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 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.
Highlights
Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening blood disorder characterized with clinical features such as thrombocytopenia, hemolytic anemia, fever, and multi-organ dysfunction
We demonstrate that the ADAMTS13-M5 variant, which is not neutralized by autoantibodies, can be secreted and has greater enzymatic activity than ADAMTS13-wild type (WT) in mice
It is observed that rhADAMTS13 with the expected molecular weight was detected in both the cell lysates and culture medium from the cells transfected with the ADAMTS13-encoding constructs, suggesting that the mRNA expressed and secreted rhADAMTS13 (Fig. 1A)
Summary
Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening blood disorder characterized with clinical features such as thrombocytopenia, hemolytic anemia, fever, and multi-organ dysfunction. The underlying pathological mechanism that causes TTP has been identified as a severe deficit (
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