This article is a response to a recently published article entitled Experts question rationale for stem cell trial for autism on SpectrumNews.org. There are several omissions and errors that we would like to address along with our difference of opinion on certain points.
Dr. Riordan with Home Depot founder, Bernie Marcus
On July 8th, 2019 a reporter from SpectrumNews.org named Hannah Furfaro contacted us via email requesting to interview Dr. Riordan for an article she was writing about our recently published clinical trial entitled: Allogeneic Human Umbilical Cord Mesenchymal Stem Cells for the Treatment of Autism Spectrum Disorder in Children: Safety Profile and Effect on Cytokine Levels
At the time, Dr. Riordan was traveling abroad and difficult to contact so we asked that Ms. Furfaro send written questions via email. Ms. Furfaro sent us 14 questions on July 9th. Dr. Riordan answered those questions and we sent them back on July 10th. Ms. Furfaro sent 3 follow-up questions on July 15th. Dr. Riordan answered those questions and the answers were emailed to Ms. Furfaro that same day. Furfaro sent 4 more follow-up questions on Friday, July 19th but we were not able to get them answered in time to meet her deadline. All questions with Dr. Riordan’s complete answers can be found at the end of this article.
Excerpts from Ms. Furfaro’s article are in italics.
So, lets dive in.
Findings from the small trial, published in June in Stem Cells Translational Medicine, suggest that this type of stem cell infusion is safe for children with autism. The trial enrolled 20 autistic children, but did not include a control group who didn’t receive stem cells — and so was not designed to assess the treatment’s effectiveness. Still, it hinted at small improvements in motor skills and social behaviors, according to the study.
The trial didn’t just “hint at small improvements”. Actually, 3 of the 15 children who completed the study went from severely autistic to below the threshold for autism at 12 months based on Childhood Autism Rating Scale (CARS) test scores. 5 of the 15 improved from CARS scores indicating mild or moderate autism to below the threshold for autism. Our article does point out that clinicians and not parents should complete the CARS. It also recommends that in the future, CARS-2 should be used. Apparently, in Ms. Furfaro’s opinion, this constitutes a “hint at small improvements”. The parents whose children are now below the threshold for autism might disagree with Furfaro.
“The trends observed in this study are indicative of potential therapeutic benefits,” lead researcher Neil Riordan, founder of the Stem Cell Institute, wrote in an email sent to Spectrum by a spokesperson.
Here is Furfaro’s question along with Dr. Riordan’s complete answer:
Furfaro – What are the big takeaways from this study in terms of safety? Can anything be said about the efficacy?
Riordan – The administration of repeated-dose UC-MSC infusions is safe and tolerable for patients with ASD. Although this phase I study included a small number of subjects without a placebo arm, the trends observed in this study are indicative of potential therapeutic benefits, reflected in lower CARS and ATEC scores that may be associated with decreases in TARC and MDC levels.
The results echo those of a 2017 study at Duke University that reported that infusions of stem cells taken from stored umbilical cord blood are safe.
This statement is completely irrelevant since the Duke study used cord blood and our study used purified MSCs from umbilical cord tissue. There are no MSCs in properly processed cord blood. These two studies have absolutely nothing in common. We made this clear to Furfaro. Here is her question and Dr. Riordan’s answer:
Furfaro – How do the results of this trial mesh with the safety findings described by Duke researchers in 2017? https://www.ncbi.nlm.nih.gov/pubmed/28378499
Riordan – The Duke trial utilized autologous umbilical cord blood not allogeneic hUC-MSCs. Therefore, there is really no comparison between the two.
“When there’s more than one group reporting similar results, it tends to look more like a validation,” says Arnold Kriegstein, professor of neurology at the University of California, San Francisco. But he cautions that the findings are about safety only, and neither study tested the treatment against a placebo.
Kriegstein is completely wrong regarding “more than one group reporting similar results”. The Duke trial used cord blood and our trial used purified mesenchymal stem cells from cord tissue. These trials have nothing in common and cannot be compared to one another. Obviously, Kriegstein did not bother to read both of them or he would have known this. Comments like this call into question the veracity of anything Kriegstein says regarding our trial.
We addressed the placebo issue in our response to one of Furfaro’s questions:
Furfaro – Why didn’t this study include a placebo group?
Riordan – A placebo group is not useful for evaluating safety since subjects in the placebo cohort are not receiving the actual product that is being evaluated. It would be quite unusual for a safety study to include a placebo group.
There is also no convincing explanation for how the stem cells might treat autism, he [Kriegstein] says.
This is an unsubstantiated opinion from one professor. He offers no actual evidence as to why our scientific rationale is not “convincing” to him. Given his erroneous comparison of our trial to the one at Duke above, it is questionable that Kriegstein even bothered to read the scientific rationale published in our article, so his opinion can be taken with a grain of salt.
“It’s not right to charge patients for unproven stem cell injections, even in the context of a study,” says Paul Knoepfler, professor of cell biology and human anatomy at the University of California, Davis. “Those running the study financially benefit from it, and stand to benefit if the results turn out a certain way.”
Dr. Riordan addressed this concern as well – twice! Once again, Furfaro only published a small part of his response:
Furfaro – I saw on the MediStem website that participants were required to pay $7,200 (for each infusion) to participate in this study. Why? Why wasn’t this information included in the published study? Was this information disclosed to journal editors at Stem Cells Translational Medicine?
Riordan – Each participant was required to pay $7200 in total (1800 per treatment cycle). This was to defray costs outside of the treatment. The actual treatments were provided free of charge. The ability to cover $7200 plus travel expenses was public information, for example it is published on clinicaltrials.gov in the Inclusion Criteria section. It can be found here:
https://www.clinicaltrials.gov/ct2/show/NCT02192749
Furfaro – I wanted to run a few things by you that I heard from other autism experts. Some experts have expressed concern that parents were required to pay to participate in the study. Can you respond to this in more detail, and provide details about what the $7,200 paid for? Was any of this profit.
Riordan – Neither Medistem Panama (lab) nor Stem Cell Institute (treatments) profited from the autism trial. As stated before, the $7,200 covered services that were provided by companies outside of the lab and clinic. All lab and clinic services were provided free of charge. While not common in well-funded clinical trials, charging subjects for outside services in smaller, less well-funded trials is not without precedent. For example, Duke and Northwestern have both charged clinical trial subjects in the past.
The team gave parents of the participants two questionnaires — the Autism Treatment Evaluation Checklist and the Childhood Rating Scale — before and after the trial. The scores of eight of the children improved on these tests, according to the parents; the researchers did not report scores for the other seven, and did not explain why.
This article was published before Dr. Riordan could answer since he was traveling at the time. Here is his response:
The 7 children were not included because they did not improve by at least one category on the CARS. 6 of them remained in the same category. 1 regressed by 1 category. While not statistically significant (one way or the other) this rate of regression (1 in 15) is lower than that which occurs in the general population of autistic children.
Riordan and his colleagues did not mention in the paper that the families had to pay for the infusions. But Riordan told Spectrum that the $7,200 the institute charged parents was “to defray costs outside of the treatment. The actual treatments were provided free of charge.” Weeks says that the trial, travel and other expenses totaled more than $20,000.
As stated in his answers above, the fact that parents had to pay $7,200 for costs outside of the actual treatments was, and still is, publicly available information on clinicaltrials.gov. It’s important to note that each child who completed the trial received 16 separate stem cell injections, the current retail price for which is approximately $64,000.
Riordan is the founder of several other clinics, including one in Costa Rica that was shut down by the government there in 2010…
The article to which Furfaro refers regarding Dr. Riordan’s clinic in Costa Rica is not accurate. The clinic in Panama opened in 2006. The Costa Rican government did not close down the clinic in Costa Rica. There was a change in government policy that made the future uncertain. Because of this and the fact that he was operating two clinics in the same geographical area, Dr. Riordan made the decision to close the clinic in Costa Rica in 2010. Since that time, the regulations in Costa Rica have shifted back. Under the current regulations, Dr. Riordan could open another clinic if he wished.
He has also launched a Texas-based company called Aidan Products that sells nutritional supplements. According to the company’s website, the supplements improve circulation, boost the immune system or “stimulate your body’s ability to mobilize your own stem cells.”
Furfaro omits that there is published scientific research to support claims made on the Stem-Kine website.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804590/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862021/
Bernard Marcus, a philanthropist whose foundation donated $26 million to the Duke trial, visited the institute for treatment for a chronic lung condition, Riordan says.
Once again, Furfaro publishes a partial answer and omits the positive details of Bernie Marcus’s experience.
Here is her question and Dr. Riordan’s complete answer:
Furfaro – What did Bernie Marcus receive stem cell treatment for?
Riordan – Bernie Marcus was treated for bronchiectasis, a chronic lung condition. Details of Bernie’s experience in Panama are published in Chapter 10 of Stem Cell Therapy: A Rising Tide – How Stem Cells Are Disrupting Medicine and Transforming Lives.
From Dr. Riordan’s book:
Bernie was treated with stem cells and shortly thereafter stopped coughing and was able to return to his work. “I was able to go back to public speaking without embarrassing myself,” he said. The next time he came down for treatment he brought his wife, who had two osteoarthritic knees that her orthopedic doctor recommended, be replaced. “As you know, total knee replacement means being out of action for six months per knee, which would mean a year of not being able to do the things she likes to do,” Bernie said. “She’s a very active woman.”
So he brought her to Panama for stem cell treatment. “We had to carry her onto the plane because she couldn’t take any steps at all without tremendous pain.” Just three weeks after her treatment she was back to playing golf four times a week with no pain. Fourteen months later she is still doing well. “When I go down again I’m going to take her with me to double up so it doesn’t happen again,” Bernie said.
Scientists who led the Duke study did not respond to multiple requests for comment, but some experts including Kriegstein have criticized the rationale for that trial.
Criticism of a completely unrelated trial by unidentified “experts” (other then Kriegstein) is not relevant to our trial in Panama whatsoever.
In conclusion, while we believe that Ms. Furfaro did her best to present both sides of this story, we would be remiss not to share all of her questions and Dr. Riordan’s complete answers with concerned readers along with additional information we feel is relevant to the story.
Questions from Hannah Furfaro with complete answers from Dr. Riordan:
Original 14 questions
1. What were the motivations for this study?
As stated in the published article, the primary motivation was to evaluate the safety of intravenous administration of human umbilical cord tissue-derived mesenchymal stem cells (hUC-MSCs) in children with autism. We also wanted to examine the relationship between macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) and the severity of autism.
2. How do the results of this trial mesh with the safety findings described by Duke researchers in 2017? https://www.ncbi.nlm.nih.gov/pubmed/28378499
The Duke trial utilized autologous umbilical cord blood not allogeneic hUC-MSCs. Therefore, there is really no comparison between the two.
3. How were participants recruited for this study?
Parents of prospective participants were recruited through clinicaltrials.gov here: https://www.clinicaltrials.gov/ct2/show/NCT02192749
We directed some people to this NIH page via social media, a Translational Biosciences website, and through cellmedicine.com
4. Why were children tested for levels of mercury and lead as criteria or participation in this study?
Because in vitro testing I’ve done in the past showed that mercury and lead are toxic to mesenchymal cells.
5. Is it accurate to say that the stem cells used in this study were isolated from donated umbilical cord tissue? Or is it more accurate to say that they were cultured cells from a cell line that originally was isolated from donated umbilical cord tissue?
hUC-MSCs were isolated from human UC tissue from voluntarily donated UC’s obtained from normal, healthy births after a rigorous screening process. hUC-MSCs were obtained through enzymatic digestion of UC Wharton’s jelly using collagenase. After isolation, the cells were expanded up to passage 5. Details of this whole process can be found in the UC-MSC Preparation and Culture section of the article: https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.19-0010
6. Why were roughly 9 million cells administered during each infusion? (What is the significance of this number)?
The dose was decided upon based on other published studies of dosages of 1-2 million cells per kilogram. The mean target age was 11 years old (6-16) and the average weight of an 11-year-old male is 36 kilograms, so each treatment cycle was comprised of 4 infusions of 9M cells (36M total).
7. Is it accurate to say that children who participated in the study were allowed to continue other medications or treatments between each follow-up appointment?
Yes, as long as there were no changes for the study duration including no changes in dietary management for 3 months prior to enrollment and no additional biomedical treatment started 6 weeks prior to enrollment.
8. What are the big takeaways from this study in terms of safety? Can anything be said about the efficacy?
The administration of repeated-dose UC-MSC infusions is safe and tolerable for patients with ASD. Although this phase I study included a small number of subjects without a placebo arm, the trends observed in this study are indicative of potential therapeutic benefits, reflected in lower CARS and ATEC scores that may be associated with decreases in TARC and MDC levels.
9. From looking at Figures 1 and 2, it looks like all efficacy results were reported as having large error bars. What do you make of this?
One major limitation of this study was the small sample size, which impacted the statistical power of the analyses.
10. Why didn’t this study include a placebo group?
A placebo group is not useful for evaluating safety since subjects in the placebo cohort are not receiving the actual product that is being evaluated. It would be quite unusual for a safety study to include a placebo group.
11. I saw on the MediStem website that participants were required to pay $7,200 (for each infusion) to participate in this study. Why? Why wasn’t this information included in the published study? Was this information disclosed to journal editors at Stem Cells Translational Medicine?
Each participant was required to pay $7200 in total (1800 per treatment cycle). This was to defray costs outside of the treatment. The actual treatments were provided free of charge. The ability to cover $7200 plus travel expenses was public information, for example it is published on clinicaltrials.gov in the Inclusion Criteria section. It can be found here: https://www.clinicaltrials.gov/ct2/show/NCT02192749
12. What other sources of funding contributed to this study?
Translational Biosciences, a subsidiary of Medistem Panama, provided all additional funding.
13. Did you collaborate with any researchers from Duke when designing this study? Have you collaborated with researchers at Duke in any way?
I know Dr. Kurtzberg at Duke. Bernie Marcus, who funded the Duke trials, has been a patient in Panama (public information) and saw children with autism benefitting from treatment with umbilical MSCs first hand. I was asked to review the Duke proposal for the Marcus Foundation and was at the Foundation Board meeting that led to the funding.
14. Do you have plans for follow-up studies, and if so, what are the goals of those studies? If you have a specific study underway now, how many children do you plan to recruit?
There is currently no follow-up study in Panama underway. We do have plans for future studies in the U.S. but there is no timeline as of yet.
First 3 follow-up questions:
1. What did Bernie Marcus receive stem cell treatment for?
Bernie Marcus was treated for bronchiectasis, a chronic lung condition. Details of Bernie’s experience in Panama are published in Chapter 10 of Stem Cell Therapy: A Rising Tide – How Stem Cells Are Disrupting Medicine and Transforming Lives.
2. Is it accurate to say that the Stem Cell Institute has served “hundreds of children with autism” Or is this number smaller, or larger?
Yes, that is accurate.
3. I wanted to run a few things by you that I heard from other autism experts. Some experts have expressed concern that parents were required to pay to participate in the study. Can you respond to this in more detail, and provide details about what the $7,200 paid for? Was any of this profit.
Neither Medistem Panama (lab) nor Stem Cell Institute (treatments) profited from the autism trial. As stated before, the $7,200 covered services that were provided by companies outside of the lab and clinic. All lab and clinic services were provided free of charge. While not common in well-funded clinical trials, charging subjects for outside services in smaller, less well-funded trials is not without precedent. For example, Duke and Northwestern have both charged clinical trial subjects in the past.
Last 4 follow-up questions:
1. In the study, I see that scores on the ATEC and Childhood Rating Scale are reported for 8 children, but not the other 7. Why weren’t the scores for these children included?
The 7 children were not included because they did not improve by at least one category on the CARS. 6 of them remained in the same category. 1 regressed by 1 category. While not statistically significant (one way or the other) this rate of regression (1 in 15) is lower than that which occurs in the general population of autistic children.
2. Did you confirm that all participants have an autism diagnosis by requiring that they undergo an ADOS or other diagnostic test? I didn’t see information about this in the study, but please let me know if I’ve missed it.
As stated in the article, “Stem cell therapy-naïve children aged 6–16 years were considered for this study if they had a prior diagnosis of autism per the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, as confirmed by the *Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview—Revised.”
*ADOS
3. I spoke with a woman named Dorinda Weeks, who told me her son Aaron Weeks was enrolled in the trial. Can you confirm that this is true?
We cannot divulge the identities of trial subjects or their parents. Therefore we can neither confirm nor deny the participation of Mrs. Weeks’s child.
4. Is it accurate to say that the participants [sic] parents completed the ATEC and the Childhood Rating Scale? (and not the clinicians? I know these are parent report measures, but I just want to double check).
Yes. As stated in the article, “Signals of efficacy were evaluated by parent-reported outcomes via the CARS and ATEC tools, in collaboration with the study pediatric psychiatrist, who evaluated the appearance, behavior, mood, speech, and intellectual functioning of the subjects to supplement parental reports…
…The original CARS version was used for this study rather than the preferred and more updated version CARS-2; in future studies with a larger population, this second version should be used and completed by clinicians to ensure standardized testing rather than relying on parental observations.”
For more information visit: www.cellmedicine.com