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Embryonic and induced pluripotent stem cells are excellent models for disease research because of their ability to self-renew and differentiate into most cell types. Somatic cells from a patient are isolated and reprogrammed into induced pluripotent stem cells or iPSCs. These iPSCs are later differentiated into the desired cell type, which mirrors the diseased cell of the patient. In this way, disease models have been created for investigating diseases such as Down syndrome, type I diabetes,...
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衰老模型用于分析药物诱导的前节律失常风险,使用心肌细胞与进发性病患者衍生诱导的多能干细胞区分开来.

Neil Daily1, Julian Elson1, Tetsuro Wakatsuki1

  • 1InvivoSciences Inc., Madison, WI 53719, USA.

International journal of molecular sciences
|August 12, 2023
PubMed
概括

哈森-吉尔福德孕症综合征 (HGPS) 患者衍生的心肌细胞显示出增加的前节律失常风险,模仿老年心脏细胞. 这一发现有助于通过改善临床前心脏安全评估,为老年人开发更安全的药物.

关键词:
这就是CiPA CiPA.哈森吉尔福德前列腺症综合征 (HGPS)在一个盘子里老化.心脏安全性心脏安全性逻辑回归的逻辑回归方法

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科学领域:

  • 心血管药理学心血管药理学
  • 干细胞生物学 干细胞生物学
  • 药物安全评估 药物安全评估

背景情况:

  • 药物诱导的前节律失常,特别是QT延长,是药物戒断的主要原因.
  • 临床前前节律失常的评估至关重要,特别是对于主要是药物消费者的老年人群.
  • 目前用于心脏安全查的"盘中老化"模型在获取方面面临重大挑战.

研究的目的:

  • 测试假设,来自Hutchinson-Gilford孕症综合征 (HGPS) 患者的心肌细胞 (CM) 可以建模老年CM表型.
  • 评估使用HGPS衍生的CMs与对照CMs相比,参考化合物的前节律失常风险.
  • 为了评估药物诱导的转移性 (CaT) 变化作为心脏刺激-收缩合的替代标记.

主要方法:

  • 从HGPS患者和健康对照中分化诱导多能干细胞 (iPSCs) 变成CMs.
  • 暴露于HGPS和控制CM的11个参考化合物,来自FDA的综合体外表表律失常试验 (CiPA).
  • 分析了药物诱导的瞬性 (CaT) 参数的变化,并应用了CiPA回归分析来对化合物进行分类.

主要成果:

  • 与对照CM (0.70 ± 0.05秒) 相比,进发性CMs表现出明显延长的CaT峰值持续时间 (0.98 ± 0.04秒).
  • 当暴露于参考化合物时,HGPS CMs在6个CaT参数中显示出更大的心律失常易感性.
  • 回归分析证实,与对照CM相比,前列腺CM的前节律失常敏感性更高,低风险化合物仍低于安全值.

结论:

  • 由HGPS衍生的CMs作为增加前节律失常敏感性的可行模型,模仿老年心脏细胞.
  • 该模型增强了临床前心脏安全评估,特别是针对老年人群的药物开发.
  • 需要进一步的研究来阐明潜在的机制,并通过更广泛的化合物集验证发现.