Sabitha K R, Shetty Ashok K, Upadhya Dinesh
Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA.
Neurosci Biobehav Rev. 2021 Feb;121:201-219. doi: 10.1016/j.neubiorev.2020.12.025. Epub 2020 Dec 25.
The pathological alterations that manifest during the early embryonic development due to inherited and acquired factors trigger various neurodevelopmental disorders (NDDs). Besides major NDDs, there are several rare NDDs, exhibiting specific characteristics and varying levels of severity triggered due to genetic and epigenetic anomalies. The rarity of subjects, paucity of neural tissues for detailed analysis, and the unavailability of disease-specific animal models have hampered detailed comprehension of rare NDDs, imposing heightened challenge to the medical and scientific community until a decade ago. The generation of functional neurons and glia through directed differentiation protocols for patient-derived iPSCs, CRISPR/Cas9 technology, and 3D brain organoid models have provided an excellent opportunity and vibrant resource for decoding the etiology of brain development for rare NDDs caused due to monogenic as well as polygenic disorders. The present review identifies cellular and molecular phenotypes demonstrated from patient-derived iPSCs and possible therapeutic opportunities identified for these disorders. New insights to reinforce the existing knowledge of the pathophysiology of these disorders and prospective therapeutic applications are discussed.
由于遗传和后天因素，在胚胎早期发育过程中出现的病理改变会引发各种神经发育障碍（NDDs）。除了主要的NDDs，还有几种罕见的NDDs，它们表现出特定的特征和由遗传和表观遗传异常引发的不同严重程度。由于研究对象稀少、用于详细分析的神经组织匮乏以及缺乏疾病特异性动物模型，直到十年前，对罕见NDDs的详细理解仍受到阻碍，给医学和科学界带来了更大的挑战。通过针对患者来源的诱导多能干细胞（iPSCs）的定向分化方案、CRISPR/Cas9技术和3D脑类器官模型来生成功能性神经元和神经胶质细胞，为解读由单基因和多基因疾病引起的罕见NDDs的脑发育病因提供了绝佳机会和丰富资源。本综述确定了患者来源的iPSCs所显示的细胞和分子表型，以及为这些疾病确定的可能治疗机会。还讨论了强化这些疾病病理生理学现有知识的新见解和前瞻性治疗应用。
