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Reversing PAI-1 deficiency in blood using mRNA lipid nanoparticles
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DOI：10.1016/j.omtm.2025.101557.png)
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Abstract
En 中文
Plasminogen activator inhibitor-1 (PAI-1) deficiency is a rare disorder that causes moderate to severe bleeding and cardiac fibrosis, caused by mutation in the SERPINE-1 gene and no detectable circulating PAI-1 protein. There are currently no therapies that can effectively replace PAI-1 because the protein has a short half-life. An alternative approach to using recombinant protein is to endogenously increase circulating PAI-1 levels using mRNA therapy. Delivering mRNA encoding PAI-1 to the liver, a major site of PAI-1 synthesis, using lipid nanoparticles (mPAI-1) is a potential approach to increase circulating PAI-1 protein. Here, we developed mPAI-1, which induced expression of PAI-1 in vivo upon intravenous administration. In both wild type (WT) mice and PAI-1 knockout mice, mPAI-1 induced supraphysiological circulating PAI-1 and inhibited fibrinolysis when measured ex vivo. In WT mice, plasma PAI-1 levels increased in a dose-dependent manner between 0.1 to 1 mg of mRNA per kg of body weight, peaking at 6 hours post-injection and returning to baseline by 48 hours. There was consistent production of PAI-1 after repeat dosing of mPAI-1 in the same mice. Expression of PAI-1 using mRNA-based approaches has the potential to be a preventative therapy for bleeding and cardiac fibrosis for PAI-1 deficient patients.
Keywords:
PAI-1 deficiency
mRNA therapy
lipid nanoparticles
fibrinolysis
cardiac fibrosis
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