The idea behind cell replacement therapy (CRT) for Parkinson’s disease (PD) is pretty simple – the motor symptoms of PD are primarily the result of dysfunction and/or death of a specific kind of cell in a specific part of the brain. So, why not go in and replace those cells? The late 80s and 90s saw a few trials of CRT for PD using cells from aborted fetuses, but these had mixed results and ran up against ethical issues and technical limitations. However, we now have a much better understanding of what kind of cells to use, how to culture and store those cells, when and how to implant them, as well as new cell types such as induced-pluripotent stem cells (iPSCs) that don’t have any of the associated ethical issues. As a result, there are now a number of clinical trials around the world pushing forward this new era of CRT for PD. The results of these trials over the next few years will go a long way towards determining if CRT for PD will be a viable therapeutic option for people living with this condition.
While we wait, I decided to reach out to some of the people at the forefront of this field to get a little more insight into its future potential…
Prof. Jeffrey H. Kordower – Director of the Research Center for Brain Repair and Neuroscience Section Head at Rush University Medical Center, USA. He was the first to demonstrate that fetal dopaminergic grafts can survive, innervate, and form synapses in patients with PD and demonstrated the presence of Lewy bodies in fetal grafts.
Prof. Jeanne F. Loring – Founder and Director of the Center for Regenerative Medicine and Professor at the Scripps Research Institute in La Jolla, California and Scientific Director of the Summit for Stem Cell Foundation, USA. Her research team is working toward a patient-specific dopamine neuron replacement therapy for Parkinson’s disease, using large-scale genomics analysis to ensure the safety and efficacy of the therapy.
Prof. Lorenz P. Studer – Founder and Director of the Center for Stem Cell Biology at Memorial-Sloan Kettering Cancer Center in New York City. He is currently leading a multidisciplinary consortium to pursue the clinical application of human stem cell-derived dopamine neurons for the treatment of Parkinson’s disease.
Prof. Anders Björklund – Professor at the Wallenberg Neuroscience Center at Lund University, Sweden. In the 1970s, his group pioneered studies of neural transplantation to the brain, and developed techniques for cell replacement in animal models of Parkinson’s disease. His current research is focused on the use of stem cells and viral vector-mediated gene transfer for disease modeling, neuroprotection and repair, with the aim of developing new therapeutic approaches for Parkinson´s disease and other neurodegenerative disorders.
Prof. Roger A. Barker – Professor of Clinical Neuroscience and Honorary Consultant in Neurology at the University of Cambridge and at Addenbrooke’s Hospital, UK. He is the coordinator of the TRANSEURO project looking at fetal cell grafting in patients with early Parkinson’s Disease and is part of the GFORCE-PD initiative as well as one of Directors of the International Society for Stem Cell Research.
Prof. Curt R. Freed – Professor of Medicine, Pharmacology, Neurology and Neurosurgery at University of Colorado School of Medicine, USA. He and collaborators did the first transplant of human fetal dopamine cells into a Parkinson patient in the United States. Since that time, Dr. Freed and his team have performed implants on more than 60 Parkinson patients. He is also the author of Healing the Brain, a first-hand account of early CRT for PD trials.
What do you think are the biggest misconceptions surrounding CRT for PD? Jeffrey Kordower – “That it will address more than the cardinal motor features and do more than DBS. Cognitive decline, dementia and falls are what get PD patients into nursing homes. Fetal dopamine grafts will have little to no impact on these and in fact most if not all non-motor symptoms.”
Jeanne Loring – “That any old cell can work. I’m concerned about the neurotrophic factor approaches that transplant dividing cells, not dopamine neurons.”
Lorenz Studer – “Many people show a lack of understanding of the rather broad range of cell types that have been proposed and are being used for cell therapy in PD. The term “stem cells” can be quite confusing and in many instances those cells are not aimed at replacing dopamine neurons but are thought to act indirectly (modulating brain environment, inflammation, growth factors etc.). However, those approaches are not very well understood and may not work consistently. In contrast, our approach, and the approach of several other groups at the verge of translation, is to coax human stem cells to differentiate into very young dopamine neurons. Those stem cell derived dopamine neurons are injected into the brain with the goal of actually replacing midbrain dopamine neurons that were lost in patient brains.”
Anders Björklund – “That CRT has been tested in patients and shown not to work. This notion is due to the negative results obtained in the two NIH-sponsored trials (performed in the early 2000) that at the time had great impact in the field. In retrospect, it is clear that these trials were performed prematurely using protocols and procedures that we know now were not optimal. Moreover, these trials were performed using tissue from aborted embryos, before the advent of the approach using cells derived from pluripotent stem cells. Now it is time to move on.”
Roger Barker – “That they are curative not symptomatic therapies for those who believe in them. And for the non-believers, that they will not be useful because fetal dopamine trials failed (which is not really true) and that they do not treat the non-motor aspects of PD (which is partly true).”
Curt Freed – “Some patients have the impression that putting new dopamine neurons in the brain will “cure” their Parkinson’s. In fact, our research in 61 patients receiving dopamine cell transplants has shown that cell implants mimic the effects of L-DOPA and so can reduce and sometimes eliminate the need to take L-DOPA or other dopamine agonists. If L-DOPA causes dyskinesia in addition to reducing rigidity and improving the speed of movement, then transplants which replace the need for L-DOPA will do the same.”
How well do you think a patient needs to understand CRT to be able to give informed consent? Jeffrey Kordower – “Hard question to answer. I guess they need to understand CRT as well as they need to understand DBS.”
Jeanne Loring – “I believe that the science behind a therapy should make sense and so should be understandable to anyone. So far I’ve been explaining the therapy to every potential patient and allowing them to ask questions long before signing an informed consent – I can go on doing that for a long time, but eventually I plan to make a video and send a competent scientist to answer questions. I want them to know the history of fetal cell transplants, the risks of surgery, exactly what we do with the cells, and importantly, that there will be a placebo effect and the benefits of the transplanted neurons may take a year to kick in.”
Lorenz Studer – “It is important for a patient to make a big effort to understand the basic goals of CRT and the specific approach proposed for his/her treatment. He/she should make sure that there is good evidence for this approach and always get a second opinion from people not affiliated with the group treating them.”
Anders Björklund – “It is very important that the patients are fully aware of the rationale behind the approach as well as the potential risks involved, the extent and quality of the pre-clinical work that is supporting the trial, and the fact that any procedure used now is highly experimental and that there is no guarantee that it will work.”
Roger Barker – “I think they need to understand the principle behind the therapy, the evidence that this has been convincingly shown pre-clinically, and how it matches up to other therapies in clinic or being trialed for use in clinic.”
Curt Freed – “Patients need to understand that transplants can only replicate the effects of L-DOPA. If dopamine agonists are ineffective at improving Parkinson symptoms, then cell transplants will have no benefit whatsoever. While the risks of stroke, brain infection, or death are quite low, all neurosurgical procedures have serious risks.”
What are the biggest unanswered questions that clinical trials will help solve? Jeffrey Kordower – “Whether cellularly released dopamine can improve motor PD and can lower the dose of L-dopa to reduce levodopa induced dyskinesia.”
Jeanne Loring – “In the two to three years in which patients are transplanted by the trials in the US, Japan, and Europe, our information will be limited. Patient selection is now based on the fetal trials, the most likely to be helped are those who respond to L-DOPA. But we don’t know if that is really the important factor, and disease progression…in years…is a variable we need to follow. I want to know the genomic sequence of patients and whether they have risk factors…or benefit factors…that make the therapy more or less effective. Long term, I want to know if the therapy helps cognitive function. I think it will, because it replaces a node in a network, not because there’s more dopamine in the brain.”
Lorenz Studer – “It is essential to test a new “product” such as cell therapy in actual human patients. By now we have tested this approach in close to 1,000 animals (mostly mice but also rats and monkeys) and we have a good idea of how it should work, but there can be surprises once we go into the clinic. Generally, the major goal is to show that the approach proposed is feasible and safe in a number of appropriate stage patients, and we obviously also hope to see encouraging signs towards efficacy. However, the initial studies will include only a few patients and we will have to be very careful at interpreting efficacy results without pursuing a fully controlled study, which would be next after the proposed Phase I/IIb.”
Anders Björklund – “Clinical trials are essential to find out whether the promising results that are obtained in rodent and primate models of PD can be translated to the human disease condition. Animal models of PD have allowed us to obtain convincing proof-of-principle that cell replacement therapy can work to reverse the PD like condition seen in these models, but everybody in the field knows that the real proof has to be obtained from patients suffering from the real disease.”
Roger Barker – “That it works well over many years; it is safe; and makes a major impact on quality of life and gets rid of the need for the anti-PD drugs that we currently use in clinic.”
Curt Freed – “We already know that the “best possible” transplants can provide enough sustained dopamine production to eliminate the need to take L-DOPA and other dopaminergic drugs. Less clear is the “average” or “typical” response and the range of likely benefit. Double-blind, placebo-controlled clinical trials are needed to see whether the average patient is able to cut drug doses by 30%, 50%, or even more. At the present time, there is no way to predict how much benefit the individual patient will get. It would be good to establish some kind of “dose-response” relationship between the number of dopamine cells transplanted and the subsequent reduction in L-DOPA doses.”
If a disease halting mechanism were discovered tomorrow, given how long cells take to mature once transplanted, would we still need CRT or would more immediate (and tune-able) approaches like DBS suffice? Jeffrey Kordower – “There is no reason to believe that CRT will be better than DBS so the latter answer is true; especially since DBS starts working in hours while grafts will take years to optimize.”
Jeanne Loring – “Possibly. I think it would be a choice that would be made by individual neurologists and patients. It’s been impossible to know whether DBS causes long term changes in the brain, because it is currently not a long term solution. There are risks associated with DBS that need to be weighed with the risks of transplantation. Finally, we also don’t know whether reduction in dopamine connections (which would persist even if there were no more cell death) causes other changes in the brain.”
Lorenz Studer – “Obviously, if we can find a way to completely prevent dopamine neuron loss we would not need to replace them. However, for any treatment where significant cell loss has occurred already (clinical symptoms may indicate loss of 50% of dopamine neuron complement) I would argue that CRT may be still the way to go. CRT should allow for dopamine neuron restoration rather than bypass of DA neuron function which has the possibility of providing superior treatment. If the disease has stopped at a relatively early stage where DA symptoms are the primary problem and can be well controlled by L-Dopa for several years, the slow maturation of DA neurons would likely not be a major problem.”
Anders Björklund – “In a longer perspective, I think CRT will be combined with disease modifying or disease halting approaches. To stop the disease and at the same time bring back lost functions will be optimal.”
Roger Barker – “I would combine the two therapies so you could recover lost dopamine cells while stopping progression in patients and in the graft.”
Curt Freed – “Dopamine cell transplants, DBS, and dopamine agonists only treat PD symptoms. If a drug can be shown to stop the progression of PD, there will still be a need for a source of dopamine or DBS to treat slow movement and other symptoms. “
Could gene therapy one day render CRT for PD obsolete? Jeffrey Kordower – “Gene therapy is a garbage pail term…what type of gene therapy? One to deliver a trophic factor? One to deliver a dopamine synthesizing enzyme? Or more importantly, one to deliver a synuclein modified species?”
Jeanne Loring – “I don’t think so. There’s a big difference between a cell that is converted to making dopamine and a legitimate dopamine neuron. We need synapses and feedback control. I worry about partial conversion of cells like astrocytes and microglia into dopamine neurons – this happens in a culture dish, so what would happen in the brain?”
Lorenz Studer – “If gene therapy were to completely prevent cell loss (see above) then obviously there would be no need for CRT. However, we still seem very far away from that. Current strategies to boost DA neuron function by gene therapy (e.g. AADC expression), to convert striatal cells into dopamine producing cells (expression of DA biosynthetic pathway) have both potential drawbacks and may not restore connectivity and the potential to get fully regulated release. Other gene therapy approaches such as neurotrophic factor release also still need to prove their therapeutic potential in the clinic.
Also, we think that CRT can be easily combined with gene therapy and cells may indeed be one of the preferred means of delivering a gene product long-term to the brain of PD patients. We are thinking of several potential cell types that could achieve that well.”
Anders Björklund – “I think these two treatment modalities in the end will fuse and be used in combination.”
Roger Barker – “Could do, but more likely to compete. If gene therapy is around growth factors then answer to question above stands, if making gene therapy is around making dopamine then gene therapy approaches may not release dopamine synaptically and physiologically- so less good.”
Curt Freed – ““Gene therapy” needs to be defined. It could mean growth factors like GDNF or BDNF, or a drug that turns on a gene like DJ-1 that can protect brain cells from aggregated proteins like alpha-synuclein. Gene therapy offers the potential for slowing or stopping the underlying disease, which would be revolutionary. CRT, like L-DOPA, only provides symptom relief.”
Will CRT be a viable strategy for replacing other cell types that get impaired in PD beyond just dopamine cells? Jeffrey Kordower – “In theory but no one is really working on that and there is less certainty as to what cell types underlie particular functional impairments. There once was great interest for cholinergic basal forebrain cells and cognition but there is less activity in that area now.”
Jeanne Loring – “If we can identify the cell type, know where to put it, and make it from iPSCs, then yes.”
Lorenz Studer – “This is an interesting and still underexplored question. We have published on replacing enteric nervous system cells which is clearly a neural cell type affected in PD. However, clinical application is still pretty far away in the context of PD and we would likely test this approach first in diseases with a primary enteric neuron loss (Hirschsprung’s disease). If safe and efficacious there, maybe one day we could offer CRT also for PD patients who very commonly have major GI problems related to enteric neuron dysfunction. Other ideas are floating around for CRT combined with gene therapy to target a-syn or to modulate inflammatory states in the brain that may help with treating and preventing cognitive dysfunction in the future. Those ideas are still at the basic research stage for now.”
Anders Björklund – “Studies along these lines are still in their infancy. Personally, I think there are interesting possibilities to combine DA neuron replacement with grafting of basal forebrain cholinergic neurons. This may hold promise to restore aspects of cognitive impairment that develop with time in many patients.”
Roger Barker – “Much harder to do this as many of the cell types affected in PD cover long distances and have widespread projections over large areas of the central nervous system.”
Curt Freed – “Very unlikely.”
What far future applications of CRT do you think are realistic? (not necessarily just in PD) Jeffrey Kordower – “There is interest in Striatal grafts for Huntington’s disease.”
Jeanne Loring – “There are diseases and injuries that could benefit from replacement of the cell types that are lost- cardiac tissue, retinal pigmented epithelium, blood vessels, pancreatic islet cells, skin.
In the CNS, striatal neurons for Huntington’s disease. But there are a lot of applications for cell transplantation to deliver something good – I would use microglia or astrocytes for lysosomal storage disease, T cells or modified microglia for multiple sclerosis, neurotrophic-factor- secreting cells for Alzheimer disease and for stroke. And they can deliver something bad- lytic virus or chemical killers for brain cancers, for example.”
Lorenz Studer – “Clearly the eye is a major target such as for macular degeneration and many other eye disorders. Stem cell based trials are already ongoing there. Similarly, diabetes (transplantation of hormone producing pancreatic insulin+ cells) is another major goal that is being pursued intensely.
Cardiac repair is another huge target with a lot of progress but still many steps to go. In the past, many poorly designed trials were performed using cells that never had a chance to turn into real heart cells. However, a new generation of cells is coming along with trials starting in the not so far future that have a real shot at replacing actual heart muscle.
In the brain, there are clearly other indications such as various myelinating disorders that could be pursued using stem cell derived oligodendrocytes (though MS is not going to be an easy target as the environment in MS seems to prevent differentiation of oligodendrocytes).
The enteric nervous system is an interesting target (see above) particularly for genetic problems causing enteric nervous system dysfunction, but possibly also other diseases where those issues are secondary including diabetes, PD and others.
Other important targets under development are Huntington’s disease, stroke, spinal cord injury or even diseases such as Alzheimer’s disease. Obviously, there are major challenges with each of them and they may not necessarily involve neuron replacement but other strategies that we are currently developing.”
Anders Björklund – “Many – difficult to list at this stage!”
Roger Barker – “I think we could make engineered cells that you can switch on and off to control aspects of disease, and ultimately even make replacement parts of the CNS through organoid technology.”
Curt Freed – “Animal models have to tell us what brain diseases can be treated by CRT. In the early 1980s, Mark Perlow and Dorothy Krieger showed that transplants of fetal hypothalamus could restore fertility to mice lacking normal hypothalamic function. Treating that kind of focal brain pathology with transplants should be pursued. Because Alzheimer’s disease involves major brain structures like cortex and hippocampus, CRT is less likely to be of value. Genes expressing growth factors like NGF, GDNF, BDNF and others could be worthwhile for treating large brain structures.”
-Introduction written with the help of Prof. Gerold Riempp
-Featured Image: Neuronal Forest (painting by Amanda Kwieraga) (Source)
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