mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice
Open accessAbstract
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.
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mRNA-based protein replacement therapies have been applied to haematological diseases, central nervous system disorders, skin diseases and hearing loss in preclinical studies.
“In addition, mRNA-based protein replacement therapies have been applied to haematological diseases (for example, haemophilia A232, haemophilia B91,104,233 and thrombotic thrombocytopaenic purpura234), central nervous system disorders67,152 (for example, Friedreich’s ataxia67), skin diseases235,236 (for example, elastin deficiency235) and hearing loss237 in preclinical”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [234]
The therapeutic level of hADAMTS13 was maintained for up to five days, significantly longer than the 24-hour half-life of recombinant human ADAMTS13 protein.
“Furthermore, therapeutic level was maintained for up to five days, which was significantly longer than the half-life (24 hours) of the recombinant human ADAMTS13 (rhADAMTS13) protein.[170]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [170]
One-time tail vein injection of formulated hADAMTS13 mRNA induced a therapeutic level of hADAMTS13 (140 ng/mL at 24 h, 90 ng/mL at 48 h) in ADAMTS13-deficient mice.
“One-time tail vein injection of formulated human ADAMTS13 (hADAMTS13) mRNA induced a therapeutic level of hADAMTS13 (140 ng/mL in the circulation at 24 h, and 90 ng/mL at 48 h) in ADAMTS13-deficient mice.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [170]
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[Advances in the treatment of thrombotic thrombocytopenic purpura].
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- Authors
- Liu-Chen, S., Connolly, B., Cheng, L., Subramanian, R. R., & Han, Z.
- Affiliations
- Alexion Pharmaceuticals (United States) (US)
- Corresponding author
- Subramanian, Romesh R.
- Venue
- Scientific Reports
- Published
- 2018-05-18
- Volume
- 8
- Issue
- 1
- Pages
- 7859-7859
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5959889
- OpenAlex
- W2803761088
- Cited by
- 20
- References
- 35
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 2
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- ADAMTS13, thrombotic thrombocytopenic purpura, mRNA therapeutics, enzyme replacement therapy, liver-targeted drug delivery, lipid nanoparticles, recombinant ADAMTS13
- MeSH terms
- ADAMTS13 Protein, Animals, Autoantibodies, Drug Carriers, Humans, Lipids, Liver, Purpura, Thrombotic Thrombocytopenic, RNA, Messenger, Genetic Therapy, Mutagenesis, Mice, Knockout, Mice, Nanoparticles, HEK293 Cells
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