The FDA and Oversight of Stem Cells: Implications for Parkinson’s Disease

The FDA recently announced that they planned to crack down on the numerous “stem cell clinics” that dealt in unscrupulous practices and were deemed by the FDA to be dangerous [1].  Dr. Scott Gottlieb, the FDA commissioner, was quoted as saying that the FDA will not allow deceitful actors to take advantage of vulnerable patients by purporting to have treatments or cures for serious diseases without any proof that they actually work. Although there were no mentions of stem cell treatments for Parkinson’s disease (PD) in this article, we applaud the FDA for taking such a stand and believe it is very important for people with PD to understand, that certain stem cell programs are based on rigorous peer-review science while others are nonscientific and exist to bilk money from vulnerable patients. Indeed, the history of cell replacement strategies for PD, is littered with examples of cell transplantation trials that were not preceded by rigorous scientific data or that were conducted in manner where the chances of success were minimal.   

The idea that replacing lost dopaminergic cells with new ones was initially established in the 1970’s and 1980’s. The field of neural transplantation took off when the first clinical trials with dopamine neuron transplants obtained from fetuses were conducted in 1987. Investigators around the world, following the standards of science that were considered rigorous in those days, established that nigral neurons from rat embryos could survive transplantation to the brain, produce dopamine and correct motor dysfunction in animal models of PD. Concurrent with this development, a miraculous cure for PD was claimed following transplantation of cells from the patients’ own adrenal medulla. This was surprising to most investigators, since the animal data suggesting that adrenal medulla grafts would exert beneficial effects was not convincing, and the mild functional effects seen in animal models of PD were at best transient. The report claiming success of adrenal medulla grafts in one PD patient was published in the New England Journal of Medicine in 1987, and triggered a flurry of activity with hundreds of patients around the world receiving such transplants. Because adrenal medullary cells do not have the ethical concerns of fetal cells, and the reported case was described as showing remarkable benefit, many neurosurgeons felt compelled to test the procedure. In general, the results were poor with no sustained beneficial effects. Instead, significant morbidity and mortality were seen in these patients.

In the early to mid 1990s, the first case reports from clinical trials with dopamine neuron transplants indicated both functional benefit and evidence of graft survival as determined by either brain imaging or post-mortem assessments using microscopy. These extraordinary data rekindled the enthusiasm for fetal neuron transplantation for PD. Despite the existence of rigorous laboratory science that had established that early gestation embryos were required for successful graft survival, several clinical investigators chose to transplant tissue into PD patients from second trimester fetuses, because this was the only tissue they had access to or were able to dissect. Furthermore, the manner in which the transplant tissue was prepared varied significantly between centers, and frequently did not follow crucial steps in protocols that had been shown to be successful in experimental animals. This was an era when oversight from the FDA (and the European equivalent agency) did not exist. Not surprisingly, with suboptimal graft donor tissue and methodology, several of the clinical trials yielded virtually no evidence of graft survival fulfilling the axiom “bad science yields bad outcomes”. The field also experienced a significant set-back when it was observed that some patients developed graft-induced dyskinesias. Nonetheless, research teams with a more rigorous approach persisted, and it is now clear is that when done properly in carefully selected PD patients, fetal dopamine neuron grafts can survive for over two decades and clinical benefit has been observed for at least 18 years, i.e. well beyond the time window when a placebo effect might be visible. Regarding graft-induced dyskinesias, animal studies during the past decade have suggested that avoiding contamination by serotonin neurons in the graft, and choosing to implant patients that have not yet experienced L-DOPA induced dyskinesias, might be two ways to minimize the risk of the unwanted side effect.

Due to ethical and practical constraints, fetal tissue grafting was never going to be a clinical treatment for the millions of PD patients who need therapies that restore brain function. Instead, stem cells have emerged as an effective and potentially widely applicable source of donor tissue for clinical application. There are many pros for using stem cells as a source of new dopaminergic neurons. First, they can be grown in limitless numbers. Second, the issue of how to reliably and reproducibly induce the differentiation of stem cellsinto nigral dopaminergic neurons (the specific dopaminergic cell lost in PD) has been solved. Third, the best protocols are also effective at avoiding cells that continue to behave like stem cells after grafting, which otherwise would entail a risk for tumor growth and prevent clinical trials from taking place. Fourth, the need to scale up cell numbers from small animal experiments to large clinical trials is now being successfully addressed, and it is possible to consistently generate large numbers of identical dopaminergic cells in a culture dish. Fifth, researchers are also responding appropriately to safety demands on stem cell therapies from regulatory agencies.

A number of groups who have systematically led the field, made sure that critical parameters are understood and adequately tested in the culture dish and animal models. In addition, these groups have been collaborative with each other and created an international study group called G-Force PD that meets annually to share data and discuss technical issues and obstacles they might have encountered [2]. The collaborative path taken by these groups, some with industry partners, enhances the possibility that future clinical trials will be conducted safely and successfully.

Despite the efforts to focus on transplantation trials based on stringent science, clinical trials that are conducted without the appropriate preclinical data are still being performed in PD.  In Australia, a California-based company called International Stem Cell Corporation is performing a dose escalation trial in PD patients, testing whether grafted parthenogenetic stem cells can be safe and produce preliminary evidence of efficacy [3]. The parthenogenetic stem cells use unfertilized human eggs as starting material, making the cells less contentious from an ethical standpoint. While the company has received approval from the Australian authorities for this clinical trial, it is unclear why a California-based company chose to bypass regulatory approval by the FDA in the United States. Importantly, we do not think that the preclinical results obtained with the parthenogenetic stem cells suggest that they provide a reasonable rationale for a clinical trial. Evidence for transplant efficacy collected in PD models in rats and monkeys is weak and there is little evidence for graft survival [4]. Indeed, in their published report there were only three monkeys in a low dose group and three in a high dose group. Critically, robust functional benefit compared to baseline was seen in the vehicle treated (i.e. the experimental control) animals and only trivial further improvement seen in the low dose stem cell transplant group. The company suggests that the mechanism of action of their stem cell grafts is not primarily to generate dopamine neurons. Instead, it is focused on protection against neurodegeneration [5]. Despite this, the animal models chosen by the company for the preclinical stem cell transplant studies cannot accurately measure such an effect because they do not mimic progressive PD. We sincerely hope that the outcome of this trial will demonstrate safety (the initial press releases indicate this to be the case), but we think it unlikely that the cells will provide even preliminary evidence of efficacy. It is a shame that the FDA did not have the opportunity to influence the design of this experiment in humans, and assess whether the time is already right to move forward to clinical trials with this particular type of stem cells.

In summary, FDA approval is required for stem cell trials in the United States and we welcome their oversight and mechanisms for approval. We also applaud their involvement in shutting down bad actors who trick individuals to spend their money on treatments with inadequate evidence of safety or benefit. There is no shortage of clinics that offer stem cell therapies for PD who advertise on the internet. By contrast, there are a handful of groups schooled in systematic scientific investigations that are moving transplantation programs with stem cell-derived dopamine neurons into clinical trials in the coming 2-3 years. It is likely it will be these research programs that determine whether dopaminergic stem cell grafting will be of benefit for people with Parkinson's disease.

Conflict of Interest Statement: Both authors are in the planning stages of a clinical trial testing the safety and tolerability of dopaminergic neurons derived from human induced pluripotent stem cells for the treatment of PD. This is being done in collaboration with Cellular Dynamics International Inc (CDI). Both Drs Kordower and Brundin are paid as consultants by CDI.




(2) Barker RA, Studer L, Cattaneo E, Takahashi J; G-Force PD consortium. G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson's disease (2015) NPJ Parkinsons Dis, 2; 1:15017. doi: 10.1038/npjparkd.2015.17. eCollection.


(4) Gonzalez R, Garitaonandia I, Poustovoitov M, Abramihina T, McEntire C, Culp B, Attwood J, Noskov A, Christiansen-Weber T, Khater M, Mora-Castilla S, To C, Crain A, Sherman G, Semechkin A, Laurent LC, Elsworth JD, Sladek J, Snyder EY, Redmond DE Jr, Kern RA. (2016) Neural Stem Cells Derived From Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson’s Disease. Cell Transplant, 25: 1945-1966.

(5) Barker RA, Parmar M, Kirkeby A, Björklund A, Thompson L, Brundin P (2016) Are Stem Cell-Based Therapies for Parkinson's Disease Ready for the Clinic in 2016? J Parkinsons Dis, 6: 57–63.


Jeffrey H. Kordower, PhD has presented at WPC 2006, WPC 2010, and WPC 2016. He is currently the Alla V. Solomon Jesmer Professor of Aging, Neurological Sciences and Neurology Director, Director of the  Research Center for Brain Repair and Director of the Neuroscience Graduate Program. He is also Professor of Neurodegeneration at the Van Andel Institute.

Patrik Brundin, MD, PhD is a board member of the World Parkinson Coalition. He has presented at WPC 2010, WPC 2013, and WPC 2016. He is currently Associate Director of the Van Andel Research Institute and Director of the Center for Neurodegenerative Science at the Van Andel Institute. 

Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®