Hemophilia B is an X-linked recessive bleeding disorder caused by abnormalities in the coagulation factor IX gene. Without prophylactic treatment, patients experience frequent spontaneous bleeding episodes. Well-characterized animal models are valuable for determining the pathobiology of the disease and testing novel therapeutic innovations. Here, we generated a porcine model of hemophilia B using a combination of CRISPR/Cas9 and somatic cell nuclear transfer. Moreover, we tested the possibility of hemophilia B therapy by gene insertion. Frequent spontaneous joint bleeding episodes that occurred in hemophilia B pigs allowed a thorough investigation of the pathological process of hemophilic arthropathy. In contrast to the hemophilia B pigs, which showed a severe bleeding tendency and joint damage, the transgenic pigs carrying human coagulation factor IX exhibited a partial improvement of bleeding. In summary, this study not only offers a translational hemophilia B model for exploring the pathological process of hemophilic arthropathy but also provides a possibility for the permanent correction of hemophilia in the future by genome editing in situ.

译文

:B型血友病是由凝血因子IX基因异常引起的X连锁隐性出血性疾病。如果不进行预防性治疗,患者会经历频繁的自发性出血发作。表征良好的动物模型对于确定疾病的病理生物学和测试新颖的治疗创新非常有价值。在这里,我们使用CRISPR / Cas9和体细胞核转移的组合生成了血友病B的猪模型。此外,我们通过基因插入测试了血友病B治疗的可能性。 B型血友病猪中频繁发生的自发性关节出血事件使对血友病性关节炎的病理过程进行了彻底的研究。与表现出严重的出血倾向和关节损伤的血友病B猪相反,携带人凝血因子IX的转基因猪表现出部分出血改善。总而言之,这项研究不仅为探讨血友病性关节炎的病理过程提供了一种转化型血友病B模型,而且还为将来通过原位基因组编辑对血友病进行永久性校正提供了可能性。

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