Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA, and Hauenstein Neuroscience Center, Mercy Health/St. Mary's, Grand Rapids, Michigan, USA.
Mov Disord. 2019 Aug;34(8):1120-1127. doi: 10.1002/mds.27742. Epub 2019 Jun 24.
The clinical experience with cell replacement therapy for advanced PD has yielded notable successes and failures. A recent autopsy case report of an individual that received implants of fetal dopamine neurons 16 years previously, but at no time experienced clinical benefit despite the best documented survival of grafted neurons and most extensive reinnervation of the striatum, raises sobering issues. With good reason, a great deal of effort in cell replacement science continues to focus on optimizing the cell source and implantation procedure. Here, we describe our preclinical studies in aged rats indicating that despite survival of large numbers of transplanted dopamine neurons and dense reinnervation of the striatum, synaptic connections between graft and host are markedly decreased and behavioral recovery is impaired. This leads us to the hypothesis that the variability in therapeutic response to dopamine neuron grafts may be less about the viability of transplanted neurons and more about the integrity of the aged, dopamine-depleted striatum and its capacity for repair. Replacement of dopamine innervation only can be fully effective if the correct target is present. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
细胞替代疗法治疗晚期帕金森病的临床经验既有显著的成功，也有失败。最近的一例尸检报告，一名患者在 16 年前接受了胎儿多巴胺神经元的移植，但尽管移植的神经元有最佳的生存记录，且纹状体的再支配最为广泛，患者却从未经历过临床获益，这引发了令人警醒的问题。有充分的理由表明，细胞替代科学领域的大量工作仍然集中在优化细胞来源和移植程序上。在这里，我们描述了我们在老年大鼠中的临床前研究，表明尽管大量移植的多巴胺神经元存活，纹状体得到了密集的再支配，但移植和宿主之间的突触连接明显减少，行为恢复受损。这使我们假设，多巴胺神经元移植治疗反应的可变性与其说是移植神经元的存活能力，不如说是与老化、多巴胺耗竭的纹状体的完整性及其修复能力有关。只有在存在正确的靶标时，多巴胺神经支配的替代才能完全有效。© 2019 作者。运动障碍由 Wiley Periodicals, Inc. 代表国际帕金森和运动障碍协会出版。
