Yesterday, a team of neurologists, neurosurgeons and stem cell biologists from across multiple institutions reported results of a stem cell trial involving one person with Parkinson’s in The New England Journal of Medicine. The trial also was covered by top science reporter Sharon Begley of STAT. In the “first of its kind” study, the patient’s own stem cells were turned into dopamine-producing cells and transplanted into his brain to treat Parkinson’s disease (PD) symptoms.
To learn more about the design, results and implications of this study, we spoke with Brian Fiske, PhD, senior vice president of research programs at The Michael J. Fox Foundation (MJFF), and trial investigator Claire Henchcliffe, MD, DPhil, a movement disorder clinician-researcher at Weill Cornell Medicine in New York City.
MJFF: What makes this trial unique?
Claire Henchcliffe (CH): I could talk about that for hours! This is the first report of a person with Parkinson’s receiving a transplant into the brain of dopamine-producing cells that were derived from his own cells. Researchers used induced pluripotent stem cells (adult stem cells that can be modified into other types of cells) to create brain cells that produce dopamine, which decreases in PD. Because the trial used the patient’s own cells, there was no need for drugs to suppress a potentially problematic immune response. These drugs, known as immunosuppressants, can be burdensome to take, increase risk of infection and bring toxicities.
Brian Fiske (BF): Echoing Claire, this is the first published demonstration of this kind of therapy. Until now, we hadn’t seen data on this approach. And, since the person’s own cells were used, this is about as personalized as you can get when it comes to creating targeted treatments for one individual. In Parkinson’s, we don’t yet have treatments that are that specific.
MJFF: What did the trial show?
CH: The results demonstrate that this approach is safe, without significant side effects. The trial also tells us what’s possible: performing surgery to deliver a certain amount of cells to the brain. Once in the brain, the cells survived. As for the individual, he was having trouble controlling PD symptoms and side effects with standard medications. Following the procedure, he had a minor improvement in movement symptoms but a more marked improvement on overall function and quality of life. It’s encouraging, but strictly speaking it’s still difficult to make any statements that the investigative therapy was the reason for these clinical changes.
BF: As Claire said, the trial showed safety and feasibility as well as some improvement in the individual’s movement symptoms and quality of life. The brain imaging seemed to be no worse over time, but it also did not seem any better. So it may be that the cells survived but haven’t yet built new connections, for example. When we think about results, we have to take trial design into account. This trial had only one patient who knew he got the therapy and there was no placebo for comparison. So the question is whether his improvement reflects a placebo effect, which is common anytime a person expects benefit, especially in Parkinson’s clinical trials.
MJFF: Often with answers (or results) come more questions. What questions did this trial raise about stem cells?
CH: Because there was only one patient involved, there are several questions around efficiency, cost and generalizability. Vast amounts of work went into research for one patient – in fact, teams of people from different institutions came together to complete this trial. So we need to make this process more efficient and standardize safety and quality control measures for cell production. We also need to learn who the best candidates are for this type of therapy. This single patient was chosen because of specific characteristics of his Parkinson’s. But, in general, who would most benefit?
BF: The big open questions are around cell dose, study length of time, and ultimately, the viability of this approach. We don’t yet know the right dose of cells to give and that will require more testing in more people. We also don’t know the length of time we need to assess for potential benefit. It takes time for cells to get settled and hopefully start building connections – but how long is that? We also need to ask how this approach will fit into our toolbox of currently available therapies. If this complex and costly treatment is say, just as effective as deep brain stimulation, how do we think about pursuing it?
MJFF: Speaking of questions, some have raised ethical concerns about the funding and design of this trial. Can you talk more about those aspects?
CH: Many questions are bound to be asked, rightfully so, when an individual patient who is also a philanthropist gets involved in a “first of its kind” study. This person provided support to the research team for many years, which allowed the scientists to not only achieve the process of cell production at the center of this trial, but also to develop new technologies and other innovations for the entire field. The financial support was backing for “research as a whole,” which is not the same as being asked to pay thousands of dollars at a local clinic to receive your own stem cell treatment.
BF: When thinking about any study, scientists look to see if it was well-designed and free from undue influence or bias (from either researchers or participants), and whether the results are reported in a transparent and trustworthy manner that lists both positive and negative findings as well as challenges. Regardless of how a study is funded, whether by an individual or by an institution, these are the core aspects that inform a solid scientific study. It does appear this study was rigorously designed, and the researchers have presented their results in a clear and unbiased manner.
MJFF: There have been reports of clinics offering stem cell treatments outside of research at a cost to patients. What should people know about these clinics and how do they compare to this type of research?
CH: These clinics offering stem cell therapies are, in general, minimally manipulating your own fat or blood cells and infusing them back into the blood. In this trial, cells were quite markedly differentiated to a very specific dopamine-producing cell and then transplanted into a targeted area of the brain. It took years of work to understand the cells’ molecular capabilities and how closely they mimicked “natural” dopamine cells. The mechanisms behind cells in stem cell clinics are less well understood – not that they don’t potentially have mechanisms, it’s just that they need to be more well-characterized.
BF: There is an important distinction between these types of clinics and FDA-approved trials. Trials are tightly regulated and structured to study safety and feasibility to learn more about stem cells as a potential treatment. And there is no cost to participate. Clinics, on the other hand, market unproven stem cell therapies, often at a significant cost and typically without a research focus. What I really want people to know is that there currently are no approved stem cell treatments for Parkinson’s. (I spoke about this topic recently on a podcast with MJFF Patient Council member Larry Gifford.)
MJFF: People are, understandably, hopeful about stem cell therapies. What do you tell people about potential benefits in Parkinson’s?
CH: Even though this work has been going on for years, we are still at the beginning. We are taking the first steps to replace a subset of cells that are lost in Parkinson’s – the dopamine-producing cells, which are responsible for the movement symptoms we see (tremor, slowness and stiffness). The hope is that with stem cell replacement we could target and alleviate those types of symptoms. It’s not a cure. We have to appreciate the limitations: These approaches don’t seem to be able to tackle some aspects of Parkinson’s you can’t see, such as cognitive changes.
BF: Like Claire said, the aim here is to replace lost brain cells in hopes that they will ease movement symptoms. This does not target the underlying mechanisms of disease (such as clumping of the protein alpha-synuclein) that we think lead to cell loss. So it’s essentially another way to deliver dopamine to the brain, not a cure.
MJFF: What’s next in Parkinson’s stem cell research?
CH: There is much ongoing work in stem cells and teams are taking different approaches. This study used cells from the individual, a trial in Japan is using cells from others, and some are trying human embryonic stem cells. We have an enormous amount of work to do to figure out the best sources of cells, as well as the best dose, brain target and candidate.
BF: I imagine this publication will light the fire under other groups that are working with or plan to work with cell-replacement therapies. At the Foundation, we believe the more research that leads to more rigorous scientific data, the better. Because that ultimately will translate to better treatments and better quality of life for people living with Parkinson’s.