Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO, USA.
Department of Physics, The University of Missouri, Columbia, MO, USA.
Expert Opin Drug Discov. 2020 Apr;15(4):443-456. doi: 10.1080/17460441.2020.1718100. Epub 2020 Jan 30.
: Duchenne muscular dystrophy (DMD) is an X-linked handicapping disease due to the loss of an essential muscle protein dystrophin. Dystrophin-null animals have been extensively used to study disease mechanisms and to develop experimental therapeutics. Despite decades of research, however, treatment options for DMD remain very limited.: High-throughput high-content screening and precision medicine offer exciting new opportunities. Here, the authors review animal models that are suitable for these studies.: Nonmammalian models (worm, fruit fly, and zebrafish) are particularly attractive for cost-effective large-scale drug screening. Several promising lead compounds have been discovered using these models. Precision medicine for DMD aims at developing mutation-specific therapies such as exon-skipping and genome editing. To meet these needs, models with patient-like mutations have been established in different species. Models that harbor hotspot mutations are very attractive because the drugs developed in these models can bring mutation-specific therapies to a large population of patients. Humanized hDMD mice carry the entire human dystrophin gene in the mouse genome. Reagents developed in the hDMD mouse-based models are directly translatable to human patients.
杜氏肌营养不良症（DMD）是一种 X 连锁致残疾病，由于重要肌肉蛋白抗肌萎缩蛋白的缺失所致。抗肌萎缩蛋白缺失动物被广泛用于研究疾病机制和开发实验性疗法。然而，尽管进行了数十年的研究，DMD 的治疗选择仍然非常有限。高通量高内涵筛选和精准医学提供了令人兴奋的新机会。本文作者综述了适合这些研究的动物模型。非哺乳动物模型（蠕虫、果蝇和斑马鱼）特别适合用于具有成本效益的大规模药物筛选。已经使用这些模型发现了几种有前途的先导化合物。DMD 的精准医学旨在开发突变特异性疗法，如外显子跳跃和基因组编辑。为了满足这些需求，在不同物种中建立了具有类似患者突变的模型。携带热点突变的模型非常有吸引力，因为在这些模型中开发的药物可以为大量患者带来突变特异性疗法。人源化 hDMD 小鼠在小鼠基因组中携带整个人类抗肌萎缩蛋白基因。在 hDMD 小鼠模型中开发的试剂可直接转化为人类患者。
