Tuesday, March 6, 2012

More Information on Zhao's Stem Cell Educator

Zhao's Stem Cell Educator phase-I trial, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2012/01/zhao-et-al-tianhe-publish-successful.html
has generated a lot of interest, so I've done some extra research on it, and this blog contains what I've learned.

Good News First

The best news that I gathered about this work, is that the published paper is not the final report on a 15 person clinical trial.  Is is the initial report on the first 15 people treated in a clinical trial which is on-going and continuing to enroll more people.  This is great news, for two reasons.  First, because it means that they are continuing to follow those 15 people.  With a little luck we can look forward to follow up reports describing what happens to these people in another year, two more years, and so on. Also (again, with some luck) we can expect reports on 50 people, 80 people, maybe even more people.  All this data is already being gathered as part of the current clinical trial.

The next good news is that the researchers very much want to start a clinical trial in the US.  That will take some time, due to regulatory approvals.   If they do start a trial in the US, it is likely to be similar to the one in China [d1].

Several people have asked me how this treatment works, and this is how it was explained to me:
First, there are proteins which train the body's immune system not to attack itself [d2].  These proteins are found on stem cells, so exposing immune system cells to the stem cells has the effect of training the immune cells not to self attack.  Second, these researchers believe that there are cells in the pancreas which are ready to become beta cells[d3], and also that there are stem cells circulating in the blood stream [d4] which can turn into beta cells.  They don't know which of these two routes are creating the new beta cells, but they believe some combination of them is creating enough beta cells to cause the large decrease in injected insulin and increase in C-peptide.

One question that I had was basically this: "Do you really think that the body can regrow so many beta cells that it can generate 25 to 38% of it's own insulin in just a few weeks?  No one else has seen anything like that when using other techniques to stop the autoimmune attack."  The answer was that was exactly what they thought was happening.  First, it was the theory that explained the results the best, and second, it was what they saw in their animal studies, so they were not surprised to see it in people.  We can only hope this is correct.  Future trials will tell.

I did ask if there was anything special about stem cells from the umbilical cord, which made that particular type of stem cell important to the research.  The response was no.  They expected that many types of stem cells would work, but they choose to use umbilical cord cells because they were convenient to use and  easy to get, as compared to other types of stem cells.

The researchers have professional connections to researchers in Amman, Jordan and Hue, Viet Nam, and that is why they might start clinical trials in those places.  Because there will be fewer regulatory hurdles, those studies could start more quickly than the one in the USA.  My feeling was that if they did studies in those place, the studies would be similar to the Chinese one, but they would try to improve ("optimize") the procedure.

Finally, I want to say that I have heard from several different sources (all private communications) that the researchers are in touch JDRF to discuss the funding of future studies.   They may well be in contact with other organizations, I hope that they are, but I've gotten specific information about JDRF.

Not-So-Good News Second

It does not look like this is the kind of treatment that the FDA is likely to allow under the "surgical exception" that I discussed in the previous discussion of this research.  So therefore, it is likely that a full FDA approval cycle will be needed, so about 4 clinical trials (and I'm not sure if this first one would count [d1]).

I do not think that any of the patients were ever free of injected insulin.  So I don't think they cured anyone, even temporarily.  On the other hand, I got the feeling everyone was helped to some degree.  In some research, there are some people where it just doesn't work.  Those people are sometimes called 'non-responders" and I think there were few to none "non-responders" in this trial.

More Reading

The research below was all done in mice so I have not read it in detail, but it is listed, for people who want a lot more details.

http://www.omicsonline.org/2161-1025/2161-1025-1-104e.pdf (2011)
http://www.sciencedirect.com/science/article/pii/S1568997210001795 (Cord Blood Background 2010)
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004226 (Mice Cure 2009)
http://www.springerlink.com/content/0640621007560k70/ (2009?)
http://www.sciencedirect.com/science/article/pii/S0006291X07012715 (Beta Cells from Blood 2007)
http://www.sciencedirect.com/science/article/pii/S0165247806002379  (2007)
http://www.sciencedirect.com/science/article/pii/S0014482706001558 (Why Stem Cells 2006)

Discussion and References

[d1] Unfortunately, the FDA doesn't give much weight to data from foreign trials, so things learned in other countries need to be relearned in the US, so the FDA will fully consider it.  I'm quite worried that even once the study starts in the US, they might be limited to a very small phase-I study, because the FDA will not consider the Chinese study as proof of safety, even it if involves more people than an American phase-I study.

One of the researchers involved told me a story -- equal parts funny and shocking -- about trying to get approval for a medical device that had been tested in Australia.   The FDA would not accept data from Australia.   They wanted studies re-done in the US, so they could review that data, as though Australia was some corruption ridden, third world country, without a quality regulatory system!

[d2] Although I'm not sure exactly which proteins they are referring to, the general idea that a protein could re-educate the immune system is not controversial.  Drugs like DiaPep277 and other antigen specific treatments are based on this idea.   Haller's work in Florida is based on similar ideas, although his effectiveness was no where near what Zhao and crew see.

[d3] Although this idea was controversial a few years ago, I think that consensus is shifting.  There is now some research that shows that stem cells already in the pancreas may be able to grow into beta cells.  Even stronger was a paper published last year (sorry don't have the reference handy) which showed very specifically that in mice, alpha cells in the pancreas could turn into beta cells that produced insulin in response to sugar. Plus there is the Joslin "Medalist" study (more than one) and  Dr. Faustman's paper just published last week which adds support to this same idea.

[d4] This was based on their own previous work in mice.  But I know that other researchers have been looking into this area.  Although the research in mice is not conclusive, there is some supporting evidence for this, in addition to the Zhao group.


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

25 comments:

GabLarConBriCar said...

Thanks Joshua. As we had discussed at the time of your original post, I think it's (unfortunately) a waste of time to even try initiate the process in the US. The FDA proved it is emphatically against considering even autologous stem cell treatments as "practice of medicine" (see Regnerative Sciences case) and in this case where there are hallogenic cells it is evident they will choose a conservative route.

I strongly prefer Dr. Zhao to continue abroad and without this kind of distractions. When the first off-insulin cases start to appear, pressure on the FDA will be enormous and/or the availability of the treatment in the US will take a decade or so. Fortunately, I don't see Dr. Zhao falling under the category of unreliable medical tourism type of providers, so I'm very hopeful this is really a paradigm shift.

Bennet said...

Thanks for keeping us current. I look forward to reading the links provided.

Much appreciated.

Anonymous said...

This is awesome news. I have two sons with T1 diabetes. One has had it for 17 years and the other 11 years. This disease is destroying their lives. When they were diagnosed, I was told five years, ten at the most. I know that you like JDRF Joshua, but I have seen their decline. They do not want to cure this disease. They want to manage it and are pushing this artificial pancreas project to the extreme. They have partnered with so many big pharma companies that do not want this disease cured. Forgive me, but I am extremely disappointed with JDRF. If they helped fund this research like you say, why is it not in their website or in their countdown magazine. AS donators to JDRF (I have given them lots of money in the past, but not much recently), is there any way that we can pressure them to provide funding for this research. This is the best news that I have seen since islet cell transplants.

Anonymous said...

Please Google Dr. Denise Faustman. Why isn't she getting the press right now? The stem cell, artificial pancreas, etc. is ridiculous. Anyone with a brain can research the finding of Dr. Denise Faustman and her lab at Massachusetts General Hospital/Harvard Medical and see she is actually onto something. Her research has shown a cure in mice as well as a positive response in humans. Phase II is about to begin. The JDRF as well as pharma companies are unwilling to support her financially - going as far as to say there is no money in the cure! The pancreas does NOT die within 1-2 years of symptoms onset - it continues to produce insulin - even NIH replicated her research and came up with the same results! Her theory based on the evidence is that if you can block the "mutant" white blood cells that attach the pancreas the body begins producing insulin again. The BCG vaccine has shown evidence that it can do just that! Check out her videos on YouTube and visit the website at www.faustmanlab.org. I am telling you - THIS is our HOPE!!! Let's not continue to support the 15 billion dollar a year industry and support the cure already!!!!

Joshua Levy said...

I know I'm behind on replying to these comments, but here is my reply to GabLarConBriCar:

I don't agree with your harsh view of the FDA's regulation of autologous stem cell treatements. I'm not an expert, but I did read a little on the Regenrative Sciences case, and it is not clear to me that the FDA was wrong. Basically the FDA felt that the treatments offered by the Regenerative Sciences (RS) guys was new and did require the same sort of testing that a new drug or device would need. The RS guys felt that they didn't need that level of testing. Sure, less testing leads to quicker, cheaper treatments, but it also leads to less safe treatments and more fraud. It is not clear to me that the FDA was wrong in this case. What the RS guys were doing was new different, and non-trivial, and I think the higher level of testing might have been justified.

In any case, Zhao and team expect to be held to the higher testing standard, so it doesn't really matter to them. Also, remember that they are not using Stem cells to grow new tissue; they are not even putting stem cells in people, so whatever the FDA didn't like about RS, they are not going to have the same problems with this work.

Joshua Levy

GabLarConBriCar said...

Thanks for your response Josh and let me clarify. I'm not giving my own opinion on FDA's stance. I'm just saying that if they consider RS not to be "practice of medicine" (not governed by FDA), I consider it extremely unlikely that they will consider Zhao to be "practice of medicine". I agree with you unde Zhao there are no stem cells into the body, however there are "particles" or "proteins" or something from those hallogenic stem cells which are secreted and target the patient's white cells for re-education.

What FDA doesn't like about RS is the fact that own stem cells are "treated" with external substances and this leads to the manufacture of a drug (RS says no, the substances are simple culture to replicate patient's own cells and only those are re-injected into the body). Well, I see this as exactly what happens with Zhao, which is to take away certain cells from the body (not stem cells but white cells) and "treat" them with particles/proteins secreted from non-patient stem cells.

Bottom line, I would be extremely surprised to see the FDA not attempting to regulate Zhao and allowing him the "practice of medicine" route.

ps: just for historic reference, I am the former "Papa Carlitos" commenting on your blog since last year.

Joshua Levy said...

For Anonymous March 6, 2012 1:50 PM. Here are some quick replies to two of your points:

You say "They want to manage it and are pushing this artificial pancreas project to the extreme."

My understanding is that JDRF spends less than 3% (roughly) of their research money on the AP. So for every $1 they put into that, they put $33 into other things. I don't consider that an extreme amount of money. (To use your phrase.) However, it is true that the AP gets more than 3% of JDRF's press releases and publicity in general. So there is a perception that the AP is a huge part of JDRF, even though it's not. Why AP gets so much publicity has several answers, and I don't have space or time to go into it here. But, in terms of money and focus, I don't think it is a huge part of JDRF's work.

As for why this work (Zhao) isn't on the web site. I don't know, but I do know that JDRF funds about 300 projects at any given time. So there isn't space for more than a small fraction. And, I'm sure know one expected this one to have such positive results. I was surprised at how well it came out. I bet others were, too.

DDR said...

Joshua, I'm 41 years old & was diagnosed with Type 1 Diabetes 4 weeks ago. I'm shocked, stunned, & depressed as I've been extremely committed to living healthy my entire life ...... now this happens. Your web-site/blog does give me hope, however. In your best estimation, how long do you think it will be before a cure is finally found (& accepted here in the states)? Is there a "point of no return" for Type 1 Diabetics, where the Pancreas has been inactive for so long that it cannot be healed? Thank you for your efforts & insightful information.

Anonymous said...

Have you looked at the work presented by Dr. Ann Clark from Oxford University at the Prague Diabetes Conference several months ago? Her research indicates that a long-standing type 1 diabetic simply cannot regenerate pancreatic beta cells in sufficient number ever to make more than a trivial difference in the exogenous insulin dose required. If true, that ends the whole line of regenerative therapy for established type 1 diabetes.

Joshua Levy said...

For DDR:

One of the reasons I started this blog was because I got soooooo frustrated with people saying that the cure would be here in 5 years, or 3 years or 7 years, or whatever fool thing they said. So, I'm not tempted to make guesses myself. Remember that it takes 10 or more years to go through clinical trails. So if a cure is in clinical trials right now, then it might be available in less than 10 years, but if it is not being tested in people already, then certainly longer than that.

Now, as to a "point of no return" with the pancreas, I'm not to worried about that. We just don't know, and even if there is such a point, the eventual cure may not be based on regrowing your own beta cells, anyway. It may use something else.

Joshua Levy

Joshua Levy said...

For Anonymous March 16, 2012 10:32 AM:

I have not read Dr. Clark's work. However, my understanding of it, is that she is referring to normal regrowth. The kind of thing that happens normally during your life. So I suspect she is right, but I don't think that matters very much to a cure, because I think that we will need to give specific treatments to cause new beta cells to grow. So Dr. Clark says it will not happen spontaneously or naturally, but that's OK with me, because I expect it to happen in response to drugs or treatments of some kind.

I guess: I thought think of naturally regrowing beta cells as a great extra bonus, but I never expected it to happen. And I don't think she is saying that beta cells can't be made to regrow. Just that it doesn't happen as part of day-to-day normal life.

Joshua Levy

DDR said...

Joshua, I was wondering if you've ever heard of a link between the drug Propecia (Finasteride) and Type 1 Diabetes. I started taking 1-mg of it per day back in September of 2011 & was diagnosed with Type 1 in February 2012. The A1C test at that time projected I had elevated glucose levels for the previous three months, the start of which would have coincided with the Propecia building in my system. I had a physical in Feb of 2011 which showed my glucose levels as normal. There are a few web postings out there by individuals who blame their Type 1 diagnosis on Propecia, but I'm skeptical. Is this purely coincidental or is there really something going on here? You hear that Type 1 needs some sort of mysterious trigger to get it started .... I wonder if the introduction of a testosterone altering hormone like this could do the pulling. What are your thoughts?

Joshua Levy said...

Propecia and Faustman blog entries are "in the works". One should be out next week, and another the week after.

Anonymous said...

I am from Brasil and Im in it just for 1 year diagnosys...I really believe that JDRF is not like cure this desease definitly!!

Anonymous said...

I think every little one shoul test their C Peptide when test A1C glicade! I believe that is simple a kind of auto imine attack and when it stops the beta cells may regroth by herselves... It has been proved by Dr Faustman and Dr Yong Zhao... So we, I mean the parents of childs type 1 diagnoses and people intersting on it should question their doctors much more than this!
Artificial pancreas does not mean the cure!!!!!
We need insulin from the body for so many things!
Whats the difference between the others auto imune deseases, like sarcoidoses one of them goes and the other keep attacking...
So I believe that we are not face at a binonimous regrows x auto imunity, but only a auto imune quastion... i feel horrible when I read a JDRF webpage! It is disgusting!

Anonymous said...

There is also Dr Pere Santamaria from Calgary UNiversity with the same results of FAustman and ZHao.
His finds is about to produce the good T cells to attack the T bad cells as much as necessary! And then the mice has not diabetes type 1 at all!
So we have 3 strong results point to the same theory : Beta cells can regrowth when the imunity is normalized!
My name is MIchele I am a mother of a 5 years little girl! I think we are close to a cure.
But I only believe in an academic research! This people is so compromised!
I am an anonymous that wrote those trhee last coments. Really sorry about my english!

Anonymous said...

In my thoghts the most recent diagnosys research is because we need somebody to tell us what is working what is not working, I means has to be some survivers beta cells to tell us about the stop of attack! but after a long period testing only recent diagnosys we dont need it anymore!
Its time to prove to imunomodulatory proccess!
About stem cell, they know the capacity of imunomodulation, but they did not know about the regeneration capacity... works in some one and not works in another obe!
I believe its because every person works with a number of soldiers to attack and to defend in white blood cells!
We have here in Brasil Dr Julio Voltarelli, with a serious randomized, double blind multicentric studies with reset of autoimunity...I agree he does not need to go so far... his mesenquimal hematopoietics works withouth quimiotherapy... I knew from them team that in holand there is a machine that counts this numbers of t bad cells! that way we should diferentiate each persons treatment!

PZoom said...

Joshua
I agree, interesting research. I have tried to look up previous research on this and still don't understand how the stem cells reducate autoreactive lymphoctes (AL).
Possibly they do, but what about the Antigen Presenting Cells (APC) that are producing the AL. From what I read, they mostly reside in the lymphatic system, so this treatment may wipe out a number of freely circulating AL, but they will reappear.
Secondly, I cannot also see an sanwer in the literate as to how much this treatment affects the immune system overall. Does it wipe all antigen memory from lymphocytes? This would make it like general immunosuppression, or is it somehow specific for AL?

Malcolm Mackay said...

Great post Joshua. This is a very encouraging line of research, given the results in humans so far.

Łukasz Moliński said...

I don't want to disappoint you guys but prof Vortarelli's work (replicated by Snarski in Poland) showed no regeneration process after restarting/ stopping failure immune system - at least it is how I read it. I know few people treated this way and now they're under strict diet, taking medications such as metformin. It looks like they only have been stopped at some level of pancreatic function without significant regeneration progress. Some say that they've changed their type 1 into type 2 only. Which for some people is not worth to undergo such risky treatment which bone morrow transplant obviously is.

Anonymous said...

Zhao's stem cell educator seems to reverse diabetes type 2 as well, please see "Stem Cell Educator Therapy in Type 2 Diabetes" http://clinicaltrials.gov/ct2/show?intr=%22Stem+Cell+Educator%22&rank=1

Joshua Levy said...

To Anonymous at 9:05 on April-17:

They have certainly been testing it on type-2, but I don't think results have been published. This is the closest I could find, but it looks like a review, not a result:

http://www.sciencedirect.com/science/article/pii/S1568997211002011

Joshua

Anonymous said...

Joshua,

when can we expect to hear from this team again? with more results. In your contact with them, did they say their more recent results confirm what we have read about so far. Same kind of results or getting better. I am anxious to hear from them more often.

Thanks
pdx_mom

Aaron said...

Joshua, Thanks for digging into this. I wanted an update and found a few things. Hopefully their new and helpful:
1. From CT.gov (http://www.clinicaltrials.gov/ct2/show/NCT01350219?term=Yong+Zhao&rank=1)
Zhoa is recruiting for Phase II in China. 100 people aged 14-60 (not just newly diagnosed(?))
It's at least partly funded by JDRF and Zhoa's company (Tianhe Stem Cell Biotech)
It's scheduled to run until 2014.


2. Zhoa published a review here: http://www.springerlink.com/content/k040682352l17n6j/?MUD=MP

stemcelltherapy said...
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