Monkeys, humans and Parkinson's

Stem cells have been targeted as being the key to unlock the cure to all sorts of diseases. So far, there hasn’t been much success down this line. This month, a new study has been published in the journal Nature by investigators in Japan, and it has made the headlines.

Although the principle of what a stem cell is is straightforward, there are many ways of obtaining them. The essence is that it is a pluripotent cell that can ‘grow up’ to be any kind of cell. The body has many differentiated stem cells – cells that produce new blood cells, skin cells or gut cells cannot produce anything other than what they’re programmed to do. At the beginning of fetal development, all the cells are pluripotent but these are unavailable by the time a person is born. New techniques have been developed to create induced pluripotent stem cell – iPS – i.e. they turn back the clock.

In this study, the team gave some Macaque monkeys a ‘kind’ of Parkinson’s by giving a drug that kills the dopamine cells in the brain. They then implanted human iPS cells that were then pushed into becoming dopamine producing cells into the affected areas of the monkeys’ brains.

Behavioural and movement testing, as well as imaging and pathology studies showed that the cells could survive and more importantly work as dopamine cells.

Although this is an exciting study, it is important to remain realistic regarding how far there is yet to go. Firstly, only a small number of the cells continued to fully mature to the ‘adult’ form of the cells. Secondly, the transplanted monkeys only recovered 48% of the normal level of dopamine transport on [¹⁸F]DOPA PET imaging. Thirdly, although the monkeys had Parkinsonism – i.e. they look and behave in the same way as PD, they don’t have Parkinson’s disease, with the ongoing accumulation of abnormal proteins and degeneration. Finally, the study only ran for two years. There are significant safety concerns about how these cells grow and divide long term, with potential for them to stop responding to normal stop signals and so become cancerous.

With so many obstacles to cross before anyone can realistically talk about iPS having a use in the treatment of humans with PD, it is vital that we continue to work hard at the other end of the spectrum – preventing it in the first place. The major step in that process is predicting who will get it, so we can target those at highest risk with new compounds that stop the disease in its tracks. Roll on PREDICT-PD! 

http://www.nature.com/nature/journal/v548/n7669/full/nature23664.html

Nature 548, 592–596 (31 August 2017) doi:10.1038/nature23664

Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson’s disease (PD), in which midbrain dopaminergic neurons progressively degenerate1, 2. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.