Activated factor X delivered by adeno-associated virus significantly inhibited bleeding and alleviated hemophilic synovitis in hemophilic mice

IF 4.6 3区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Gene Therapy Pub Date : 2024-09-10 DOI:10.1038/s41434-024-00479-5

Feixu Zhang, Xinyue Zhou, Baolai Hua, Xinyi He, Zhanao Li, Xiao Xiao, Xia Wu

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Abstract

In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and restore coagulation in hemophilia patients. In this study, the cassettes that expressed FXa, FXaop and FXa-FVII were packaged into an engineered AAV capsid, AAV843, and were delivered into hemophilia A and B mice by intravenous injection. AAV-FXaop could be stably expressed in vivo and showed the best immediate and prolonged hemostatic effects, similar to those of commercial drugs (Xyntha and Benefix). AAV-FXaop also significantly inhibited bleeding in hemophilia A mice with inhibitors. In addition, FXa expression in joints significantly alleviated the occurrence of hemophilic synovitis. AAV-delivered FXa may be a novel target for treating hemophilic and hemophilic synovitis.

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通过腺相关病毒递送的活化 X 因子可显著抑制血友病小鼠出血并缓解血友病滑膜炎

在血友病患者中，因子 VIII 或 IX 的缺乏会阻止共同凝血途径的激活，并抑制 FX 向活化的 FXa 的转化，而活化的 FXa 是凝血酶生成所必需的。我们假设，直接表达的 FXa 有可能激活血友病患者的共同凝血途径并恢复凝血功能。在这项研究中，我们将表达 FXa、FXaop 和 FXa-FVII 的基因盒打包到一个工程化的 AAV 胶囊 AAV843 中，并通过静脉注射将其输送到 A 型和 B 型血友病小鼠体内。AAV-FXaop 可在体内稳定表达，并显示出最佳的即时和持久止血效果，与商业药物（Xyntha 和 Benefix）的止血效果相似。AAV-FXaop还能显著抑制A型血友病小鼠在抑制剂作用下的出血。此外，在关节中表达 FXa 能明显缓解血友病滑膜炎的发生。AAV递送的FXa可能是治疗血友病和血友病滑膜炎的新靶点。

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来源期刊

Gene Therapy 医学-生化与分子生物学

CiteScore

9.70

自引率

2.00%

发文量

审稿时长

4-8 weeks

期刊介绍： Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.