April 10, 2017

expert reaction to reprogramming brain cells for Parkinson’s

In a new study publishing in Nature Biotechnology researchers describe how they reprogrammed human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons.

Prof. David Dexter, Deputy Director of Research, Parkinson’s UK, said:

“This is a very robust study where the authors have provided good evidence of being able to turn astrocytes into cells that resemble dopamine neurons both in cultured cells and directly in the brains of an animal model of Parkinson’s.

“Replacing the cells that are lost in Parkinson’s is a possible way to reverse its symptoms, and could one day be a cure for the condition.

“This research is hugely promising, as it offers a completely new way to replace cells that are lost in Parkinson’s.  However, the location of the new cells created through this process could make it difficult to control the delivery of dopamine to the brain.

“Further development of this technique is now needed, so it encourages dopamine to be produced and released in a controlled manner, like the original brain cells. If successful, it would turn this approach into a viable therapy that could improve the lives of people with Parkinson’s and, ultimately, lead to the cure that millions are waiting for.”

Dr Patrick Lewis, Associate Professor in Cellular and Molecular Neuroscience, University of Reading, said:

“This is a very interesting study, demonstrating that human astrocytes can be directly converted into cells that are very similar to the dopaminergic neurons that are lost in Parkinson’s, and using the same technique to test whether this approach can work in a mouse model for dopamine neuronal loss.  Since replacing these lost neurons has long been thought of as a potential game-changing therapy for Parkinson’s, this paper adds to a growing body of research in this area.

“This study builds on previous research showing that mouse astrocytes could be converted into dopamine neurons, so in some ways the results of this study aren’t surprising – but the challenge of moving from mouse to human cells shouldn’t be underestimated, so this does represent a step forward.

“The dopamine neurons that they generated using their optimized technique show some of the properties of fully functional brain cells. The most detailed comparison they carried out was between their astrocyte derived neurons and embryonic human midbrain neurons cells, and is not clear how closely these embryonic cells match up to mature adult DA neurons. Even taking this into consideration, the astrocyte-derived cells were not a perfect match.

“A key test of whether newly derived dopamine neurons are functional is whether they can replace these cells in animal models that have a similar dopamine deficit to that seen in humans with Parkinson’s. The authors have shown that they can use this technique to correct some, but not all, of the symptoms seen in one of these mouse models so there is clearly some way to go before this approach can be used to fully compensate for dopaminergic cell loss in a mouse. Importantly, they have not yet demonstrated that human dopaminergic neurons derived from astrocytes can replace function in mice – so it is important to note that moving from this study to doing the same in humans will be a huge challenge. But this study does begin to provide the proof of concept required for further studies.”

Dr Christopher Morris, Senior Lecturer in Neurotoxicology, Newcastle University, said:

“The astrocyte-derived nerve cells appear to be very similar to the dopamine cells lost in Parkinson’s disease and certainly appear to function in a very similar way. The only thing that the researchers haven’t perhaps done is to show that the new nerve cells actually produce and release dopamine, although that is probably simply a matter of time to do those experiments.

“Given that a reasonable number of mice have been used in the study, the data from the mice looks sound and suggests that the treatment works for the mice, at least in the short term. Some additional tests would be useful in the mice and particularly to see if the cells actually form the right types of connections in the brain. This will be essential since the connectivity of the human brain in Parkinson’s disease has been altered in a slightly different way due to the long term nature of the condition, and the nerve cells may have to connect over long distances to produce sufficient dopamine to replace what has been lost.

“What would also be useful to find out is how the new cells function in the long term – can they still help the mice after several months? We also know from previous human studies that new nerve cells when transplanted into the brain still degenerate and develop the pathological changes of Parkinson’s disease. This will therefore be a major hurdle. If the treatment is to be used in people with Parkinson’s disease, then how these new nerve cells survive over a period of years will need to be found out.  Could this treatment be used in people with Parkinson’s? Possibly, certainly delivering the new treatment could be done but this would potentially involve major surgery so it may only be for people who have very severe problems associated with Parkinson’s. An alternative would be to alter how the treatment is delivered to the brain and to find a novel way of doing this.”

* ‘Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model’ by di Val Cervo et al. published in Nature Biotechnology on Monday 10^th April.

Declared interests

Dr Lewis: Employee of the University of Reading, funded by the Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institutes of Health, Newton Scheme, honorary position at University College London, member of the Royal Institution, Biochemical Society, Fabian Society and Society for Neuroscience, member of the BBSRC pool of experts, scientific advisory committee for Ataxia UK, grant assessment panel for Parkinson’s UK and the research strategy committee of the MS Society, and provided support by Merck for research conference hosting, paid honorarium by Astex Pharmaceuticals.

Dr Morris: Scientific Director of the Newcastle Bran Tissue Resource at Newcastle University and Chair of the Multiple Sclerosis and Parkinson’s Tissue Bank at Imperial College.

Others: None received