小柯机器人

美国约翰·霍普金斯大学医学院Gabsang Lee团队报道了帕金森病临床前模型和光遗传α -突触核蛋白聚集。2023年6月19日，国际知名学术期刊《细胞—干细胞》发表了这一成果。

他们开发了一种光遗传学辅助α-突触核蛋白(α-syn)聚集诱导系统(OASIS)，该系统可快速诱导帕金森病(PD) - hiPSC -中脑多巴胺能神经元和中脑类器官中α-syn聚集并产生毒性。他们基于OASIS的SH-SY5Y细胞初级化合物筛选鉴定了5个候选化合物，并通过OASIS PD hiPSC-中脑多巴胺能神经元和中脑类器官进行了二次验证，最终选择了BAG956。

此外，BAG956通过促进病理α-syn聚集物的自噬清除，在体外和体内显著逆转α-syn预制纤维模型的PD特征表型。根据FDA现代化法案2.0对替代非动物试验方法的强调，他们的OASIS可以作为突触核蛋白病药物开发的无动物临床前试验模型(新称为“非临床试验”)。

据介绍，hiPSCs为疾病建模和药物发现提供了优势。然而，重建先天细胞病理，特别是在迟发性神经退行性疾病积累蛋白聚集，包括PD，一直具有挑战性。

附：英文原文

Title: Advanced human iPSC-based preclinical model for Parkinson’s disease with optogenetic alpha-synuclein aggregation

Author: Min Seong Kim, Eun A. Ra, Sin Ho Kweon, Bo Am Seo, Han Seok Ko, Yohan Oh, Gabsang Lee

Issue&Volume: 2023-06-19

Abstract: Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modelingand drug discovery. However, recreating innate cellular pathologies, particularlyin late-onset neurodegenerative diseases with accumulated protein aggregates includingParkinson’s disease (PD), has been challenging. To overcome this barrier, we developedan optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS)that rapidly induces α-syn aggregates and toxicity in PD hiPSC-midbrain dopaminergicneurons and midbrain organoids. Our OASIS-based primary compound screening with SH-SY5Ycells identified 5 candidates that were secondarily validated with OASIS PD hiPSC-midbraindopaminergic neurons and midbrain organoids, leading us to finally select BAG956.Furthermore, BAG956 significantly reverses characteristic PD phenotypes in α-syn preformedfibril models in vitro and in vivo by promoting autophagic clearance of pathological α-syn aggregates. Following theFDA Modernization Act 2.0’s emphasis on alternative non-animal testing methods, ourOASIS can serve as an animal-free preclinical test model (newly termed “nonclinicaltest”) for the synucleinopathy drug development.

DOI: 10.1016/j.stem.2023.05.015

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00211-4

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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