Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do, Korea; Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do, Korea; Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do, Korea.
Cell Stem Cell. 2023 Jul 6;30(7):973-986.e11. doi: 10.1016/j.stem.2023.05.015. Epub 2023 Jun 19.
Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modeling and drug discovery. However, recreating innate cellular pathologies, particularly in late-onset neurodegenerative diseases with accumulated protein aggregates including Parkinson's disease (PD), has been challenging. To overcome this barrier, we developed an optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS) that rapidly induces α-syn aggregates and toxicity in PD hiPSC-midbrain dopaminergic neurons and midbrain organoids. Our OASIS-based primary compound screening with SH-SY5Y cells identified 5 candidates that were secondarily validated with OASIS PD hiPSC-midbrain dopaminergic neurons and midbrain organoids, leading us to finally select BAG956. Furthermore, BAG956 significantly reverses characteristic PD phenotypes in α-syn preformed fibril models in vitro and in vivo by promoting autophagic clearance of pathological α-syn aggregates. Following the FDA Modernization Act 2.0's emphasis on alternative non-animal testing methods, our OASIS can serve as an animal-free preclinical test model (newly termed "nonclinical test") for the synucleinopathy drug development.
人类诱导多能干细胞（hiPSCs）在疾病建模和药物发现方面具有优势。然而，重现先天细胞病理学，特别是在具有累积蛋白聚集体的迟发性神经退行性疾病中，如帕金森病（PD），一直具有挑战性。为了克服这一障碍，我们开发了一种光遗传学辅助的α-突触核蛋白（α-syn）聚集诱导系统（OASIS），该系统可快速诱导 PD hiPSC-中脑多巴胺能神经元和中脑组织球体中的α-syn 聚集和毒性。我们基于 OASIS 的 SH-SY5Y 细胞的初步化合物筛选确定了 5 种候选药物，并用 OASIS PD hiPSC-中脑多巴胺能神经元和中脑组织球体对其进行了二次验证，最终选择了 BAG956。此外，BAG956 通过促进病理性 α-syn 聚集体的自噬清除，显著逆转了体外和体内α-syn 原纤维模型中的典型 PD 表型。继 FDA 现代化法案 2.0 强调替代非动物测试方法之后，我们的 OASIS 可以作为神经突触核蛋白病药物开发的无动物临床前测试模型（新称为“非临床测试”）。
