One clinical study, which was released 2 weeks before Christmas holidays captured my attention (but not attention of mass media). One of the most scandalous Indian “stem cell tourism” clinic Nutech Mediworld published(!) results of the study, which evaluates embryonic stem cell transplantation in children with cerebral palsy. Yes, you’re reading it correctly – embryonic stem cells in children! Now, I have no idea how this study was approved by Independent Ethics Committee (as stated in the paper) and how this manuscript passed peer review of Journal of Translational Medicine, but here is the fact – study is done and results are published. I think, we should at least read it, try to analyze it (it’s not easy!) and maybe discuss it. Before we dive into the study, I’d like to give you a little bit of background.
Geeta Shroff – a director of Nutech Mediworld – is a highly controversial and highly criticized by “westerners” figure in “stem cell tourism”. She is “a retired obstetrician and self-taught embryonic stem cell practitioner”, who used to be skeptical about sharing data with peers:
Dr. Shroff does not share data, has not submitted to peer review (she’s said she has “no peers”) and has performed no controlled clinical trials. While patients call her a saviour, other researchers call her a quack, a fraud or names even less flattering.
Well, seem like she changed her mind lately. I remember, that many “critics” refused to believe that actual embryonic stem cells (ESC) were used by Nutech. They thought that Nutech used term “embryonic” for fetal cells, derived from aborted material. But, according the paper it’s real single ESC line, derived from preimplantation embryo post IVF.
Let’s move to the study. As I mentioned above, study protocol was approved by Ethics Committee. Also, it was reported to “National Apex Body” (I don’t know what is it, but sounds like something on government level). Yet another interesting fact – the last author of the paper is a government worker (Ministry of Home Affairs, Government of India). I’d like to remind you that this is not the first “embryonic stem cell study” from India. So, I think, one thing we have to realize is that if these kind of studies could be “shocking” and “hard to imagine” in US or Europe, it could be “normal” and totally acceptable for India or some other countries. Also, we have to realize that reporting of some particular number of patients (“cherry picking”?), treated in one particular “stem cell clinic” is very different from well designed clinical study or trial. We have no way to check how information, presented in the paper is accurate, since it’s not a registered trial and there is no (as far as I understand) oversight from any agency.
Next, I’d like to touch ESC product composition, which was used in kids with cerebral palsy. The authors did not bother much with differentiation of ESC into mature cells. In fact, transplanted ESC were Oct4+, SSEA3+, Nanog+, Sox+, betaHCG+, CD34+, Nestin+, GAF+ and NeuN+. So, it was a great mix of undifferentiated ESC and neurally induced progenitors. There is a reference to Shroff’s patent in the paper. If we look at this patent (which btw covers everything – all types of ESC derivatives and all kind of diseases), we can see that ESC product contains at least 40% of undifferentiated cells:
…in one embodiment, the portion of undifferentiated stem cells will be no more than about 80% of the total population of cells. In another embodiment, the portion of undifferentiated stem cells will be no more than about 40% of the total population of cells.
ESC progeny in the product are not characterized and could be hematopoietic, neural, mesenchymal, hepatic… Cells were infused and injected multiple times via all possible routes: intramuscular, intravenously, “intra-caudal”, as eye drops, as nasal spray, retro-bulbar, as oral or ear drops. Since, there was no immunosuppression, researchers check hypersensitivity to ESC product via skin probe before starting a treatment. One more interesting thing – the cells were cryo-stored in pre-filled syringes at -20C. There is no viability data in the paper.
91 children were included in the “study” with age from 1 month to 18 years with different degree and course of disease. The authors noticed functional improvement in all ages and starting scores of disease, based on functional scales (GMFCS-E & R). Also, they indicate improvement in cognition. Of course, we cannot make solid conclusions about efficacy, since it was not randomized and controlled trial. About 10% of patients had adverse events, such as swelling, itching, fever, chest congestion and others. However, there is no information about long-term safety and, especially, about such important potential complication as ESC-related excessive tissue growth. According the paper, about half of patients were not followed more than 3-6 months after the first treatment (did not return for 2nd and 3rd phases of treatment).
Of course, this “study” causes a lot of questions on every level – from ethical approval (without any pre-clinical animal studies) and study design to cell product characterization and clinical outcome. What puzzles me is that, apparently, Indian government agencies, as well as independent ethics committee were aware of the study and did not see any problem with it. I’d assume that Nutech itself did not see any problem with experimentation on children (for money!), because they had previous experience with ESC-based treatments of adults. Unfortunately, we cannot learn a lot from this study simply because of its design and lack of valuable information in the paper. I think, we as community should be aware of such “studies”, because it is a part of “cell therapy” or “stem cell therapy” or even “stem cell therapy industry”. What do you think of all this, guys?