Ferraresso Francesca, Skaer Chad W, Badior Katherine, Pulente Serena M, Paul Manoj, Ketelboeter Laura, Chen Taylor H S, Cullis Pieter R, Gupta Sweta, Shapiro Amy, Mulvihill Erin E, Kastrup Christian J
Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Mol Ther Methods Clin Dev. 2025 Aug 12;33(3):101557. doi: 10.1016/j.omtm.2025.101557. eCollection 2025 Sep 11.
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 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 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 . In WT mice, plasma PAI-1 levels increased in a dose-dependent manner between 0.1 and 1 mg of mRNA per kg of body weight, peaking at 6 h post-injection and returning to baseline by 48 h. 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 preventive therapy for bleeding and cardiac fibrosis for PAI-1-deficient patients.
纤溶酶原激活物抑制剂-1（PAI-1）缺乏症是一种罕见的疾病，由该基因突变导致，会引起中度至重度出血和心脏纤维化，且循环中检测不到PAI-1蛋白。目前尚无能够有效替代PAI-1的疗法，因为该蛋白半衰期较短。使用重组蛋白的替代方法是利用mRNA疗法内源性提高循环PAI-1水平。通过脂质纳米颗粒（mPAI-1）将编码PAI-1的mRNA递送至肝脏（PAI-1合成的主要部位）是提高循环PAI-1蛋白的一种潜在方法。在此，我们研发了mPAI-1，静脉注射后可诱导PAI-1表达。在野生型（WT）小鼠和PAI-1基因敲除小鼠中，mPAI-1诱导产生超生理水平的循环PAI-1，并在检测时抑制纤维蛋白溶解。在WT小鼠中，血浆PAI-1水平在每千克体重0.1至1毫克mRNA之间呈剂量依赖性增加，在注射后6小时达到峰值，并在48小时恢复至基线水平。在同一小鼠中重复注射mPAI-1后，PAI-1持续产生。使用基于mRNA的方法表达PAI-1有可能成为PAI-1缺乏症患者出血和心脏纤维化的预防性治疗方法。
