Trials to treatments: stem cells

We take a look at the science behind trials that aim to slow and reverse Parkinson’s by using stem cells or other cell therapies.

Dr Beckie Port
Sep 24, 2018 · 15 min read

Parkinson’s is caused by the loss of brain cells that produce the chemical dopamine. Research over the last few decades has focused on finding ways to slow or stop this loss to slow the progression of Parkinson’s. Indeed, there are ongoing trials of promising therapies that aim to protect and nurture remaining dopamine-producing cells. But with half these cells lost or damaged by the point of diagnosis, a cure for Parkinson’s may also require a therapy that can reverse the damage that has already been done — this is where cell-based therapies that aim to replace those cells come into their own.

Quick summary if you’re in hurry

  • There are many different cell-based clinical trials happening all over the world.
  • Because of the different types of cells being used and where they are being put into the body, some trials may help to protect brain cells and slow Parkinson’s while others aim to reverse the condition.
  • Currently, there is no stem cell or cell transplant therapy available that has been shown to slow or reverse Parkinson’s, despite what you may read on the internet. But we are making huge strides towards this becoming a reality.

Early clinical trials of cell-based therapies

When it comes to clinical trials of cell-based therapies, Parkinson’s was at the forefront of research at the turn of the century. Researchers were focusing on transplanting cells into the brain to directly replace those that had been lost.

The first cell transplant trial for Parkinson’s happened in the 1980s and was followed by the first placebo control trial in 2001. However, these trials produced a mixed bag of results. Some participants did remarkably well and saw improvements in their symptoms even after many months — a few were even able to come off their Parkinson’s medication. But others experienced little or no improvement. There were also a few who unfortunately developed distressing uncontrollable movements known as dyskinesia.

The theory was that better results would come from improving the techniques being used as well as transplanting more dopamine-producing cells. But these weren’t the only hurdles that needed to be overcome, there was also a problem due to the type of tissue being used. These trials used cells from human foetal tissue — a scarce and precious resource. If transplants are ever to become a viable treatment a different source of cells had to be developed.

It was time to turn to stem cells...

The potential of stem cells

When it comes to cell therapies in Parkinson’s, many people will have come across stem cells. They are the original cells from which we are made and are responsible for repairing our tissues and organs when they get damaged. Indeed, these cells are so powerful that in some animals — like the salamander and starfish — they are responsible for the superpower-like ability to grow entire new limbs or body parts when the original is damaged.

It is because of their regenerative capacity that researchers have been trying to find ways to use them to treat conditions like Parkinson’s where cells have been lost or damaged beyond repair. The hope is that we may be able to use them to grow new healthy cells and replace those lost in Parkinson’s.

But that’s not all, stem cells also produce key protective factors that may also help other cells repair and regrow — so simply having stem cells in the right part of the body could also have benefits.

Perhaps this latter fact is one of the reasons why, if you were to search for stem cell therapies in Parkinson’s online, you can find a number of clinics in other countries offering treatments. Sadly, these treatment centres are often a scam — there is no current cell-based therapy available for Parkinson’s that has been proven to work in clinical trials, so we don’t know if they are safe or if they work. They also charge thousands of pounds, which we believe to be highly unethical.

You can find out more about this and read James’s story about undergoing treatment in our blog, “What’s in an anecdote?”

However, this shouldn’t put you off of reading the rest of this post and finding out about real advances being made towards effective cell-based therapies for Parkinson’s.

Today, there are a number of trials investigating the potential benefits of injecting different types of stem cells into the body. While it’s unlikely that these cells will be able to enter the brain, they may still hold potential to slow the progression of Parkinson’s because of the protective factors they make — only time will tell if this is the case. Perhaps more exciting are the advances being made in transplantation studies — that aim to introduce new cells directly into the affected area of the brain — as they hold the most potential for not only slowing Parkinson’s but perhaps even rewinding the clock.

We will look at current trials in more detail later, but to understand how they differ let’s first take a look at some of the types of stem cells being explored.

The many types of stem cells

While the regenerative power of stem cells is at the cutting-edge of research, people have known that our tissues and organs have the capacity to regrow for thousands of years. The regenerative ability of the liver even features in Greek mythology. The myth goes that when Prometheus defied the gods they sentenced him to eternal torment, each day a vulture would eat his liver only for it to regrow as fast as it was damaged.

We now know that the ability of our tissues to regrow is due to the presence of stem cells. But it’s not just when cells get damaged that stem cells are activated, there are types of stem cells that are active throughout our lives.

Whatever your age, your body is many years younger. This is because almost all of our organs and tissues contain ‘adult stem cells’ that can turn into many different types of cells and help our body to replace old or damaged tissues. But adult stem cells can only develop into a limited number of cell types. For example, bone marrow stem cells naturally develop into blood cells but not brain cells.

Adult stem cells were first discovered in the 1960s, and we now know they can be found all over the body, including in our brains. Some forms of adult stem cells already provide vital treatments. For instance, bone marrow contains adult stem cells that make all our different blood cells which means that bone marrow transplants from healthy donors can be used to treat blood disorders like leukaemia.

Unfortunately, when it comes to repairing the body naturally, adult stem cells can only do so much — and the stem cells present in our brains (called neural stem cells) are not able to prevent or repair the damage being done in Parkinson’s.

And while neural stem cells can feasibly develop into new brain cells, taking a brain biopsy to collect neural stem cells from a donor would do too much damage. So we need a different source of stem cells to make new brain cells for people with Parkinson’s.

Stem cells that can develop into any type of cell in the whole body were discovered in the early 1980s inside developing embryos. This multifaceted ability, known as ‘pluripotency’, makes embryonic stem cells extremely powerful as they are much easier for researchers to manipulate into the cells they need. It also allowed researchers to start working on developing the recipes for making different types of cells, including dopamine-producing brain cells.

Making new brain cells

Following the semi-successes of early cell transplantation studies, in the early 2000's the focus of research shifted to how to make new dopamine-producing brain cells for transplant.

Some early successes came by using a complex method that involved giving the stem cells different proteins and factors at different times to coax them into turning into brain cells, and then specifically towards the dopamine-producing variety.

Results from experiments, such as those published in Nature in 2002, showed that transplanting these new cells into the brain may be able to relieve the symptoms of Parkinson’s, at least in rats.

But with the ability to turn stem cells into different types of adult cells, some researchers became interested in whether the reverse might be possible. With the right combination of proteins and factors, could adults cells also turn back into stem cells?

In 2006, a major breakthrough came when scientists in Japan showed it was indeed possible to turn adult cells into stem cells. They called these man-made cells ‘induced pluripotent stem cells’ or iPS cells. The ability to make stem cell in this way has opened new doors for research because of the advantages of using iPS cells over other types of stem cell:

  • Firstly, researchers no longer need embryonic stem cells as a starting point for experiments — the ethics of which requires these type of research to very carefully controlled. Instead, they can now take a sample of adult cells and turn them into man-made stem cells, which do not have the same level of ethical concern.
  • It also means that scientists can now study brain cells from patients in the lab to investigate what goes wrong in conditions like Parkinson’s — something that is really handy as getting a sample of brain cells by any other means is somewhat tricky.
  • Finally, iPS cells could provide a way of using a patient’s own cells to treat their Parkinson’s. This may help to reduce the risk of ‘rejection’ that can be a problem in organ transplants because the immune system recognises the new cells as foreign and attack them. So people receiving cell transplants in future might not need to take immunosuppressant drugs.

Using iPS cells made from human skin cells, in 2010 US scientists showed it was possible to use transplanted brain cells to improve the symptoms of Parkinson’s in a rat model of the condition. Then in 2017, researchers at Japan’s Kyoto University published results showing man-made dopamine-producing cell transplants were able to improve movement symptoms in macaque monkey model of Parkinson’s. They also used brain scans to show that the cells were functioning like normal dopamine-producing brain cells and were successfully producing dopamine.

Finally, the team published results showing they had successfully used the principles of matching for organ donation to select the best brain cells for transplantation. This reduced the immune response to these human transplants, which is vital for ensuring the survival of the transplanted cells.

These results have finally paved the way for clinical trials to test the potential of transplanting new brain cells made from stem cells in people.

Current cell-therapy clinical trials

When it comes to active clinical trials of cell-based therapies, there is lots to talk about. There are trials using different types of cell, from stem cells to various types of brain cells that have been produced in different ways. There are also trials that attempt to inject cells, transplant them into the brain and even get them into the body through the nose.

1. Giving stem cells outside of the brain

There are a number of trials looking that the potential of using different types of adult stem cells for Parkinson’s happening all over the world. One example is a phase 1/2 trial based in Texas that started in 2015. The study is using stem cells collected from bone marrow, and aims to recruit 20 participants to see if injection of these cells into the blood is safe. It will also collect results on if this type of therapy can improve movement symptoms of Parkinson’s, among other measures.

Another study worth note, although not for its scientific merit, is taking a slightly different tack to getting stem cell into the body. In a rather ambitious phase 2/3 trial happening in China, researchers will attempt to give neural stem cells through the nasal track of 12 participants to see if it can cause Parkinson’s to go into remission. Personally I don’t hold out much hope for the success of this particular trial.

Potential of this type of therapy: Stem cells produce a range of protective factors that could help to protect brain cells and slow the progression of Parkinson’s. The pros of this technique are that various types of adult stem cells — such as those from bone marrow — are easily accessible and the therapy doesn’t involve brain surgery so would be less invasive than other therapies in this post. The cons are that these cells will be unable to get into the brain, and the lack of proximity could hamper their effectiveness.

2. Transplanting brain cells collected from foetal tissue

Today it has been over 20 years since the first cell transplant trial in Parkinson’s ended. While results from previous trials have been inconsistent, much progress has been made in our understanding of the brain and the surgical techniques used for transplants. We have also benefited from some of those who took part in the early trials, who have since passed away, donating their brains to research . This has allowed us to see that in some people the cells that were transplanted survived for many years and integrated into the brain. So, now researchers are working to prove that cell transplants can work consistently for people with Parkinson’s.

The TRANSEURO trial, which started in 2012, aims to test the safety and effectiveness of transplanting brain cells collected from foetal tissue into the brains of 40 people with Parkinson’s. The phase 1 trial, which involves the collaboration of researchers from several European countries, including the UK, is well underway and should finish in 2021.

“We are continuing to work on developing the next generation of stem cell therapies for Parkinson’s. If we can prove that transplants can work consistently for people with Parkinson’s, we’ll be able to move into trials with stem-cell derived nerve cells as quickly as possible.”

— Roger Barker, research lead on the TRANSEURO trial

Additionally, a further phase 1/2 study is happening in Korea, which also aims to test the transplantation of foetal brain cells in 15 people with Parkinson’s. If successful, these studies could provide a blueprint for emerging stem cell therapies — giving insight into the best way to transplant these new cells and understanding of if these cells survive and integrate into the brain.

Potential of this type of therapy: Result from studies of transplanted foetal tissue have been mixed, but with advances in the techniques there is real hope that these trials may reverse Parkinson’s. The pros of this technique are that the foetal tissue contains the developing dopamine producing cells that are being lost in Parkinson’s, and these cells have previously been seen to integrate into the brain. The main drawback is that the availability of foetal cells means this therapy could not be made available for everyone.

3. Transplanting other types of brain cells

While TRANSEURO aims to transplant cells from an area of the foetal brain that would contain developing dopamine producing brain cells, other transplant trials have focused on the potential of other types of brain cells.

NTCELL® therapy uses a type of cells from an area of the brain known as the choroid plexus. These cells are naturally occurring ‘support’ cells , which release chemicals that help protect other brain cells. The current phase 2b trial is due to finish next year and will use choroid plexus cells taken from pigs, which are packaged inside a specially designed capsule. It aims to find out if the therapy is safe and reduce Parkinson’s symptoms, and results from the study announced earlier this year are looking positive so far.

Potential of this type of therapy: The type of cells used in NTCELL® therapy produce factors that help protect brain cells, which could slow the loss of cells in Parkinson’s. The main pro of this technique is that the cells being used may be more available than other therapies in this post. The limitation is that these cells do not produce dopamine and cannot replace what’s already been lost, so are unlikely to reverse Parkinson’s.

4. Transplanting stem cells into the brain

The first trial of this kind came early in 2016 when California-based company, the International Stem Cell Corporation (ISCO), announced their phase I trial that aims to inject a type of neural stem cells into the brains of 12 people with Parkinson’s.

The 12 month trial is taking place in Melbourne, Australia, and is currently recruiting people with moderate to severe Parkinson’s. During the trial, doctors will transplant brain stem cells grown from human stem cells, into participants’ brains. However these cells are not the same type of cell that is lost in Parkinson’s and when the trial was first announced, world-leading scientific experts, including Parkinson’s UK researcher Professor Roger Barker from the University of Cambridge, raised questions about the approach being used in an article in the Journal of Parkinson’s Disease.

Since this first trial was announced, other transplant trials using neural stem cells have reportedly begun, including a phase I/II trial in China that is currently recruiting 50 participants.

These early-stage clinical trials will focus on the safety of the therapy, so we may have to wait for further trials before we know if transplanting neural stem cells can help in Parkinson’s.

Potential of this type of therapy: Neural stem cells produce protective factors that could help to slow the progression of Parkinson’s. The pros of this technique are that we can make this type of cell and by transplanting them into the right brain areas they may be able to help protect remaining cells. The cons are that we still don’t know enough about the long term safety of transplanting cells that have been grown in a lab and, despite having the capacity to turn into dopamine producing brain cells in the lab, we do not expect them to do so in the brain.

5. First transplant trial of lab made dopamine-producing brain cells

Following successes in monkeys, researchers in Japan have announced a clinical trial to transplant dopamine-producing brain cells made in the lab from iPS cells will start in 2018.

You can read more about this trial on our website.

We will eagerly be awaiting more information and the outcome of this and the other trials mentioned in this post and hope that it will contribute to more research in this area, and future opportunities for those in the UK to take part.

Potential of this type of therapy: Dopamine-producing brain cells are the type of cell lost in Parkinson’s and transplanting them into the brain may be the best hope for repairing the damage and reversing the condition, making this study one of the most exciting ones to follow going forwards. Potential challenges to this approach are all about safety — these techniques are still very new, so we don’t know much about the long-term safety of lab-made cells.

Stem cells definitely hold huge potential for developing therapies for Parkinson’s, but we still have a number of questions to answer and challenges to address before they will be a therapeutic option for people with the condition. We still don’t know enough about if these transplant therapies will improve both motor and non-motor symptoms of Parkinson’s, such as problems with thinking, memory, pain, and anxiety. We also need to know:

  • Are they safe? Because stem cells are so powerful and have the ability to become many cell types, they could lead to tumours forming in the brain or the cells could even escape into other areas. We need to be confident that the cells we introduce stay in the right place and do the right thing.
  • Will they survive? The brain is unimaginably complex, it contains billions of nerve cells which are all connected in complex circuits. How can we be sure that the new, healthy cells we add will be able to integrate into the brain and do the job of the ones that have been lost? And will new cells be able to survive in the Parkinson’s brain when other cells have already died?
  • Are they practical? Using living cells to treat illnesses is much more complicated than using drugs. Each patient may need 100 million cells! How will we grow enough cells of the right type to treat thousands of patients? And how will we regulate these new treatments to make sure the cells being produced are the right ones and are of high enough quality? Will stem cell treatments be cost-effective enough to be provided on the NHS?

How long this will take is, unfortunately, impossible to say. We may solve the problems straight away but, then again, we may uncover new challenges too. But the more we and other funders can invest in the research, the faster we’ll get there.

Enjoyed this blog? Read another from the trials to treatments series

Parkinson’s is a progressive neurological condition that affects about 145,000 people in the UK and an estimated 7–14 million people worldwide. There is currently no cure, and we desperately need better treatments.

You can help us speed up the development of new and better treatments, and a cure for Parkinson’s by donating to groundbreaking research today.

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