Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
Department of Medical Research, Hualien Tzu Chi Hospital, Hualien 970, Taiwan.
Molecules. 2020 Apr 24;25(8):2000. doi: 10.3390/molecules25082000.
Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.
神经退行性疾病是我们老龄化社会中未满足的重大医疗需求。大多数这些疾病没有有效的治疗方法，而且我们对发病机制的了解相对较少。在为神经退行性疾病开发治疗药物的过程中，面临的挑战之一是这些综合征通常很复杂，并且小动物模型不能完全再现人类神经系统的独特特征。人类诱导多能干细胞（iPSC）是一种新技术，它可以使我们从个体患者中生成神经元细胞，从而消除使用动物模型时固有的物种特异性问题。iPSC 衍生细胞的特定表型可以使研究人员识别亚型，并区分独特的簇和组。最近，iPSC 已被用于包括阿尔茨海默病（AD）、肌萎缩性侧索硬化症（ALS）、脊髓小脑萎缩症（SCA）和寨卡病毒感染在内的神经紊乱的药物筛选和测试。然而，仍有许多挑战摆在面前，包括如何有效地再现散发性疾病表型，以及如何选择理想的表型和进行大规模药物筛选。幸运的是，已经开发出了相当多的新策略，这些策略可能与基于 iPSC 的模型相结合，以解决这些挑战，包括类器官技术、单细胞 RNA 测序、基因组编辑和深度学习人工智能。在这里，我们将回顾基于 iPSC 的神经退行性疾病模型在关键药物筛选中的当前应用和潜在的未来方向。
