The future of stem cell therapies for Parkinson disease

Abstract

Cell-replacement therapies have long been an attractive prospect for treating Parkinson disease. However, the outcomes of fetal tissue-derived cell transplants in individuals with Parkinson disease have been variable, in part owing to the limitations of fetal tissue as a cell source, relating to its availability and the lack of possibility for standardization and to variation in methods. Advances in developmental and stem cell biology have allowed the development of cell-replacement therapies that comprise dopamine neurons derived from human pluripotent stem cells, which have several advantages over fetal cell-derived therapies. In this Review, we critically assess the potential trajectory of this line of translational and clinical research and address its possibilities and current limitations and the broader range of Parkinson disease features that dopamine cell replacement based on generating neurons from human pluripotent stem cells could effectively treat in the future.

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Fig. 1: Timeline of developing cell therapies for Parkinson disease.
Fig. 2: Cell sources being trialled for clinical cell-replacement therapy in Parkinson disease.
Fig. 3: Advantages of PSCs versus fetal ventral mesencephalon tissue as a cell source for transplantation.

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The authors all researched data for the article, contributed substantially to discussion of the article’s content, wrote the article, and reviewed and edited the manuscript before submission.

Correspondence to Malin Parmar.

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Competing interests

M.P. is the owner of Parmar Cells AB and co-inventor on the US patent application 15/093,927 owned by Biolamina AB, EP17181588 owned by Miltenyi Biotec and PCT/EP2018/062261 owned by New York Stem Cell Foundation. C.H. has received consultancy fees from US WorldMeds, Adamas Pharmaceuticals, Prevail Therapeutics and Mitsubishi Tanabe Pharma America.

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Glossary

Magnetic resonance-guided focused ultrasound ablation

An intracranial thermal ablative procedure with multiple ultrasound beams that are precisely targeted to facilitate non-incisional pallidotomy or subthalamotomy that may potentially alleviate symptoms of Parkinson disease.

Unified Parkinson’s Disease Rating Scale

A widely used, validated clinical rating scale that evaluates non-motor symptoms, activities of daily living, motor signs and complications of levodopa therapy.

Neuroectoderm

Derived from the ectoderm, the outermost of the three primary germ layers in the early embryo; its formation is the first step in development of the nervous system.

Stromal feeder cells

Feeder cells that provide extracellular secretions to help another cell to proliferate or differentiate. Often the cells of the feeder layer are irradiated or otherwise treated to arrest growth.

Amphetamine-induced rotation

Drug-induced turning behaviour used to assess unilateral dopaminergic lesions and effects of transplants in rodent models of Parkinson disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

A prodrug of 1-methyl-4-phenylpyridinium, a neurotoxin leading to loss of dopamine neurons in the substantia nigra, and used to create animal models of Parkinson disease.

Indirect pathway

A neuronal network pathway from the striatal medium spiny neurons primarily expressing dopamine D2 receptors via the globus pallidus pars externa to the subthalamic nucleus. Activation of this pathway inhibits movement and action selection. This pathway is abnormally active in Parkinson disease, as the loss of dopaminergic tone leads to disinhibition of the pathway.

Lewy body

Abnormal intracytoplasmic protein aggregates occurring in neurons in certain neurodegenerative disorders, including Parkinson disease.

Autophagy

A complex intracellular process that uses hydrolytic enzymes in the lysosomes to degrade modified or damaged macromolecules and organelles.

Corridor test

A drug-free behavioural test of lateralized neglect in animals, which is sensitive to unilateral dopamine-denervating lesions and subsequent graft-derived striatal dopaminergic replacement.

Dysosmia

Distortion in sense of smell.

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Parmar, M., Grealish, S. & Henchcliffe, C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci 21, 103–115 (2020). https://doi.org/10.1038/s41583-019-0257-7

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