Stem Cell Therapies for Parkinson's

Although the underlying cause of Parkinson's disease is unknown, scientists do know that Parkinson's (PD) results from the impairment and death of dopamine producing cells in an area of the midbrain called the substantia nigra.

It stands to reason therefore that replacement of those cells is a viable and potentially potent treatment method. Although it is acknowledged that Parkinson's symptoms extend to other areas of the body, namely the gut, treating the brain with new neurons could in theory address these problems as well.

The most promising therapy being developed in this treatment method is stem cell therapy, now commonly referred to as cell replacement therapy or CRT. It works by placing new dopamine producing neurons into the part of the brain where the dead or dying neurons were once producing sufficient dopamine. CRT will therefore generally be for people who have had PD for a longer time and whose remaining healthy neurons are not capable of providing enough dopamine.

Stem cell therapies in the late 80’s and 90’s saw a number of CRT trials for Parkinson’s with mismatched protocols and mixed results. But science has progressed in this field enormously and we now have a much better understanding of what kind of cells to use, how to develop and nurture the cells, how to implant them, and for whom this therapy would be best suited. 

The TRANSEURO study led by Prof. Roger Barker which is part-funded by CPT, is looking at human foetal dopamine transplants and aims to address issues of consistent efficacy and avoiding the side effects of the involuntary graft induced movements from earlier mismatched studies. This new study is reinforcing correct protocols for the future of stem cell therapy. To date in this trial 7.5 people have been transplanted with foetal grafts in Cambridge and 2.5 people in Sweden (where .5 is one side of the brain). A total of 13 people will receive the transplant cells and will be followed up long term. Planning is also underway for further embryonic stem cell-based clinical trials of cell transplantation in PD between Sweden and the UK led my Professor Malin Parmar. Professor Barker and Professor Parmar are part of an international consortium of labs around the world cooperating with each other for CRT in PD under the name of GForce-PD. Each lab in the GForce-PD aims to bring CRT for PD to clinical trial within the next few years.

Read Prof. Malin Parmar's recent blog post for The World Parkinson Coalition

There are two further types of cell which are viable for transplantation. Embryonic stem cells or ESC's - taken from IVF tissue donation -  and induced pluripotent stem cells or iPSC's - chemically reprogrammed cells, usually from adult skin tissue and blood cells and capable of becoming almost any cell in the body. ESC's and iPSC's are both capable of being made into dopamine-producing cells. In the lab these cells become too mature to then be transplanted. They therefore have to be chemically 'coaxed' to a stage in their development whereby they are just at the phase before becoming dopaminergic neurones, which then, when transplanted are able to grow and mature into neurons which produce dopamine as the graft in the brain becomes established. Pre-clinical studies in the lab are resulting in fully functioning dopamine producing neurons. We are in the midst of these significant trials now.

Dr. Lorenz Studer - U.S. - and part of G-Force-PD - pioneered many of the reprogramming techniques being used around the world to convert pluripotent stem cells into dopamine producing neurons. His lab was recently announced to be part of a huge funding initiative from Bayer Pharmaceuticals to help speed up development of CRT. Dr. Studer’s lab is aiming to start transplantation of embryonic stem cells in human trials in early 2018.

Dr. Jun Takahashi’s lab in Kyoto, Japan is working on producing several iPSC's for the Japanese population. One advantage they have is the relative homogeneity of Japanese people allows them to use a dozen or so iPS lines for almost everyone in the country. The lab recently made headlines with results from pre-clinical trials that showed human iPS cells graft safely, with no signs of malignant growth, two years after transplantation. 

Further Understanding of PD and developing new drugs:

Transplantation is not the only application for stem cells. Scientists are making IPSC's from patients with Parkinson’s disease, and using these stem cells to produce diseased neurons in the lab. These neurons act as a powerful tool to study the neuropathology of PD and can be used to test substances developed into new drugs to effectively treat the disease. Dr Tilo Kunath's laboratory in Edinburgh is leading the way here. CPT is providing funding for Dr Kunath's research.

Dr Kunath, under the GForce collaboration - is also producing pure batches of dopamine neurons under a highly technical process that only a few labs in the world are capable of doing safely and effectively to better differentiate and characterise the cell lines which are planned to be used for transplantation.

So what does the future hold?

These therapies being developed for Parkinson’s disease will, in essence, be version 1.0 of CRT. Clinical trials are set to begin next year and the therapy is expected to be widely available to people diagnosed with Parkinson’s disease within the next 5-10 years.

Version 2.0 will be CRISPR-modified (through gene editing), disease resistant grafts, with genetic switches to modulate dopamine production and graft size.

Version 3.0 will make use of an emerging field called in vivo direct programming where viruses are inserted into the brain and transform other existing cells into dopamine producing cells

Thanks to Dr Simon Stott - 'The Science of Parkinson's Disease' and 'Futurism' Ben Stecher

Further Reading:

https://www.nature.com/articles/npjparkd201614

http://www.press.bayer.com/baynews/baynews.nsf/id/Bayer-Versant-Ventures-Join-Forces-Launch-Stem-Cell-Therapy-Company-BlueRock-Therapeutics-USD

https://www.nature.com/news/reprogrammed-cells-relieve-parkinson-s-symptoms-in-trials-1.22531

'Parkinson's Cell Transplants Show Good Innervation After 24 Years' news article May 2016.

Parkinson's disease induced pluripotent stem cells - Nature Communications 2, Article number: 440

Note: Although there is a lot of excitement surrounding CRT, we must proceed with care. The field has potential for setbacks from some of the less rigorous trials being conducted in places like Australia and China where regulatory standards are not as stringent as they perhaps should be. Researchers in these areas are already going ahead with trials that do not meet the standards set by the GForce-PD. These have the potential to set back if not halt proceedings on all cell replacement therapies. This editorial in the Journal of Parkinson’s disease is worth reading - it is open access ~ Click here to read the article .

Image courtesy of Dr Tilo Kunath ~ Ediburgh University