The struggle to model muscular dystrophy.
The struggle to model muscular dystrophy.
复制标题
肌肉营养不良模型的斗争。
DOI：
10.1002/mus.22124
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发表时间：
2011
期刊：
影响因子：
3.4
通讯作者：
Kang,PeterB
中科院分区：
文献类型：
--
作者：
Kang,PeterB
人们对肌营养不良症新疗法进行前瞻性人体试验的兴趣越来越大，其中之一是由齐默尔曼和同事在本期杂志上总结的。[1]不幸的是，他们的研究结果令人失望，这项研究与其他研究结果相似。然而，该报告带来了宝贵的经验教训：（1）公布阴性结果很重要，特别是当发生意外不良事件时;（2）我们需要更多的预测方法来模拟肌营养不良症;（3）我们绝对必须继续尝试。齐默尔曼研究评价了喷替福林对17名杜氏肌营养不良症（DMD）男孩的治疗潜力。1喷替福林是一种抗炎剂，被发现可以改善mdx小鼠的营养不良表型。2然而，当用于人类受试者时，由于显著的不良反应，包括白细胞减少症，只有9人能够完成试验，这在以前没有报道过这种药物。这些结果值得注意，值得发表，以便其他研究人员知道不要进一步探索这一途径，并记录新的副作用。然而，这项研究再次提出了一个令人不安的问题，即为什么肌肉萎缩症的动物模型无法预测人类成功的新疗法。这个问题并不是肌营养不良症所独有的，但在这种疾病中尤其令人烦恼。DMD最常用的动物模型是天然存在的mdx小鼠，其在鼠抗肌萎缩蛋白的外显子23中具有无义突变。3-5 mdx小鼠DMD的表型比人类的表型轻。存在具有更严重表型的DMD的替代小鼠模型，包括具有组合的肌营养不良蛋白-肌营养不良蛋白缺陷的小鼠模型，7，8和具有人工产生的肌营养不良蛋白缺陷的其它小鼠模型，例如mdx 5cv小鼠，其在外显子10中具有由乙基亚硝基脲诱变产生的突变。9 mdx 5cv小鼠模型还具有比mdx模型具有更少的回复突变纤维的优点，使得在处理后更容易确定肌营养不良蛋白阳性纤维的来源。斑马鱼是一个较新的模型，用于研究肌肉萎缩症，它表达了许多基因参与肌肉萎缩症。10-12它在遗传学上比哺乳动物模型更远离人类，但它具有某些独特的优势。牠们的繁殖周期快，窝卵数大，因此可以一次在大量动物身上进行快速实验。因此，这些实验更适合于统计分析。此外，斑马鱼是半透明的，并且肌肉疾病在低倍显微镜下在活鱼中通常是明显的，无论是通过双折射模式还是通过它们的移动性。突变株13，14和吗啉抑制特定基因参与肌营养不良症11，15，16说明了这种模式的效用，斑马鱼已被用于大规模筛选潜在的药物治疗肌营养不良症。17. xmd金毛猎犬是DMD的自然发生的狗模型，具有引起外显子跳跃和肌营养不良蛋白表达完全缺乏的点突变。18，19 xmd狗的表型比小鼠模型更接近人类，但使用这些模型存在一些障碍，包括更高的成本和更长的生殖周期。从20世纪80年代末开始，在肌肉萎缩症动物模型与人类的治疗结果之间的不一致性一再出现。注射肌肉前体细胞成功诱导mdx小鼠20和人类21的肌营养不良蛋白表达，但临床结果...
There is increasing interest in conducting prospective human trials for novel therapies in muscular dystrophy, one of which is summarized by Zimmerman and colleagues in this issue of the journal. 1 Their findings are, unfortunately, disappointing, and the study joins others with similar results. However, the report carries valuable lessons:(1) it is important to publish negative results, especially when unexpected adverse events occur;(2) we need more predictive ways to model muscular dystrophy; and (3) we absolutely must keep trying. The Zimmerman study evaluated the therapeutic potential of pentoxifylline in 17 boys with Duchenne muscular dystrophy (DMD). 1 Pentoxifylline is an anti-inflammatory agent that was found to ameliorate the dystrophic phenotype in mdx mice. 2 However, when used in human subjects, only 9 were able to complete the trial due to significant adverse effects, including leukopenia, which had not been reported previously with this medication. These results are noteworthy and merit publication so that other investigators know not to explore this avenue further, and also to document a new side effect. However, this study raises anew the troubling issue of why animal models of muscular dystrophy have not been able to predict successful novel therapies in humans. This problem is not unique to muscular dystrophy, but it is especially vexing in this disorder. The most commonly used animal model of DMD is the naturally occurring mdx mouse, which has a nonsense mutation in exon 23 of murine dystrophin. 3–5 The phenotype of mdx mouse DMD is milder than that in humans. 5, 6 Alternative mouse models of DMD with more severe phenotypes exist, including one with a combined dystrophin–utrophin deficiency, 7, 8 and others with artificially created dystrophin deficiencies, such as the mdx5cv mouse, which has a mutation in exon 10 that was generated with ethylnitrosurea mutagenesis. 9 The mdx5cv mouse model also has the advantage of having fewer revertant fibers than the mdx model, making it simpler to determine the origin of dystrophin-positive fibers after treatment. The zebrafish is a newer model for the study of muscular dystrophy, and it expresses many of the genes involved in muscular dystrophy. 10–12 It is phylogenetically more distant from humans than mammalian models, but it has certain unique advantages. It has a rapid reproductive cycle and large clutch sizes, allowing for rapid experiments that may be performed on large numbers of animals at a time. These experiments are thus more amenable to statistical analysis. In addition, the zebrafish is translucent, and muscle disease is often apparent under a low-power microscope in live fish, both by the birefringence pattern and by their mobility. Mutant strains13, 14 and morpholino suppression of specific genes involved in muscular dystrophy11, 15, 16 illustrate the utility of this model, and zebrafish have been used for large-scale screening of potential pharmacological therapies for muscular dystrophy. 17 The xmd golden retriever is a naturally occurring dog model of DMD with a point mutation that causes exon skipping and a complete deficiency of dystrophin expression. 18, 19 The phenotype of the xmd dog is much closer to that of humans than are mouse models, but there are several obstacles to the use of these models, including the higher cost and longer reproductive cycles. The discordance between therapeutic results in animal models versus humans with muscular dystrophy has arisen repeatedly, beginning in the late 1980s. Injection of muscle precursor cells successfully induced dystrophin expression in mdx mice20 and humans, 21 but clinical outcomes …
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