Editors' ChoiceParkinson’s Disease

Remote control of transplanted neurons in Parkinson’s disease

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Science Translational Medicine  18 May 2016:
Vol. 8, Issue 339, pp. 339ec81
DOI: 10.1126/scitranslmed.aaf9193

The prospect of controlling movement deficits in Parkinson’s disease (PD) using dopaminergic neuron replacement therapy has garnered attention, particularly given the interest in human pluripotent stem cell (hPSC) technology. Transplantation of neural progenitor cells derived from hPSCs in animal models of PD has produced some encouraging results. Yet, to help realize the potential of cell replacement therapy, achieving proper functional integration into existing neural circuits and precisely regulating neurotransmitter release are crucial goals.

In new work, Chen and colleagues tackle this issue by engineering DREADD (designer receptor exclusively activated by designer drug) into hPSCs to enable fine-tuning of the activity of differentiated midbrain dopaminergic neurons using the receptor agonist clozapine-N-oxide (CNO). Both inhibitory and excitatory DREADDs were knocked-in to H9 human embryonic stem (ES) cells using CRISPR technology. The activity of differentiated midbrain dopaminergic neuron cultures was responsive to CNO treatment, with excitatory DREADDs promoting depolarization and action potential generation, and inhibitory DREADDs having the opposite effect. Dopaminergic neuron progenitors were transplanted into mice with 6-hydroxydopamine-induced lesions in the substantia nigra, a model of PD. Engrafted neurons showed substantial innervation of the host striatum and expression of midbrain dopamine neuron markers. Medium spiny neurons downstream of dopamine signaling were responsive to excitatory DREADD activation, and this was blocked by dopamine D1 receptor antagonists. Finally, excitatory DREADD activation provided enhanced benefit in measures of locomotor function over that observed with a graft that had not been treated to modulate its activity.

This work provides evidence that modulating the activity of transplanted human neurons is a potential way to maximize therapeutic benefit in PD. In this study, excitatory DREADD activation leading to augmented dopaminergic neuron activity provided restoration of motor function. However, it is unclear whether this work can be translated to treating patients with PD. The potential dysfunction of engrafted neurons could lead to graft-induced dyskinesias; thus, a better understanding of graft-host interactions is necessary. Despite this, the ability to fine-tune graft output using chemically-controlled DREADDs represents a conceptual advance that may move us a step closer to achieving success with cell replacement therapy in treating PD.

Y. Chen et al., Chemical control of grafted human PSC-derived neurons in a mouse model of Parkinson's disease. Cell Stem Cell. 10.1016/j.stem.2016.03.014 (2016). [PubMed]

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