对威尔逊病的AAV8-tATP7B载体进行临床前药理和毒理研究
Zixuan Wang1, Mengyu Wang1, Mengyuan Wu1
1Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clinical and molecular hepatology
|March 4, 2026
概括
使用AAV8-tATP7B的新型基因疗法通过恢复铜代谢,对威尔逊病 (WD) 显示出前景. 这种治疗在动物模型中显示出有效性和良好的安全性,为人类临床试验铺平了道路.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 威尔逊病 (WD) 是一种遗传性疾病,由于ATP7B基因的突变,影响铜代谢.
- 目前对WD的治疗方法可以控制症状,但不能解决潜在的遗传原因.
- 需要有效的基因疗法来纠正WD中的铜代谢缺陷.
研究的目的:
- 开发和评估一种新的腺相关病毒血清型8 (AAV8) 基因疗法载体,携带针对威尔逊病的截断ATP7B基因 (AAV8-tATP7B).
- 评估AAV8-tATP7B在恢复WD动物模型中的铜平衡和肝功能方面的疗效.
- 在临床前毒性研究中确定AAV8-tATP7B的安全性和最大耐受剂量.
主要方法:
- 构建编码为子优化的全长或截断的ATP7B (tATP7B) 基因的AAV8载体,使用肝脏特异性促进体.
- 在HepG2细胞中体外评估载体表达和铜出口活动.
- 在体内对Atp7b-/-小鼠的疗效研究以及对斯普拉格-道利大鼠和Cynomolgus的毒性评估.
主要成果:
- 截断的ATP7B (tATP7B) 在体外显示出更高的表达效率和可比的铜出口活动,而不是全长的ATP7B.
- 在Atp7b-/-小鼠中AAV8-tATP7B治疗以剂量依赖的方式恢复了铜恒温和肝功能,扭转了肝损伤.
- 毒性研究表明,在老鼠和子中没有系统性毒性,在子中观察到高剂量的可逆性肝脏变化,确定6×1013vg/kg作为最大耐受剂量.
结论:
- 在威尔逊病的临床前模型中,AAV8-tATP7B基因治疗载体有效地纠正铜代谢缺陷和肝功能障碍.
- AAV8-tATP7B显示出有前途的安全性概况,支持其在WD患者中临床应用的潜力.
- 这些发现为治疗威尔逊病的AAV8-tATP7B的临床转化提供了强有力的理由.
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