Two presentations at the International Society for Stem Cell (ISSCR) conference, from two different sides of the pond, looked at ways to get stem cell therapies out of the lab and into patients. They both focused on the problems that need to be overcome, but came to the positive conclusion that this could be done.
Lorenz Studer, from the Sloan Kettering Institute for Cancer Research, has been working since 1995 to try and find a renewable source of cells to treat Parkinson’s Disease. He thinks he’s finally found it.
Let’s back up a little. Studer says the key movement problems seen in people with Parkinson’s (tremors, rigidity, difficulty moving) are caused by a loss of the dopamine-producing neurons in their brain. The good news is that this creates a great target for researchers to try and find a replacement. The bad news is it’s devilishly difficult producing the right kind of cell to survive and function in the brain.
In the 1980s fetal tissue transplants were tried to treat the disease and while these tissues seemed to engraft into the brain and have survived, in some cases, for more than 30 years, they only benefitted a small number of patients and had some unexpected side effects in others. So Studer focused his approach using dopamine-producing neurons (the kind that are destroyed by Parkinson’s disease) that derived from human embryonic stem cells (hESC).
He found that these hESC dopamine neurons worked well in animal models, surviving term and mirroring the normal development of a human neuron.
Studer says new MRI technology means we can be much more precise in where we place these cells in the brain, ensuring that they go exactly where we want them.
So Studer feels he has the right cells in the right number and the ability to place them in the right location. But that still left a number of questions: how do we know they are engrafting into the brain and producing dopamine, and is that producing any impact on behavior?
Studer turned to optogenetics, the use of light to control neurons, to assess and measure what was happening in the brain with these transplanted cells. He put markers into the neurons that were being transplanted and then used pulses of light to switch them on and off. Turning the cells off stopped the dopamine production; turning them back on increased it. They found that the cells were indeed functioning and producing the dopamine.
That still left the question of whether that actually changed behavior. So he devised a study comparing mice with healthy brains to those with Parkinson’s-like lesions on one side of the brain. He put the mice in a tunnel with food pellets on either side of it. The mice with a healthy brain went along the tunnel and ate food from both sides. The other mice ate food almost completely from just one side: the side opposite where the lesion in their brain was.
Then Studer transplanted the dopamine-producing neurons into the study mice and repeated the experiment. This time they ate from both sides of the tunnel suggesting the transplanted cells were producing dopamine, affecting behavior in a positive way.
He hopes to be in clinical trails in patients in late 2016 or early 2017.
For Roger Barker of the University of Cambridge, UK, finding the right cells was only one of four basic questions that need to be considered when trying to take stem cell therapies into clinical trials:
- What is the evidence that cell therapies work in replacement
- Can you make an authentic, effective cell replacement
- How can you test such therapies in patients
- Are these competitive to existing therapies
Baker says numerous studies in animals over the years have shown that using dopamine-producing stem cells to replace the damaged cells can increase dopamine levels.
A European contingent called TransEuro is about to start a clinical trial to see if this also works well in people. This consortium is using fetal tissue and will treat patients with more early stage disease when, at least in theory, it’s more likely to respond to the therapy. They hope to transplant their first patient in the next four weeks.
Can you make an authentic dopamine producing neuron? Baker said Studer’s work suggests you can, as long as it is a form of the cell called an A9 NIGRAL dopaminergic neuron. Barker says even these cells are not perfect cells but they have enough qualities to suggest they are worth trying.
Barker says many therapies have been tested in early stage clinical trials in the past that, based on preclinical evidence, weren’t good candidates. When they failed they set the field back by creating the impression that stem cells wouldn’t work for this kind of approach when the real lesson is that stem cells may well work, but they have to be the right ones, used in the right way.
He says GFORCE—a consortium featuring CIRM, and groups in New York, the UK and Japan—is now working as a group to set common standards and agreed upon best practices, so future trials can be compared to each other rather than stand alone.
Here at the stem cell agency we have also created a Regenerative Medicine Consortium to bring together leading companies, academic and funding institutions to share best practices and resources, and to help speed up this process and make it more consistent and efficient.
Many existing therapies today work very well in helping control some of the symptoms, at least in the early stages. To be effective these new stem cell therapies have to be at least as good—and at least as affordable—as existing treatments. Whether that proves to be the case will determine whether, even if they show they are effective, they become widely available.
Both scientists acknowledge we have come a long way in recent years. Both also acknowledge we still have a long way to go. But at least now we seem to all be asking the same questions and that is a clear sign of progress.
At the stem cell agency we have invested more than $43 million in 23 different research projects aimed at finding new treatments for Parkinson’s.