Autologous transplantation of iPS cell-derived dopaminergic neurons alleviates motor and depressive behaviors in Parkinson’s model monkeys

The significance of this research
A research team led by Professor Su-Chun Zhang and Professor Marina E. Emborg at the University of Wisconsin–Madison, confirmed that Parkinson’s disease (PD) model monkeys receiving autologous transplantation of iPS cell (iPSC)-derived dopaminergic progenitor cells exhibited recovery from motor and depressive signs. In this study, autologous cell transplantation was performed in a way that mimicked clinical application and the efficacy was verified.

Current treatment for Parkinson’s disease
PD is a progressive disease caused by the reduction of dopaminergic neurons in the substantia nigra of the midbrain and dopamine deficiency. Dopamine, which is produced in the substantia nigra, acts in the striatum (composed of the caudate nucleus, putamen, etc.) of the cerebrum as a messenger between the parts of the brain and nervous system and helps control body movements. Dopamine deficiency induces such symptoms as shaking in limbs, difficulty in walking, and decreased movement. Current medication that replenishes dopamine can be expected to improve symptoms to some extent, but it does not prevent the reduction of dopaminergic neurons. As the disease worsens, the medication becomes less and less effective.

Autologous transplantation of dopaminergic progenitor cells
If dopaminergic progenitor cells are transplanted into the brain, dopamine is increased, and symptoms of PD should be improved permanently. Autologous transplantation, in which a patient’s own cells are used, does not need immunosuppression. In a previous study, three PD model monkeys underwent autologous transplantation of iPSC-derived dopaminergic progenitor cells, but only one monkey was reported to have limited motor behavior improvement. In another study, one patient with PD showed minor recovery 2 years after autologous transplant. These results demonstrated the feasibility of the approach, but it was not clear whether autologous transplantation is truly effective.

Results of this study
The research team established rhesus iPSC (RhiPSC) lines from five rhesus monkeys and generated dopaminergic progenitor cells from these RhiPSCs. Then, they generated a hemiparkinsonian model by unilateral right intracarotid artery infusion of the neurotoxin MPTP. Juvenile monkeys under 3 years old are less sensitive to MPTP and often spontaneously recover over time. To ensure a stable PD model, they used rhesus monkeys aged 5–9 years and transplanted the dopaminergic progenitor cells 2–3 years after intoxication. (One of five monkey were killed due to clinical reasons unrelated to cell transplantation.) They did not use immunosuppression for these animals.

After transplantation, the amount of movement was increased, and speed and fluidity were also improved. To assess the monkeys’ parkinsonism, they used a clinical rating scale (CRS) and a fine-motor skill (FMS). The CRS began to improve a few months after transplantation and stabilized between 6 and 12 months after transplantation with an average CRS recovery ratio of 40%. Three of four monkeys showed the improvement of FMS. Thus, the monkeys with autologous grafts exhibited substantial improvement in motor function. Besides motor deficits, the PD model monkeys displayed signs of mood disorders. Anxious pacing was present in all monkeys before and 6 months after grafting and resolved over time.

They examined dopamine synthesis by [11C]DTBZ-positron emission tomography (PET) and found that dopamine synthesis in the affected putamen was increased by 366% (P = 0.007) and the caudate by 200% (P = 0.055) after transplantation. In addition, immunostaining for tyrosine hydroxylase (TH), a dopaminergic cell marker, was performed in the brain sections. It demonstrated the presence of dopaminergic neurons and extension of their dopaminergic fibers in the putamen and the caudate up to 2 years after transplantation. The grafts did not have a clear boundary and often merged to monkeys’ brain tissue. The number of TH+ cells within the grafts were 9.11 ± 5.85 × 104 cells, and there were no tumor cells. Statistical analysis showed correlations between the number of surviving dopamine neurons with PET signal intensity and behavior recovery, which suggests that PET and motor behaviors can predictive surviving dopamine neuron number.

These results indicate that autologous transplantation of iPSC-derived dopaminergic progenitor cells is effective for the treatment of PD.

Additional information for researchers
Several factors may have contributed to the mitigation of depression symptoms, including grafted cell types and distribution. Grafted cells consisted of both A9 and A10 types of neurons. (A9 neurons, dopamine neurons of the substantia nigra, project to the striatum. On the other hand, A10 neurons, dopamine neurons of the ventral tegmental area, project to the limbic system.) Furthermore, dopamine neurites extend not only toward the dorsolateral putamen, but also the pre-commissural putamen and nucleus accumbens, suggesting the potential modulation of limbic system function by grafted cells and hence improvement in mood.

Article: Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys

Authors: Aaron Gordon1, Se-Jin Yoon  2,3, Stephen S. Tran4,5, Christopher D. Makinson  6, Jin Young Park2,3, Jimena Andersen2,3, Alfredo M. Valencia2,3, Steve Horvath  7,8, Xinshu Xiao5,9,10, John R. Huguenard  6
,Sergiu P. Pașca  2,3 ✉ and Daniel H. Geschwind

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