Induced Pluripotent Stem Cells Reveal Functional Differences Between Drugs Currently Investigated in Patients With Hutchinson-Gilford Progeria Syndrome
Induced Pluripotent Stem Cells Reveal Functional Differences Between Drugs Currently Investigated in Patients With Hutchinson-Gilford Progeria Syndrome
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DOI：
10.5966/sctm.2013-0168
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发表时间：
2014-04-01
影响因子：
6
通讯作者：
Nissan, Xavier
中科院分区：
文献类型：
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作者：
Blondel, Sophie;Jaskowiak, Anne-Laure;Nissan, Xavier
Hutchinson-Gilford早衰症是一种罕见的先天性疾病，其特征是儿童过早衰老。对突变和相关分子机制的鉴定迅速导致了独立的临床试验，这些试验测试了不同的市售药物，并在临床前记录了对这些机制的影响。然而，这些药物的广泛的功能作用基本上仍未被探索。我们已经进行了一项系统的比较研究，目前管理或提出的三种主要治疗方法，即，法尼基转移酶抑制剂，氨基二膦酸盐和他汀类药物（唑来膦酸和普伐他汀）的组合，以及大环内酯类抗生素雷帕霉素。这项工作是基于这样的假设，即中胚层干细胞，这是来自哈钦森-吉尔福德早衰综合征诱导的多能干细胞表达与疾病相关的主要缺陷，可能有助于揭示这种影响。尽管所有三种治疗均显著改善了通常与早衰症相关的畸形细胞核，但在前层蛋白A法尼基化、早老蛋白表达、缺陷性细胞增殖、过早成骨分化和ATP产生的功能改善方面观察到差异。最后，我们评估了不同药物组合对该细胞模型的影响。这项研究表明，与单一药物治疗相比，没有额外的益处，而系统地观察到与单独法尼基转移酶抑制剂相当的细胞抑制作用。总之，这些结果揭示了不同药物的作用模式的复杂性，即使它们是基于类似的机制假设选择的，并强调使用诱导多能干细胞衍生物作为标准化比较药理学研究的关键和强大的工具。
Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.