Stem Cells for Parkinson’s: Hype or Hope?
You might have heard about stem cells for PD for many years now, and perhaps you’re wondering: Where are these stem cells - will they ever reach the clinic, or have they ended up in a dead-end? And is there even any evidence that they’re any good? Here, we’ll try to give you an overview of what’s been going on behind the scenes for the past 20 years, and what the current status is on stem cells and their use in the clinic.
As you might already know, a core feature of PD is the loss of dopamine neurons deep in the brain, in an area called the Substantia Nigra. Although other brain areas may also be affected in PD, it’s the loss of these dopamine neurons which is the cause of the motor symptoms in the disease. The use of stem cells for treatment of PD builds on the concept that one can replace the lost dopamine neurons through transplantation of new, functional dopamine neurons generated from stem cells in the lab. The aim is that the new transplanted neurons will integrate with the host neurons in the patient’s brain tissue and start release dopamine. Since dopamine neurons carry an intricate set of receptors and membrane pumps on their surface, they’re excellent at sensing the levels of dopamine in the brain tissue, and they can therefore perform fine-tuned control of dopamine release and re-uptake to ensure that there’s never too much or too little dopamine in the brain. This feature makes a dopamine neuron transplant very different from drug treatment, as dopamine medications can often lead to fluctuations in dopamine release, resulting in oscillating ON and OFF states and in some cases also severe drug-induced dyskinesias. Another advantage of transplanted dopamine neurons is that they can be placed precisely in the region of the brain where the dopamine is most needed (i.e. in the putamen), thereby avoiding production of dopamine in areas of the brain where it’s not beneficial (e.g., in the cortex, where dopamine can cause hallucinations).
OK, so that all sounds very good, but how do we know that this Sci-Fi-like treatment can ever work in patients? Here, we need to go back in time to the late 80’s and 90’s, when scientists in Europe and the USA performed a number of small transplantation trials of dopamine neurons in PD patients. At this time, stem cells were not available, and instead these scientists obtained dopamine neurons from aborted human fetal tissue, i.e. they used a tiny piece of brain tissue obtained from early aborted fetuses (around week 6-10 weeks of pregnancy), coming from clinics conducting legal and controlled abortions. The fetal brain dopamine neurons were transplanted into the putamen of PD patients and changes in their symptoms were followed over time. It turned out that some of these studies failed to show any effects of the transplants whereas others showed a remarkable effect, so what’s really the story here? After many years of scrutinizing data from transplanted patients from different sites around the world, here’s how we today interpret the variable outcome of these fetal tissue transplantation trials. In retrospect, this is likely due to several reasons: 1) Many patients did not receive sufficient amounts of transplanted dopamine neurons (i.e. problems of tissue availability led to underdosing in many patients); 2) Some of the trials used only very short periods of immunosuppression which led to an immune response, i.e., rejection of the transplanted cells by the host immune cells; and 3) Some trials only had a short follow-up of their patients (1-2 years), whereas we know today that the maximal effect of a dopamine transplant is likely to be evident at 2-5 years after transplantation. In contrast, in those studies where patients had good survival of the transplanted cells, there was evidence of marked clinical benefits on motor function and some patients were even able to go off their dopaminergic medication for more than 10 years. Taking everything together, we find that there is good evidence from clinical studies, as well as from the preclinical studies that have been performed in animal models, that when the quality and dosing of the cells is optimal and the clinical trial design is performed correctly, the transplanted dopamine neurons can give significant and long-lasting improvement of motor function.
Since the clinical studies in the 80’s and 90’s, science has continuously advanced, and we’re now able to produce high-quality populations of dopamine neurons from stem cells in the lab. This means that we’re no longer dependent on using aborted fetal tissue, which is hampered by ethical issues as well as being highly variable in quality and availability. Instead, we can now produce much more standardized and pure populations of dopamine neurons in the lab, and we can produce these on a large scale, making it possible to treat thousands of patients. After many years of testing in animal models, this new second-generation class of dopamine neuron transplants has only recently advanced to the stage where it’s ready to go into clinical trials. We’re now entering exiting times where several groups across the world are bringing well-controlled and high-quality stem cell-derived dopamine neurons into clinical trials after having worked to optimize their cell products for the past 10-15 years. As of now, clinical transplantation trials with stem cells have been initiated in Japan (by Kyoto University Hospital) and New York (by Blue Rock Therapy), and there are several other clinical trials in the pipeline in Chicago (by Cellular Dynamics Inc) and in Europe (by Hospitals in Lund and Cambridge). For safety reasons, these first-in-human clinical trials are all small (around 7-15 patients) but are expected to be followed up by larger trials in the near future. We’re following these trials closely and hope that their joint outcome will enable the hype of stem cells to be turned into a genuine hope and prospect for a new kind of therapy for PD based on the replacement of those cells which have been lost in the disease.
Malin Parmar, PhD presented at past WPC Congresses. She currently serves as a Professor of Cellular Neuroscience at Lund University in Sweden.
Agnete Kirkeby, PhD presented at past WPC Congresses. She is an Associate Professor at Lund University in Sweden and at the University of Copenhagen in Denmark.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®