Mutagenesis Recombinant DNA Hepatic stellate cell Nanoparticles lcsh:Q business |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-9 (2018) |
| ISSN: | 2045-2322 |
| Popis: | 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 hADAMTS13 at or above therapeutically relevant levels in mice for up to five days. This proof-of-concept study suggests that mRNA therapy could provide a novel approach for TTP treatment. |
| Databáze: | OpenAIRE |
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