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Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson’s Disease

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Abstract

There is escalating interest in cell-based therapies to restore lost dopamine inputs in Parkinson’s disease. This is based upon the rationale that implanting dopamine progenitors into the striatum can potentially improve dopamine-responsive motor symptoms. A rich body of data describing clinical trials of previous cell transplantation exists. These have included multiple cell sources for transplantation including allogeneic (human embryonic mesencephalic tissue, retinal pigment epithelial cells) and autologous (carotid body, adrenal medullary tissue) cells, as well as xenotransplantation. However, there are multiple limitations related to these cell sources, including availability of adequate numbers of cells for transplant, heterogeneity within cells transplanted, imprecisely defined mechanisms of action, and poor cell survival after transplantation in some cases. Nonetheless, evidence has accrued from a subset of trials to support the rationale for such a regenerative approach. Recent rapid advances in stem cell technology may now overcome these prior limitations. For example, dopamine neuron precursor cells for transplant can be generated from induced pluripotent cells and human embryonic stem cells. The benefits of these innovative approaches include: the possibility of scalability; a high degree of quality control; and improved understanding of mechanisms of action with rigorous preclinical testing. In this review, we focus on the potential for cell-based therapies in Parkinson’s disease to restore the function of dopaminergic neurons, we critically review previous attempts to harness such strategies, we discuss potential benefits and predicted limitations, and we address how previous roadblocks may be overcome to bring a cell-based approach to the clinic.

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Acknowledgements

Claire Henchcliffe acknowledges funding from the C.V. Starr Foundation and New York State Stem Cell Science (NYSTEM). Harini Sarva acknowledges funding from the Daisy and Paul Soros Clinical Scholar Award.

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  1. Department of Neurology, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY, 10021, USA

    Claire Henchcliffe & Harini Sarva

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  1. Claire Henchcliffe
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Correspondence to Claire Henchcliffe.

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Conflicts of interest

Dr Henchcliffe has received honoraria for consulting for the California Institute of Regenerative Medicine (CIRM) Grant Working Group and research funding as an investigator in a research consortium from New York State Stem Cell Science (NYSTEM). Unrelated to this manuscript she has the following disclosures: honorarium for lecture from the Houston Methodist Neurological Institute; honoraria for ad hoc advisory board participation from US WorldMeds, Adamas Pharmaceuticals, Mitsubishi Tanabe Pharma Inc., and Prevail Therapeutics; and funding from the Michael J. Fox Foundation, National Institute of Health, Insightec, and Prevail Therapeutics. Dr H Sarva has received funding from the Michael J Fox Foundation, and clinical trial support from Biogen, Insightec and Lundbeck Pharmaceuticals. She has received honoraria for participation in advisory boards for Merz and Amneal pharmaceuticals, and for serving as an independent video rater for Neurocrine Neurosciences.

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Henchcliffe, C., Sarva, H. Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson’s Disease. CNS Drugs 34, 559–577 (2020). https://doi.org/10.1007/s40263-020-00727-3

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