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Replacing what's lost: a new era of stem cell therapy for Parkinson's disease.
Translational Neurodegeneration ( IF 12.6 ) Pub Date : 2020-01-07 , DOI: 10.1186/s40035-019-0180-x
Yong Fan 1 , Winanto 2 , Shi-Yan Ng 1, 2, 3, 4
Affiliation  

Background Stem cells hold tremendous promise for regenerative medicine because they can be expanded infinitely, giving rise to large numbers of differentiated cells required for transplantation. Stem cells can be derived from fetal sources, embryonic origins (embryonic stem cells or ESCs) or reprogrammed from adult cell types (induced pluripotent stem cells or iPSCs). One unique property of stem cells is their ability to be directed towards specific cell types of clinical interest, and can mature into functional cell types in vivo. While transplantations of fetal or ESC-derived tissues are known to illicit a host immunogenic response, autologous transplantations using cell types derived from one's own iPSCs eliminate risks of tissue rejection and reduce the need for immunosuppressants. However, even with these benefits, cell therapy comes with significant hurdles that researchers are starting to overcome. In this review, we will discuss the various steps to ensure safety, efficacy and clinical practicality of cell replacement therapy in neurodegenerative diseases, in particular, Parkinson's disease. Main body Parkinson's disease (PD) results from a loss of dopaminergic neurons from the substantia nigra and is an ideal target for cell replacement therapy. Early trials using fetal midbrain material in the late 1980s have resulted in long term benefit for some patients, but there were multiple shortcomings including the non-standardization and quality control of the transplanted fetal material, and graft-induced dyskinesia that some patients experience as a result. On the other hand, pluripotent stem cells such as ESCs and iPSCs serve as an attractive source of cells because they can be indefinitely cultured and is an unlimited source of cells. Stem cell technologies and our understanding of the developmental potential of ESCs and iPSCs have deepened in recent years and a clinical trial for iPSC-derived dopaminergic cells is currently undergoing for PD patients in Japan. In this focused review, we will first provide a historical aspect of cell therapies in PD, and then discuss the various challenges pertaining to the safety and efficacy of stem cell-based cell transplantations, and how these hurdles were eventually overcome. Conclusion With the maturity of the iPSC technology, cell transplantation appears to be a safe and effective therapy. Grafts in non-human primates survive and remain functional for more than 2 years after transplantation, with no signs of tumorigenesis, indicating safety and efficacy of the treatment. However, immunosuppressants are still required because of the lack of "universal stem cells" that would not evoke an immune response. The results of ongoing and upcoming trials by a global consortium known as GForce-PD would be highly anticipated because the success of these trials would open up possibilities for using cell therapy for the treatment of PD and other degenerative diseases.

中文翻译:

弥补丢失的东西:帕金森氏病干细胞治疗的新时代。

背景干细胞具有无限的发展前景,因为它们可以无限扩展,从而产生了再生医学的巨大希望,从而产生了移植所需的大量分化细胞。干细胞可以来源于胎儿,胚胎来源(胚胎干细胞或胚胎干细胞),也可以来自成年细胞类型的重编程(诱导性多能干细胞或iPSC)。干细胞的一个独特特性是其针对临床上特定的细胞类型的能力,并且可以在体内成熟为功能性细胞类型。尽管已知胎儿或ESC来源的组织的移植会非法产生宿主免疫原性反应,但使用衍生自自身iPSC的细胞类型的自体移植消除了组织排斥的风险并减少了对免疫抑制剂的需求。但是,即使有这些好处,细胞疗法伴随着研究人员开始克服的重大障碍。在这篇综述中,我们将讨论确保神经变性疾病(尤其是帕金森氏病)中细胞替代疗法的安全性,有效性和临床实用性的各个步骤。主体帕金森氏病(PD)是由黑质引起的多巴胺能神经元缺失导致的,是细胞替代疗法的理想靶标。在1980年代后期,使用胎儿中脑材料的早期试验为某些患者带来了长期益处,但存在多个缺点,包括移植的胎儿材料的非标准化和质量控制,以及某些患者经历的移植物诱发的运动障碍。结果。另一方面,多能干细胞(例如ESC和iPSC)可作为有吸引力的细胞来源,因为它们可以无限次培养并且是无限的细胞来源。近年来,干细胞技术以及我们对ESC和iPSC的发展潜力的了解已加深,并且日本正在对PD患者进行iPSC衍生的多巴胺能细胞的临床试验。在此重点综述中,我们将首先提供PD细胞疗法的历史方面,然后讨论与基于干细胞的细胞移植的安全性和有效性有关的各种挑战,以及最终如何克服这些障碍。结论随着iPSC技术的成熟,细胞移植似乎是一种安全有效的疗法。非人类灵长类动物的移植物在移植后可以存活并保持功能超过2年,没有肿瘤发生的迹象,表明该治疗的安全性和有效性。然而,由于缺乏不会引起免疫应答的“通用干细胞”,仍然需要免疫抑制剂。由GForce-PD组成的全球财团正在进行和即将进行的试验的结果将是人们高度期待的,因为这些试验的成功将为使用细胞疗法治疗PD和其他退行性疾病开辟可能性。
更新日期:2020-04-22
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