Vatine et al. show that human iPSC-based modeling can pinpoint the origin of a neuronal disorder in the brain as a defect in transport of thyroid hormone across the blood-brain barrier, rather than in the neurons themselves.
Yesterday, a breaking news in the stem cell field came from a case report published in the New England Journal of Medicine (a respected journal in medical research) (http://www.nejm.org/doi/full/10.1056/NEJMoa1609583?query=featured_home).
What is probably the most intriguing about this case report from a stem cell clinic, that had a clinical trial submitted to the FDA and subsequently withdrawn in 2015 (https://clinicaltrials.gov/ct2/show/NCT02024269?term=NCT02024269&rank=1).
This case report focuses on three patients, elderly patients (70+) and all three suffering from age-related macular degeneration (AMD).
They all three being injected with mesenchymal stem cells. For those not familiar with stem cells, stem cells comes into different flavors depending on their origin and potency abilities. The most pluripotent type of stem cells are the embryonic stem cells (hESCs) that are derived from embryos. Following in their pluripotency comes in the induced pluripotent stem cells (iPSCs). Unlike hESCs, iPSCs are reprogrammed somatic cells (usually skin fibroblasts). Then we have bone marrow stem cells (from bone marrow) that have a narrower pluripotency but proven efficacious for treating patients with leukemia. Finally we have the mesenchymal stem cells (MSCs) obtained from the stream fraction of adipose tissue. Usually these cells are obtained by liposuction and isolated from the fat tissue via defined protocols.
Now this last type of cells has a certain classification that allows to use a loophole. In order to conduct a clinical trial, you have to submit an investigative new drug (IND) application to the Food & Drug Administration to show evidence of safety and efficacy from pre-clinical studies. These are safeguards that ensure patients and medical researchers enrolled in such trials.
Now, when you are dealing with MSCs, these stem cell “clinics” can exploit some loopholes and apply for a non-IND application if your trial follows two criteria: it is an autologous procedure (you are injecting cells from yourself back into your body) and there is no procedures that modify the material used (in that case, the purification steps are not altering the MSCs identity and function). In addition, these trials have to be done without any financial link. In academic institutions, you neither ask the patient to pay for the clinical trial nor provide the patient with a financial compensation (only a possible therapeutic outcome, if the treatment work). In this case reports, all patients paid $5000 to that clinic. it is also important to note a certain level of deception from the stem cell clinic as this registration at the ClinicalTrials.gov website appeared to these patients as a clinical trial were it was not. It is even mentioned by the authors of this case report that none of the consent form signed by these patients displayed “clinical trial”.
There is also report in the consent form that the patient were informed of the risk of blindness and were requesting to have the procedure done in both eyes.
These patients rapidly developed post-operative complication including retinal detachment, increased ocular pressure and hemorrhagic events, such complications were not taken care by the clinic involved in the stem cell procedure and were done in eye clinics in patients domicile.
By coincidence, NEJM also published another case report of the use of stem cells in AMD in a clinical trial in Japan (http://www.nejm.org/doi/full/10.1056/NEJMoa1608368?query=featured_home). This procedure was done using iPSCs from patients and derived into retinal pigmented epithelial cells (RPEs). These cells are lining the outer side of the retina and serve as a barrier for protecting the retinal neurons involved in vision. This is the famous “iPSC clinical trial” from Takahashi and colleagues that had to be halted due to some safety issues that were corrected (https://ipscell.com/2016/06/good-stem-cell-news-as-takahashi-ips-cell-trial-to-resume/).
So far, the encouraging part is the absence of post-operative complication and graft rejection and the patient showed an improvement in her vision.Yet, this is a single report and the authors were also very cautious about to make overstating conclusion.
These two cases report should inform into two things: we are making little steps but confident steps in stem cell based therapies but it is also important to raise awareness and vigilance about the methods of some stem cell clinics making unrealistic claims of stem cell therapies or posing as clinical trial center.
My recommendation is if you decide to jump into a clinical trial is to verify the affiliation of the center (avoid any private firms and check the credentials of any institution supporting this trial), ask your doctor to help you read through the consent form and never ever be asked to pay for the procedure. The trial is funded by research grants, if it is requested that you cover the expenses of such procedures run away!
This post is related to a recent testimony of Rhonda, a follower of my Facebook page, that asked me whether stem cells can cross the BBB. As a BBB and stem cell scientist, this was a very good question asked. If I have to tell my thought in a sentence, I would it’s complicated. To support my claim, I will use the recent review from Aylenik and colleagues (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106911/) and Liu and colleagues (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753739/)
First, it is important to remember the reader about what is a stem cell and what are the different types of stem cells. A stem cell is a particular type of undifferentiated cells capable of self-renewal and capable to differentiate into any cell type following the right molecular and environmental triggers.
In the scientific research, we have different types of human stem cells: we have firstly the pluripotent stem cells coming from embryos (human embryonic stem cells or hESCs) or from reprogrammed adult cells (induced pluripotent stem cells or iPSCs). These are the most used in basic research because they have the most potency to differentiate into any cell type. However these are also the type of stem cells that have the most important concerns in terms of safety as such undifferentiated cells rapidly develop aggressive tumors.
The second type of stem cells that are more in use in clinical research are stem cells derived from placental cord blood or from bone marrow (hematopoietic stem cells or HSCs) or from the stroll fraction of adipose tissue (mesenchymal stem cells or MSCs). These cells have a much less pluripotency as these cells are already engaged into a defined lineage. However this lineage restriction make these cells much less prone for developing tumors and are considered safe.
Now let’s get into the details. In this post, we will not talk about stem cell delivery that bypass the BBB such as intranasal, intrathecal or intracerebroventricular injections. We are discussing here about intra-arterial or intra-veinous injection of stem cells and their delivery across the BBB, in particular the delivery of MSCs across the BBB.
One interesting aspect of the MSCs delivery is their particular attraction to sites of injury, including inflammation sites as mentioned in Liu’s review. What we know is that MSCs can cross in vitro models of the BBB (cell culture models) but yet we have a very limited number of studies that have demonstrated similar approaches in animal models.
The mechanism by which such MSCs may cross the BBB appears to use similar keys used by leukocytes to infiltrate across the BBB but also may include a localized degradation of the basement membrane (a biological mesh lining blood vessels) to allow their infiltration. However, as mentioned by Liu in his review, early clinical trials have shown mixed if not negative results (see Ankrum J et al., Trends in Molecular Medicine 2009; Karp et al., Cell Stem Cells 2009).
Stem cell-based therapies have a important potential to improve regeneration following injury, but yet claims that such stem cells can cross the BBB remains weak and still needed to be demonstrated. Yet, a recent trend observed in the US and in other countries is the emergence of “stem cell clinics” and the subsequent “stem cell tourism”. Such clinics that operates on protocols not approved by the Food & Drug Administration and not published in peer-reviewed journals (to ensure their efficacy and reproducibility) often laud “miraculous claims”, promising patients to cure their diabetes, knee arthritis if not more serious neurological disorders including stroke, Alzheimer’s disease, autism spectrum disorders, lysosomal storage disorders, cerebral palsy or multiple sclerosis.
The main problem with these clinics is not only their claims are not based on science-based medicine, but also until now stem cell therapies in academic settings (including university hospitals) are still in their infancies (Phase I and IIA clinical trials), mostly focusing on the safety of such therapy before we can consider assessing their efficacy.
Such “therapies” are indeed very costly ($30’000+ price tags) but also the nature of such treatment remains shoddy and unclear. Worse, a recent case report recently published by the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMc1600188) reported the case of the growth of a proliferative lesion on the spinal cord of a patient that underwent such “stem cell therapy” following a stroke injury. Indeed, a recent opinion letters written by Turner and Knoepfler in Cell Stem Cell discuss more deeply more about such recent phenomenon (http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30157-6).
In conclusion, stem cell therapies have shown interesting potentials in pre-clinical models and early stages of stem cell therapies are providing optimistic news about the use of certain stem cells to assess their clinical efficacy in a rigorous and reproducible experimental paradigm, especially for aiming to treat neurological diseases.
However, the delivery of such cells remains an important challenge with a weak literature to support the claim that such cells can cross the BBB once injected via IV route.
In addition, because stem cells have an important potential, a recent rise in stem cell clinics promoting unproven treatments raises questions of safety and concern for vulnerable patients to what appears to me as a rise of a new generation of “snake-oil sellers”.
One of biggest danger facing the stem cell field is the proliferation of “stem cell clinics” inside and outside the United States promising miracle cures for any neurological diseases. The problem with this “stem cell tourism” is not only the huge financial investment into a medical procedure that has yet to filter through scientific rigor and clinical efficacy (at this time, we are still at the stage to assess if these procedures are safe), it is also the risk of developping post-operative complications with “worst case scenarios” happening often, in particular growth of tumor. This is what happened to a stroke patient that not only did not see his stroke injury recovered but now has to fight off the grow of a tumor inside his brain.
Neurology Today discuss the case of this patient, with the intervention of different experts explaining the current state of stem cell clinical trials and the danger of stem cell tourism.
Waking up this morning with a “stunning” finding about the recent publication of a study by Stanford researchers that noted the improved outcome in stroke patients following injection of stem cells have been positively headlined in the fairly serious “Washington Post” journal.
As a neuroscientist and stroke researcher, this sounds like a very good news because there are not much good news when we discuss stroke clinical trials that show something better than placebos. But also me and others like Pr. Paul Knoepfler as he rightly wrote in his blog post to not fail into overhyping and overselling a pilot study and by the way promising the moon to patients and come back to them with a disappointing news.
I thought it would be a great idea to discuss a bit more about this paper, its observations and outcomes and current limitations.
1. What is the study that was has been cited in the Washington Post and how does it stand in terms of scientific publication?
According to the Washington Post, this study has been published in Stroke journal and authored by Gary Steinberg, MD-PhD (Stanford University) listed as leading author. Based on the information, we are likely referring to the following article. I have attached a screenshot of the abstract page from the journal website:
First thing, is to classify the authorship ranking. Dr. Gary Steinberg is what we refer as the primary author, usually the person that has performed most of the experiments and analyzed the data. On the other hand, we have Dr. Neil E. Schwartz as a senior author. It is usually the one that has the first thought process, planned the experimental design, wrote and finalized the manuscript and usually the one that have put the money on the table (the funding awardee) to run this study. Here, I would argue that we have a difference in what we consider as the lead author of the paper. I would consider Dr.Schwartz as the lead author due to the ranking, but thats some science bickering.
The paper got published in Stroke, that is the flagship journal of the American Stroke Association (a subdivision of the American Heart Association). Being published in a society journal is a good step but in case not enough to justify the overhyping. Why? Impact factor. Impact factor matters. Stroke, according to the American Heart Association, has an impact factor of 5.76. Thats good but a clinical paper can get better rating. For instance, Circulation (the highest-ranked AHA journal) is listed with an IF~15, whereas Nature Medicine (a mastodon for high-impact translational studies) has an IF of 27.
The paper is surely good, but does it qualify for the “stunning” adjective? Certainly not and the overselling of it is not justified by the publication metric.
Also note the title, this is a Phase I, IIa. So it means it is very a early stage of the clinical trial. Phase I in the first stage of clinical trial in which we test the safety of a novel treatment, Phase IIa is to try if there is any efficacy in a very small subset of patients (less than 50). Again, at this stage, it is a dangerous step to oversell something that yet to show efficacy with hundreds of patients.
2. What does the paper says?
The paper is behind paywall so I cannot publish any figures and text. The paper got one round of revision, as it was received in February 9, revised in April 1 and accepted in April 26. If we consider a 4-6 weeks turnover between the time you submit your draft and the editor respond to you with reviewer comments, we can speculate that the revision was minimal and quickly addressed by the author.
This study rely on using mesenchymal stem cells (MSCs) in a small cohortof patient. The study uses a particular type of MSC, the SB623 bone marrow MSC cell line.
MSCs are a particular type of stem cells. They have the least pluripotency because they have already been engaged inside a differentiation (to make it simple, they are programmed to give rise to blood cells such as white blood cells, red blood cells or platelets) and therefore have little opportunity to be re-wired to form neurons or cardiac cells. However, because they are already into a certain differentiation stage, these cells are considered as the safest for implantation. Other stem cells (such as embryonic or induced pluripotent stem cells) are nefariously known to wreck havoc if injected as undifferentiated (they cause what we call teratomas), safety of differentiated precursor cells (such as neural precursor cells) remains to be addressed. Thats also alleviate the issue encountered with previous stem cell therapy based studies that consisted as injecting a mixture of bone-marrow stem cells without knowing exactly which sub-population is carrying the protective effect. Interestingly, these MSCs carry a plasmid allowing the overexertion of a protein called Notch-1 intracellular domain (ICD). Notch-1 ICD is a fragment of the full Notch-1, that is cleaved by certain enzymes. Such ICD can therefore act as a messenger inside the cell and exert some biological activity.
The study used three doses of cells and were directly injected around the site of infarct (peri-infarct area). In stroke injury, we have the core or infarct area that is considered as the ground zero. We consider it as the necrotic area or the wasteland zone. Everything inside is dead and highly hostile for repopulation. However, the peri-infarct surrounding this zone is battling for days and weeks, torn between signals telling neurons to survive the injury from signals telling neurons to die. This fine balance is one target for therapies as we consider finding factors that can title neurons in favor of survival can help them recover and minimize the loss done by the stroke injury.
What is interesting is that these MSCs have been shown to only survive for one month. Thats a good point for the safety issue. In this cohort of patients (18 in total), very few side effects were noted suggesting a fairly safe method for up to 12 months. However, one caveat of this study is the lack of proper control or placebo.
3. Why this study has been overhyped and oversold by the WaPo?
All patients improved over the 12 months period compared to their initial timepoint (the day after stroke injury). Furthermore, all three doses have been pooled together, so we cannot tell if there is a better recovery with a higher number of cells. This is a serious concern that has to be mentioned: we cannot tell if these patient recovered by their own or due to the treatment.
If we had a placebo group, we could have been able to compare and contrast the gain due to the stem cell treatment. We also cannot see how each individual and each group have been recovering. It would be interesting to see how age and sex (male/female) played a role in the recovery.
This is the sin of mainstream news media: they have again sinned in overselling a study that is interesting but still lacking solid evidence to sell that case. The study and approach is interesting but the version sold in the news is a far-stretched version of where the study actual said. Selling it as “stunning” is not only wrong and inappropriate, it is also a dangerous move that will serve some for-profit stem cell clinics to make profits on patients that have been experiencing stroke and despairingly looking for a “miracle cure”.
Happy Stem Cell Day! To celebrate it, I have posted a picture of differentiated patient-derived induced pluripotent stem cells (iPSCs) differentiated into neuron-like cells. These cells express two types of proteins involved in cell cytoskeleton (Nestin in red, beta-III tubulin in green) showing these cells are still in transition of becoming full neurons. Cell nuclei (DAPI blue) were used as a counterstain.