Dr Eilish Dowd (NUI Galway) Report on World-First in Parkinson's Cell Transplantation:

This Week: A World-First in Parkinson’s Cell Transplantation

 

Please note: This article refers to using tissue from aborted human foetuses which some readers may find distressing.

 

You may have read the news reports this week about a person who received a world-first cell transplant for his Parkinson’s. These reports centre around an article published on Friday 14th May in the prestigious medical journal, The New England Journal of Medicine, which described a case study of a man given a transplant of brain cells that were generated, in the laboratory, from his own skin cells.

 

This is indeed a world-first, and to explain why, I want to take you on a brief journey through the development of cell transplantation for Parkinson’s from its earliest days, right through to this current report.

 

What is cell transplantation for Parkinson’s?

Cell transplantation for Parkinson’s has a very simple premise – if some of the main symptoms of the condition are caused by the loss of brain cells called dopamine neurons, then it should be possible to treat the condition by replacing these with healthy dopamine neurons. The concept is simple, but the execution has proved anything but.

 

The first question with any transplantation therapy is where to get the transplantable tissue from. In most cases of tissue and organ transplantation, these are taken from consenting donors, but this is simply not possible with brain cell transplantation because of the extraordinary complexity of the cells.

 

The brain cells that are required for transplantation in Parkinson’s are the dopamine producing neurons that originate in the middle of the brain (in the substantia nigra) and project forward to a part of the brain responsible for enabling movement (the striatum). In the striatum, these cells branch like the most complex tree you can imagine (see image below) so that they can connect to the cells in the striatum, release dopamine, and allow us to move. Not surprisingly then, it is impossible to remove these cells from the brain without damaging them and causing them to die.

 

Dr Eilís Dowd

NUI Galway

 

What was the first source of cells for transplantation in Parkinson’s?

Because of the complexity of the dopaminergic neurons, researchers quickly came to realise that they could only be removed from the brain at an early stage in their development before they had formed their projections to, and branches within, the striatum; essentially while they were still small round cells in the developing substantia nigra. This meant, in countries where abortion was a legal medical procedure, taking the cells from the developing human foetus after elective abortion (with informed consent from the maternal donor).

 

The early clinical trials of cell transplantation

Once a source of dopamine cells for transplantation was identified, clinical trials of the procedure could begin. The first trials initiated in the 1980s and trials have continued intermittently over the intervening decades, right up to the present day with one such trial ongoing in the UK. These trials, using human foetal donors, have shown us that these dopamine cells can survive after transplantation into the brains of people with Parkinson’s, that they can form branches that connect them to the cells in the striatum, and that they can release and restore dopamine levels. For some, but not all patients, this led to a considerable improvement in their movement and quality of life, as well as a reduction in intake of their Parkinson’s medication.

 

Of course, it goes without saying, that using human foetal cells for transplantation could never be rolled-out as a wider therapy for Parkinson’s, not just because of the associated ethical issues, but also because of the sheer impracticality of it (the logistical and safety issues were virtually insurmountable). So researchers turned to finding a better source of cells, one that would work just like the foetal dopamine cells, but that would also be more ethical and easier to source.

 

Embryonic stem cells as a source for transplantation

A major breakthrough came in the late 1990s when the first embryonic stem cells were isolated from very early human embryos, after in vitro fertilisation, and grown in the lab. Embryonic stem cells are “immature” cells which can multiply and replicate themselves, and which have the capacity to develop and mature into other types of cells such as skin cells or muscle cells, or in the case of cell transplantation for Parkinson’s, dopamine neurons.

 

Nevertheless, there were still several major obstacles facing researchers. The first was that they had to figure out how Mother Nature converts embryonic stem cells into dopamine neurons so that they could replicate this in the laboratory. The second was that, because of their ability to multiply and replicate themselves, using embryonic stem cell sources carries an inherent risk of tumour formation after transplantation onto the brain. And finally, although using embryonic stem cells isolated after in vitro fertilisation may be more ethically acceptable (to some) than using human foetal tissue sourced after abortions, it certainly did not resolve the issues completely.

 

Induced pluripotent stem cells (iPSCs) as a source for transplantation

The next major breakthrough in the field came as recently as 2006 when Japanese scientist, Shinya Yamanaka from Kyoto University, reported that he had developed a protocol for “deprogramming” mature cells, such as skin cells, back into a stem cell state. The discovery of these so-called induced pluripotent stem cells (iPSCs) was a pivotal point in this field of research, which led to Yamanaka being awarded the Nobel Prize for Physiology or Medicine in 2012.

 

With the discovery of iPSCs, the ethical issues were completely resolved as a simple skin biopsy could be used as the source of the cells. These could then be deprogrammed from skin cells to iPSCs, multiplied in the lab to the numbers required for transplantation, and then, theoretically, be reprogrammed into dopamine neurons by replicating the signals developed by Mother Nature over millions of years of human evolution.

 

Over the following 10 years or so, researchers from all over the world, focussed on developing protocols for reprogramming these iPSCs into the exact type of dopamine neuron required for transplantation in Parkinson’s, and also on developing protocols for minimising the risk of tumour formation in the brain if these cells were used for transplantation.

 

The decades of work described above led to the very first clinical trial of transplantation for Parkinson’s using dopamine neurons derived from stem cells. This trial, which is currently ongoing, was initiated in 2018 by Jun Takahashi and colleagues from Kyoto University, and will see 7 patients transplanted with iPSC-derived dopamine neurons. This trial is a world-first and we all anxiously await its outcome.

 

So what did this week’s study show?

This week’s report is also a world-first. It is a case study of a man in the US who was transplanted with iPSC-derived dopamine neurons, much like the ongoing Japanese study, but with one major difference; in this case, the patient was transplanted with cells that were generated from his own skin cells. This is the very first time anyone, anywhere has been transplanted with their own skin cells deprogrammed into iPSCs and reprogrammed into dopamine neurons.

 

Before reviewing this report, it is important to realise that this report is a case study of a single person, that both he and his medical team knew that he had received a cell transplant (which could influence the outcome), and that there was no control (such as a fake surgery or dummy transplant) built into the study design. With these realisations front and centre of our minds, let’s look at the report.

 

The patient, who is not named in the scientific publication, but several news articles name him as George Lopez, is a 69 year old man from California. At the time of his surgery, Mr Lopez had been experiencing Parkinson’s symptoms for 10 years, and was taking several medications (including Sinemet®). As mentioned above, Mr Lopez underwent a skin biopsy from which iPSCs were derived, multiplied and converted into dopamine neurons. He then received a transplant of 4 million cells into his left striatum, followed 6 months later by 4 million cells into his right striatum. Mr Lopez was then monitored for 2 years from the time after his first surgery.

 

PET and MRI imaging data indicate that this world-first, patient-derived iPSC transplant is surviving in Mr Lopez’s brain, that it is releasing dopamine where it is required, and that it has not formed any tumours. Most importantly to all of the readers, Mr Lopez was also followed up for improvements in his symptoms using rating scales some of you may be familiar with (the Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the 39 item Parkinson's disease questionnaire (PDQ‐39)).

 

On the MDS-UPDRS, which was scored by Mr Lopez’s neurologist, some improvement was evident during both OFF and ON periods but it was slight. On the PDQ-39, in which Mr Lopez scored his ability to perform everyday activities such as washing and dressing himself, tying his laces and doing up his buttons; looking after his home, carrying his shopping, or going for a short walk; his emotional wellbeing, his cognition and his ability to communicate, Mr Lopez reported a dramatic improvement in his quality of life.

 

So what does this all mean?

From my perspective, this is an exciting report as it is a true world-first in a field that I have been working in for almost 20 years. It is exciting to know, after all of the issues that have dogged the cell transplantation field for Parkinson’s for so many decades, that someone, somewhere has received a transplant of an ethically-sound source of dopamine neurons. Whether the approach has “worked” is impossible to say from a single case study, and we all still anxiously await the outcome of the Japanese iPSC clinical trial. Nevertheless, we – you, the patients, your families, the researchers, the scientists, the clinicians – are all edging towards cell transplantation as a valid therapeutic option for some people with Parkinson’s.

In the meantime, the very best we can all do for our brains is to keep them active to whatever extent that is possible, for any given person, on any given day. Physical activity, emotional activity, mental activity, spiritual activity – alone or with family or friends, it all counts towards keeping our brains healthy.

Keep well everyone.

Eilís

Dr Eilis Dowd, NUI Galway.

Senior Lecturer in Pharmacology and Parkinson’s Research Scientist.

Also daughter, sister, aunt, wife and mother.

References

The original New England Journal of Medicine article is available to read here (but it is behind a paywall): https://www.nejm.org/doi/10.1056/NEJMoa1915872

The RTÉ report on the article is here: https://www.rte.ie/news/world/2020/0513/1138285-reprogrammed-skin-cells-helps-parkinsons-patient/

For more on cell transplantation therapies, this review was written in memory of the late, great Tom Isaacs: https://onlinelibrary.wiley.com/doi/full/10.1111/ejn.14109

 

 

 

 

 

 

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