Abstract
Human aging is the most important factor leading to an increased incidence of neurodegenerative diseases worldwide. One common structural hallmark of neurodegenerative disorders is the progressive loss of distinct vulnerable neural cells most likely linked to pathological aggregates of specific proteins. The most prevalent neurodegenerative movement disorder is Parkinson’s disease (PD) characterized by cardinal motor symptoms such as bradykinesia, rigidity, and tremor. The current gold-standard therapy applying Levodopa results in severe adverse effects leading to hyper- and dyskinesia as well as a decreasing therapeutic response. Due to an intraneuronal deposition of alpha-synuclein in dopaminergic midbrain neurons and its consequent severe loss of these cells, PD represents the prototypical disease of the brain for cell-based therapies using a defined neurotransmitter phenotype. In the late 1960s, first pioneer cell-based therapies were initiated leading to transplantation approaches of human fetal ventral mesencephalic tissues in the 1990s for cellular replacement in PD. Despite initial promising outcomes based on first proof-of-concept transplantation efforts in a low number of PD patients, larger randomized double-blind follow-up studies were not able to demonstrate a clinical meaningful benefit for transplanted PD patients. Notably, grafted fetal cells developed inclusions of synuclein several years postgrafting, thereby increasing the pressure to search for alternate cell sources suitable for neural transplantation. After the discovery of human embryonic stem cells in the late 1990s, Takahashi and Yamanaka succeeded to generate somatic cell-derived human-induced pluripotent stem cells (hiPSCs) in 2007. Initial preclinical studies in nonhuman primates demonstrated the high restorative potential of hiPSCs as prospective cell source for transplantation. In 2018, the first in-human studies for hiPSC transplantation in Parkinson’s disease were initiated in Japan. In 2020, a single case was reported in the New England Journal of Medicine describing the successful autologous transplantation of hiPSC-derived dopaminergic neurons in a PD patient. In this review, we will highlight the history as well as the current efforts toward cell-based therapy in PD with a special emphasis on important biological, clinical, and ethical aspects of this regenerative cell-based approach.
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Notes
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Acknowledgments
Je.W. and Y.S. are graduate students of the research training group 2162 “Neurodevelopment and Vulnerability of the Central Nervous System” of the Deutsche Forschungsgemeinschaft (DFG 270949263/GRK2162). S.T. was a postdoctoral researcher and consequent principle investigator of the research training group 2162 “Neurodevelopment and Vulnerability of the Central Nervous System” of the Deutsche Forschungsgemeinschaft (DFG 270949263/GRK2162). J.W. is a member of the research training group 2162 of the Deutsche Forschungsgemeinschaft (DFG 270949263/GRK2162) and speaker of the Bavarian Research Network for Induced Pluripotent Stem Cells (ForIPS), as well as consequent member of the Bavarian Research Network of Interaction of human brain cells (ForInter). Je.W., Y.S., and S.T are associated with the Bavarian Research Networks for Induced Pluripotent Stem Cells (ForIPS) and for the Interaction of human brain cells (ForInter). The work was supported by the Forschungsstiftung Medizin, University Hospital Erlangen. All figures were created with BioRender.com.
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Schneider, Y., Wihan, J., Turan, S., Winkler, J. (2022). Cell-Based Therapy and Genome Editing in Parkinson’s Disease: Quo Vadis?. In: Dederer, HG., Hamburger, D. (eds) Brain Organoids in Research and Therapy. Advances in Neuroethics. Springer, Cham. https://doi.org/10.1007/978-3-030-97641-5_3
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