June 24, 2020

expert reaction to paper looking at restoring lost brain cells, in mice as a model of Parkinson’s disease and in human cells

A study, published in Nature, looked at restoring lost brain cells, in mice as a model of Parkinson’s disease and in human cells.

Prof David Dexter, Associate Director of Research at Parkinson’s UK, said:

“Cell transplants have, for a long time, aimed to replace lost cells in Parkinson’s but their effectiveness has been limited since they struggle to integrate and function effectively within the brain.

“This new technique has overcome this major hurdle in mice and opens the door to an exciting new treatment approach, which may be able to reverse Parkinson’s in people, in future.

“While people affected by Parkinson’s should be greatly encouraged by the rapid advances researchers are making, such new technology requires extensive additional research and safety testing before it can be trialled in humans.”

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK, said:

“The human brain is a complex organ, with researchers constantly looking at ways to restore the balance of chemistry in the brain during disease.  In this intriguing study researchers used gene therapy to reduce the levels of a protein in a mouse with features of Parkinson’s, converting the brain’s support cells known as astrocytes into the nerve cells that are usually affected in Parkinson’s, helping restore the delicate balance of chemistry in the brain.

“Advances in technologies like this are vital and this is promising and well-conducted early-stage research, but it is in mice and it’s not yet clear whether this approach could be used in people.  Further research will need to develop a better understanding of the potential adverse effects of converting these cells in this way before we can know whether this technique is even possible in a human brain.

“Findings like this do highlight the potential of medical research, but critical progress is at stake and it’s essential that dementia research is backed by the government throughout the COVID-19 crisis.  Research is the only way we can end the fear, heartbreak and harm that diseases like Parkinson’s cause.”

Dr Tilo Kunath, Group Leader in the Centre for Regenerative Medicine, University of Edinburgh, said:

“This is a remarkable study that describes the production of new dopamine-releasing nerve cells in the mouse brain by the suppression of a single gene, PTBP1.  This simple, one-step procedure uncovers surprising biology and therapeutic potential of non-nerve cells known as astrocytes in the brain.  If this gene therapy is shown to work in humans, it will have significant implications for regenerative medicine for Parkinson’s disease and other neurodegenerative conditions – but we are not at that stage yet.

Does the press release accurately reflect the science?

“Yes, not over-hyped and good to state “authors caution further research is needed”.

Is this good quality research?  Are the conclusions backed up by solid data?

“Very solid data, and agrees with paper in Cell in April 2020 (Zhou et al) that reported very similar biology using a different technique.

Can we tell much about what might happen in people from this research in mice and cells?

“I think the mouse data is a good predictor of what might happen in humans, and they also use human cells.

How does this work fit with the existing evidence?

“It fits and agrees will with several papers on PTB biology and the gene networks that regulate formation of neurons.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“The authors did an incredible job of addressing confounders.  The opto-genetics experiments definitely show the converted neurons are the ones responsible for rescuing the dopamine deficit.

What are the implications in the real world?  Is there any overspeculation?

“Implications for therapy are quite big since only one gene is manipulated, and it only needs to be transient.  The use of antisense oligonucleotides (ASOs) in the last figure shows they are preparing for clinical applications.  ASOs are already being trialled for numerous neurological conditions, including Huntington’s.

Should Parkinson’s patients raise their hopes because of this study, or would that be premature at this stage?

“This is a big scientific leap forward, but it’s still premature for Parkinson’s disease patients to raise their hopes at this stage.  The road to translation could still be long.

Prof Robert Howard, Professor of Old Age Psychiatry, UCL, said:

“That astrocytes can be converted to functioning neurons through the silencing of a single gene in the mouse brain and the observation that this can lead to new neurons that resemble those lost in a mouse model of Parkinson’s disease, with improvements in motor symptoms, is an extraordinary scientific discovery.  This opens up a completely novel avenue for development of treatments to “rebuild” damaged brains in Alzheimer’s and Parkinson’s diseases.

“We will, one day, have effective treatments for these devastating degenerative brain diseases and a specific discovery like this will turn out to have been a pivotal step on the journey – it’s important to bear in mind, however, that this kind of advance rarely translates into safe and effective treatments.  Consider the failure of stem cell technologies to help neurological disorders, for example.”

Prof Tara Spires-Jones, UK Dementia Research Institute at the University of Edinburgh & Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:

“This paper by Fu and team presents some fascinating data showing the potential to convert one type of “supporting” brain cell, called astrocytes, into functional neurons that wire up in mouse brain and are able to rescue some function in a model of Parkinson’s disease.  While the principle of this study is remarkable and promising, it is important to note that it was conducted in mice with group sizes from 3-8 and there is a long way to go to translate this into a treatment for people.”

Prof John Hardy, Professor of Neuroscience, UCL, said:

“I think this is a very interesting piece of work in which glial cells in mice in the substantia nigra (the site where cells are lost in Parkinson’s disease) are directly converted into dopamine neurons.  This is a very exciting and (to me) an unexpected result from a theoretical point of view.  As a piece of basic science, it is really exciting.  Whether it will help in the development of therapies for Parkinson’s disease is much less clear… but exiting work.”

Prof Bart De Strooper, Director of the UK Dementia Research Institute, UCL, said:

“This is a very complete, in-depth and promising study in the search for treatments of Parkinson’s disease.

“Using cellular and animal models, the authors have shown that suppressing just one protein is sufficient to convert supporting cells in the brain into neurons.  These converted cells functionally replace dopaminergic neurons lost in Parkinson’s and can restore deficits in an animal model of disease.  The authors have used multiple approaches, of which one or two may be feasible in humans.

“As with all proof-of-concept, preclinical studies, there are still several hurdles to overcome before we see this in the clinic and providing real benefits for those living with the condition.  The main question now, as discussed by the authors, is whether this treatment will be effective in older people where the brain has lost some plasticity with age.

“That said, this is an extremely refreshing study in the neurodegeneration field and opens up avenues for further research exploring the restoration of brain circuitry in Parkinson’s disease.  It may even be possible to apply the same approach to other neurodegenerative disorders, as well as brain trauma.”

‘Reversing a model of Parkinson’s disease with in situ converted nigral neurons’ by Hao Qian et al. was published in Nature at 16:00 UK time on Wednesday 24 June 2020.

DOI: 10.1038/s41586-020-2388-4

Declared interests

Dr Tilo Kunath: “No conflicts of interest. My research is funded by Cure Parkinson’s Trust.”

Prof Robert Howard: “Trustee of ARUK.”

Prof Tara Spires-Jones: “I have no conflict with this paper.”

Prof John Hardy: “No conflicts.”

Prof Bart De Strooper: “No conflicts of interest to declare.”

None others received.