Pinnapureddy Ashish R, Stayner Cherie, McEwan John, Baddeley Olivia, Forman John, Eccles Michael R
Department of Pathology, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin, 9054, New Zealand.
AgResearch, Invermay Agricultural Centre, Mosgiel, New Zealand.
Orphanet J Rare Dis. 2015 Sep 2;10:107. doi: 10.1186/s13023-015-0327-5.
Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.
能够精确模拟人类疾病的动物在医学研究中具有极高价值，有助于深入理解疾病机制，并为在临床前研究中评估治疗性化合物的效果提供机会。全球范围内使用多种类型的动物模型，最常见的是小型实验动物，如小鼠。然而，尽管啮齿动物在研究中被广泛使用，但它们往往不能忠实地复制人类疾病。这种差异部分归因于生理差异，如体型和寿命。相比之下，包括绵羊在内的大型动物模型由于与人类在生理上有更多相似之处，为生物医学研究提供了小鼠之外的另一种选择。许多物种全基因组序列的完成以及新一代测序（NGS）技术的出现，意味着现在有可能在大量家养动物群体中筛选出与人类遗传疾病相似的遗传变异，并生成能更准确模拟罕见人类病理的模型。在这篇综述中，我们讨论了将绵羊用作大型动物模型的概念及其在模拟人类遗传疾病方面的优势。我们举例说明了一些与人类疾病基因直系同源的基因中现有的天然绵羊变异，如用于贝敦氏病的Cln6绵羊模型。这些以及其他绵羊模型，除了为在体型和器官大小与人类相似的动物中试验新疗法提供机会外，还为我们理解相关人类疾病过程做出了重大贡献。因此，绵羊在模拟罕见人类遗传疾病方面是一个重要的物种，我们在本综述中对此进行了总结。
