The full story on "Stem cells reverse woman’s diabetes — a world first"

If you've been reading news recently you might have seen headlines like these:

Stem cells reverse woman’s diabetes — a world first

Stem Cell  treatment reverses Type 1 Diabetes!

Chinese scientists have put a young woman’s type 1 diabetes into full remission using stem cell treatment.

And even if you didn't your friends and relatives might have seen them and asked you about them.

(And that first one is from the journal Nature, which is a major scientific publication.)

Unfortunately, those headlines are basically hype.  There is some news, and it is good news, showing important progress, but it is no where near as good as the headlines make it sound.

What Was Reported

The researchers took some adult stem cells from a person with type 1 diabetes, and treated those stem cells with a specific recipe of drugs, which caused them to change into beta cells.  They then implanted those cells back in the person who donated them.  The results were spectacular.  After about 2 months the person stopped injecting insulin, and then was followed for another 10 months without needing any injected insulin.

The woman was not your average person with T1D.  She had been diagnosed 11 years prior, so was well established.  However, she had previously had two liver transplants and one pancreas transplant (more on that below).  At the end of a year, her A1c was 5% and her blood glucose time-in-range was 96%, both great numbers.

Not A Cure

Before getting this transplant, this person had already had several transplants, and was therefore on immunosuppressive drugs and would need to stay on those drugs for the rest of her life.  Therefore, by my definition, she was not cured but rather traded one treatment (insulin for T1D) for another treatment (immune suppression for a transplant).  I don't consider this a cure.  Some people may prefer one drug regimen over another, but it is not clear to me that one is generally better than the other.  My understanding is that people who have whole life immune suppression generally have shorter life spans than people with T1D.  

But in any case, I don't consider this a cure.  Of course, you may, and if you do, then you should look into existing transplantation surgeries, because there are some available now that have similar results to what is seen here.

Shows Progress

The big headline "no insulin injections for almost a year" is misleading because those results have been seen previously in transplants when whole life immune suppression has been used.  The JDCA has published two great overviews in 2016 and 2022, which you can read here:

• https://www.thejdca.org/publications/report-library/archived-reports/2016-reports/islet-cell-transplantation-update-new-phase-iii-study-results-show-insulin-independence-unchanged.html
• https://www.thejdca.org/publications/report-library/archived-reports/2022-reports/pioneering-islet-cell-transplant-team-publishes-20-years-of-data.html

The bottom line is that no insulin injections for a year occurs in half the cases, and for two years in over 40% of the cases.  So the headlines are hyping something we can already do. (If you are willing to suppress your immune system for the rest of your life.)

If fact, there is an FDA approved transplant protocol, where over 2/3s of the people did not have to inject insulin for more than a year, but it does require immune suppression:

https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes

However, the research reported here does show some specific progress, and some strong future possibilities.  The key improvements seen here are:

1. More stem cell availability.  Previous transplants have used beta cells from cadavers, pigs,  occasionally live doners, and just recently from the patient themselves.  This research sources beta cells from the patient, which means there will always be a strong supply.  The treatment that they use to mature the stem cells into beta cells is new and unique and the researchers claim it is much better than previously available techniques.  They think it gives them more control over the resultant beta cells and also is more effective.  It is this technique that is the real progress.

2. Using a person's own stem cells.  My memory is that this is not the first ever case where T1D  transplantation used cells from the person being treated.  However, this is a very recent and experimental technique.  The success here is important.  Most importantly, there is hope that these cells will not be automatically attacked by the person's immune system, because they are not foreign.  This is a serious issue with other transplants.  Because these cells are not foreign, this transplant may not require long term immune suppression.  That would be a huge breakthrough.

Unfortunately, since this person is already using long term immune suppression, there is no way to know from this trial if this kind of immune suppression is needed or not.

Furthermore, even if this procedure becomes immune suppression free in the future, it is not clear what will happen to the new beta cells long term without it.  Will the person's T1D immune system attack the new beta cells just like it attacked the original ones?   We don't know.  That is future research that must be done.

There are four hopeful possibilities here (lines of research which might prevent this attack).  They are theories held by some researchers.  The first two are active areas of research, with several research groups working on each one, and the second two are tested on occasion, but are less actively pursued:  

1. Several research groups are investigating encapsulation, so that the immune system cannot physically get to the new beta cells, which would protect them.
2. Other groups are developing the process of converting stem cells to beta cells so that the new cells were invisible to the immune system and protected that way.  The immune system tends to focus on very specific structures in the "skin" of the cell to identify what to attack.  If those structures are missing, then maybe the immune system would ignore the new cells.
3. The trigger of the autoimmune attack on beta cells might be time specific.  It occurs at a specific time for a specific reason.  So therefore, years later, when the new cells are transplanted, the trigger is no longer there and the cells will not be attacked.  
4. Finally, the immune attack on beta cells might be location specific.  It occurs because of the situation in the pancreas specifically.  Therefore beta cells not implanted in the pancreas won't trigger the immune response.

The researchers were waiting for results from the first person, but now that they have them, they will start up two more people.  It is a little hard to tell, but I suspect these two people will also have prior transplants and therefore long term immune suppression.

The study is ongoing and they are recruiting more people with T1D in Tianjin, China.  The study is described as "Phase 0", but I don't know what that means in China.  It is similar to an American phase-1 "pilot" study: no control group, no blinding, three people who will be followed for two years (I think) after transplantation.  Primary end point is A1c.  Secondary end points are C-Peptide and insulin use.

Contact: Wang Shusen        +86 136 1218 3907  shusen1976@126.com

               Shen Zhongyang  +86 138 0301 9898  zhongyangshen@vip.sina.com

More Information

This research was published in the journal Cell, which is a big name scientific journal:

https://www.cell.com/cell/abstract/S0092-8674(24)01022-5

JDCA's report: https://www.thejdca.org/publications/report-library/archived-reports/2024-reports/established-t1d-patient-insulin-independent-is-it-really-a-practical-cure.html

Chinese Clinical Trial Registry: https://www.chictr.org.cn/showproj.html?proj=192835

WHO Clinical Trial Registry: https://trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR2300072200

Coverage: https://www.sciencedirect.com/science/article/abs/pii/S0092867424010225

General Article: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-024-03636-0

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog! 

NextCell Starts a Phase-I Study of Mesenchymal Stromal Cell Treatment

NextCell pharma is running a clinical trial of their ProTrans product.  This is a stem cell product derived from "Wharton´s Jelly", which is a specific part of the umbilical cord.  ProTrans is made from umbilical cords from third parties, not the person receiving the transplant.  (So this is not self transplants, where the person gets stem cells which were originally harvested from themselves.)

The difference between ProTrans (the product being tested), and generic stem cells from Wharton's Jelly in the umbilical cord, is some proprietary testing.  NextCells thinks they have a way of identifying which batches of stem cells will be more effective, so they test each batch of stem cells, and the ones that pass are used to make ProTrans.

The Clinical Trial

The clinical trial being run right now, can be thought of as two mini-trials, being run one after the other.  They were both approved at the same time, which is why there is only one clinical trial registry.  However, when you read it, it is very clear that there is a 9 person trial, followed by a 15 person trial.  The first part is focused on finding the best dose, and the second part is focused on finding how effective that dose is.  The researchers have published their entire study protocol, which you can read here:
http://www.clinicaltdd.com/article.asp?issn=2542-3975;year=2018;volume=3;issue=2;spage=32;epage=37;aulast=Carlsson
Note that this published protocol description is not the same as the FDA clinical trial registry description.  I'm assuming that the published protocol is correct, as it was published months after the FDA registry was last updated.

Both parts of this study are limited to adults (18-40 years old) who are within 2 years of diagnosis.
The first part will be men only, the second part will be men and women.  The treatment is one intravenous infusion.  No immune supressives will be given.  The primary end points are safety and C-peptide generation (this measures the body's ability to generate insulin) after a year.  Secondary end points include insulin independence, insulin use, A1c numbers, and more C-peptide results.

Part 1

This part of the study is not blinded, and will include three groups of three people each, all of whom will get the treatment (no control group).  Each group will get a different dose of stem cells.  The first group will get 25 million cells, the next 100 million cells, and the third will get 200 million.

Results: No serious adverse effects as of June-2018.  Initial (one-month) results expected Oct-2018.

Part 2

This part of the study is double blind.  Ten people will get the treatment and five will get a placebo as a control group.  Everyone in this group will get the same dose, and that dose will depend on which one gives the best results in the first part of the trial.

Results:  Full results expected 2020.

NextCell's web site: http://www.nextcellpharma.com/
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03406585
Paper on Wharton's Jelly in general:
https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.16-0492


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Important Update For Stem Cells Arabia

If you are interested in potential cures for type-1 diabetes, then I urge you to read this report from the JDCA about Stem Cells Arabia:
http://thejdca.org/pc-2017-stem-cells-arabia
(Note that as a Fellow of the JDCA, I did contribute to their report.)

Stem Cells Arabia is in the middle of a clinical trial were they combine two stem cell procedures as a possible cure for type-1 diabetes.  However, the real excitement is fueled by the results of a very small pilot study they did previously.  The results from the pilot study were presented at a conference, but not published in a journal.  But those results are very strong: all four treated patients went months without needing to inject insulin and never needed anti-rejection drugs.  If you find that exciting (and I certainly do), then you'll want to read the JDCA report which contains more details, and you'll be looking forward to the results of their larger trial, which is expected to complete in early 2019.


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Update on the University of Jordan's Stem Cell Project

The University of Jordan recently announced the start of a phase-I trial of stem cells. While researching that, I found that they had already published results from a pilot study done at Stem Cells of Arabia (also in Jordan). So in this blog posting, I will first discuss the results of the pilot study, and then the phase-I study they are starting now. Even though these trials were sponsored by different organizations, I consider them part of the same research program.

What Is Being Tested?

These researchers are taking someone's own blood, and then process it before putting it back into the person's body.  I'm not sure the exact nature of this processing.  The pilot study makes it sound similar to Dr. Zhao's work (exposing the patient's cells to stem cells).  However, an interview in ASweetLife.com makes it sound like a filtering process.  It may be both.  The description in the FDA Clinical Trial record for their upcoming phase-I study talks about donors and "passaging" the cells, which might be a shorthand for the same process used in the pilot study.  Whatever their process is, it focuses on three types of immune cell markers: CD34+, CD133+, and CD271+. The process is similar to Dr. Zhao's and also to the T-Rex study. This is not a classic transplant, because the patient is getting their own cells back, and immune suppression drugs are not used.

Results from Stem Cells of Arabia's Pilot Trial of Stem Cells

The only information I have is from an abstract. I think it is from a talk given at the 2015 International Cord Blood Symposium conference, and was published in the journal Transfusion (abstract only).
The patients' average age was 35 years old, but ranged from 13-52, but there was no information on their honeymoon status.  The average A1c at start was 9.0, average Fasting Blood Sugar 350 (although I'm not sure what that means in a type-1 diabetic), C-peptide average was 0.06 (three people had 0.00 and one had 0.23.
Here is the complete results section of the abstract: 

There were no complications over the follow up period (14-51 months). Three out of four patients completely stopped their insulin requirement at 6 months. All 4 patients showed significant improvements in Fasting Blood Sugar (average 145), C-peptide (average 1.01), and HbA1c (average 7.0), during 12 months post transplantation.

Discussion

This is a study where only having the abstract really hurts.  Obviously, these results look very good, but there are key details missing. If the reported C-peptide numbers are fasting, and measured in ng/ml, those are excellent, but if they are in response to eating, then they are not particularly strong. (The abstract does not say.) Having 3 out of 4 patients not using insulin at six months is great, but there is no information on how long each person did not need to use insulin.  The results are great for established type-1 diabetes, but the abstract doesn't say how many people are established vs. honeymooners.

Based on those results, it is easy to see why this group is excited about doing a larger study. I'm excited too!

   University of Jordan Starts a Phase 1 Trial of Stem Cells

This is the start of the study which was previously discussed on ASweetLIfe:
https://asweetlife.org/jordanian-researchers-working-on-stem-cell-treatment-for-type-1-diabetes/
Now the study has officially started and there is a FDA Clinical Trial Record with the details of how the study will work.

This is a 20 person study, which will enroll adults (between 18 and 35) who have been diagnosed within 3 years, or are still generating C-peptide at a rate of 0.5 ng/ml or more. They expect to finish the study in July 2018.  Some people will get a small dose of stem cells, while others get a larger dose.  There is no control group.  Patients will be followed for 36 weeks.  The primary outcome is safety after 6 months.  No effectiveness outcomes are mentioned.

Cell Therapy Center,  Amman, Jordan, 11942
Contact: Abdalla Awidi, MD    0096265355000 ext 23960    abdalla.awidi@gmail.com
(I think this phone number would be  +96265355000 ext 23960, where + means "whatever you need to do to get an international number".)

Web site: http://www.stemcellsarabia.net/ and http://centers.ju.edu.jo/en/ctc/Home.aspx
Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02940418

Discussion

This is a quick study.  Expecting to have results in less than 18 months is much faster than most clinical trials, and from my point of view, that's a good thing.  On the other hand, there is no mention of reporting on the things that people with type-1 would care about.  No A1c data, no C-peptide data, and no insulin usage data is listed in the secondary outcomes.  Hopefully those things will be reported on, but most studies (even phase-I studies) list these as secondary outcomes.

This research is based on the same basic ideas which also led to Dr. Zhao's "Cell Educator" research, but the two approaches are not the same treatment.  Dr. Al-Zoubi's group is taking stem cells from a person with type-1 diabetes, treating them, and then injecting them back into that patient.  Dr. Zhao is taking stem cells from third parties, and then exposing people's immune cells to proteins made by those cells, but the stem cells themselves are never injected into the patient.   But both approaches are trying to harness proteins created by stem cells.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Possible Cures for Type-1 in the News (March)

ViaCyte Starts A Three Year Follow-up Safety Study in Subjects Previously Implanted With VC-01™
This clinical trial is studying people who were part of ViaCyte's clinical trial of VC-01™, an encapsulated beta cell cure.  Once the device is removed at the end of the study, the patients can enroll in this follow on study which tracks them for three additional years, looking for adverse effects.

ViaCyte is a commercial company testing an encapsulated beta cell cure.  You can read my previous blogging about them here: http://cureresearch4type1diabetes.blogspot.com/search/label/ViaCyte
They are in the middle of a large Phase-I study, which could finish as early as 2020.

Clinical record: https://clinicaltrials.gov/ct2/show/NCT02939118

Discussion

I'm hopeful that this means that one person has finished the ViaCyte protocol, which is motivating them to start this follow on.  The other option is that they are just planning ahead.  Since there is no control group, the interim data could be published, if ViaCyte wanted.

Two Phase-I Studies Start with Umbilical Cord Treg Cells 
These two studies have a lot in common, so I'm going to discuss them together: first, their similarities, then their differences. Here are the similarities:

• They are both run by the same researcher (Dr. Zhiguang Zhou) at the same hospital (Second Xiangya Hospital of Central South University).
• They recruit at the same place: Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China, 410011
  Contact: Zhiguang Zhou, MD/PhD    86-731-85292154    zhouzg@hotmail.com
• They have already started recruiting 40 people, and expect to finish in 2019.
• These trials are open to people who have been diagnosed within 3 years and are between 6 and 60 years old.
• Each has a primary end point which is safety related, and secondary endpoints which are effectiveness related and include C-peptide, A1c, insulin usage, etc.
• Both studies will work with stem cells which have been harvested from umbilical blood, separated into components, and had the T-reg cells "grown out" for two weeks.  These enriched T-reg cells will be infused into patients.  T-reg cells are regulatory cells which are part of the immune system, and work by controlling other immune cells so that those other cells don't attack beta cells.

The first study is Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg on Autoimmune Diabetes: This study will have two groups, one will get the treatment, and one will be a control group and will not get the treatment.

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02932826

The second study is Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes: This study has four groups.  One will get the treatment and also Liraglutide, another just the treatment, a third just Liraglutide, and a fourth will be a control group.  Liraglutide (sold as Victoza) is similar to exenatide (Byetta), which is a common type-2 medication, but is also sometimes used on type-1.  Victoza is a weekly injection. 

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03011021

Discussion

The researchers are not clear on why they are using Liraglutide, but site its "various benefits for beta cells". They expect it will increase the effectiveness of the new T-regs, possibly by encouraging beta cell growth.

JDCA's Update on Dr. Faustman's Research

An update on Dr. Faustman's BCG research by the JDCA (Juvenile Diabetes Cure Alliance) is here:
http://eepurl.com/cHrGqX

My key takeaway points are:
* The Phase-II trial should finish in 2023.
* They have enrolled 125 out of the 150 they need.
* An 8 year follow up from their Phase-I trial should be published by the end of 2017.

(Remember, I am a fellow of the JDCA and we regularly discuss various research programs, including this one.)
Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Research In The News (May)

This blog posting covers a couple of different topics, but starting with a piece of bad news:

Perle Biosciences Ends A Phase-II Trial of a Combination Cure

In November 2015 I blogged on a clinical trial by Perle Biosciences testing a combination of Cyclosporine and Omeprazole.  You can read the details here:
http://cureresearch4type1diabetes.blogspot.com/2015/11/perle-biosciences-starts-phase-ii-trial.html
Unfortunately,  that trial was listed as "Prematurely Ended", but I'm not sure exactly when.  There hasn't been an official press release on the trial, but JDCA quoted Perle Biosciences's president as saying the trial was stopped because "Enrollment was disappointing in Europe and we are planning to move all studies to the U.S."

Of course, I'm hopeful that they do start a trial in the US, and soon.  They are working with a combination of drugs: one of which stops the autoimmune attack and the other regrows beta cells. Both are already approved in the US (one is over the counter).  So you can see why this is an exciting treatment.

Unfortunately, this is not the first time Perle has had problems starting a study.  Prior to starting this European study, Perle filed paperwork to start two studies in the US.  This paperwork languished for over two years and the American studies never did start.   A parallel effort in Europe did led to this study, which has now been ended.

JDCA Coverage: http://thejdca.org/practical-cure-project-update-perle-bioscience-drug-combination-human-trial-ends-prematurely

Not In Human Trials: Stem Cells From Self

Researchers were able to create beta cells from stem cells, the stem cells having been created from skin cells of people with type-1 diabetes.  This might be important for a couple of reasons.  First, these cells could be used to test new drugs.  Many people have noticed (especially in the world of type-1 diabetes) that treatments which work on mice often don't work on people.  This is a way to test treatments on beta cells similar to a type-1 diabetic's actual beta cells.  Second, these cells could be used in transplants.  But remember, that only solves half the transplant problem.  Transplanted beta cells have two problems: the body's good immune system is trying to kill them because they are foreign and the body's bad immune system is trying to kill them because they are beta cells.  Since these cells are from the patient's own body, they will not have the first problem, but might still have the second problem.

To the best of my memory, previous reports of making beta cells from stem cells always involved the use of 3rd party stem cells (ie. the stem cells did not originate from the person who would eventually get the beta cells).  So this is a step forward in that regard.

This is animal research only right now, but could get into human trials in 3-5 years, which would then take an additional 10-15 years to become generally available.  That is, assuming it is successful.

Press Release: https://www.sciencedaily.com/releases/2016/05/160510132809.htm
Paper: http://www.nature.com/ncomms/2016/160510/ncomms11463/full/ncomms11463.html


Stepping Back from Artificial Pancreas Coverage

I've decided to scale back my coverage of artificial pancreas research.  This is for two reasons:

1. Because limited functionality Artificial Pancreas devices are already available from Medtronic now in Europe (the 640G) and in the United States (the 530G), and because an all-but-meal Artificial Pancreas device (the 670G) is planned for release in both places in the next few years, there is a lot of "regular" news coverage on Artificial Pancreas developments.  I do not think I'm adding a lot of value to Artificial Pancreas research reporting.  To be blunt: DiabetesMine, diaTribe, ASweetLife, and similar web sites are doing such a good job publicising AP progress, I don't feel like I'm needed in that area.
2. Because there is so much progress being made, on so many different Artificial Pancreas fronts, the avalanche of information is overwhelming me.  I just can't keep up.

Obviously, these are both good reasons to stop coverage.  I'm absolutely confident that a full Artificial Pancreas will be available in the United States in a few years, and I'd rather spend my time following research that is less certain, and harder to interpret.

If you are desperately in need of an AP update, read these:

• http://www.healthline.com/diabetesmine/artificial-pancreas-what-you-should-know which includes one paragraph on each of 11 (!) different commercial companies working on APs.
• http://insulinnation.com/treatment/bigfoots-artificial-pancreas-could-hit-the-market-by-2018/ for an update on Bigfoot, specifically.
• http://www.wsj.com/articles/tech-savvy-families-use-home-built-diabetes-device-1462728637 "do it yourself" AP in the news.
• http://www.healio.com/endocrinology/pediatric-endocrinology/news/online/%7Bdca7dc70-73a6-471c-be8a-2d394d288308%7D/artificial-pancreas-more-effective-than-sensor-augmented-pump-in-young-children reports on AP vs. CGM+Pump trial for kids at summer camp.  AP wins.

My Internet World

I use Blogger, LinkedIn, Facebook, and Twitter, but I divide up my internet world like this: The blog is very specifically focused on clinical trials aimed at curing type-1 diabetes. If that is what you care about, then either follow the blog or sign up for mail notifications when a new entry is posted. (There is a field in the upper right hand corner of the blog for that.)  My twitter covers type-1 diabetes more broadly and also some non-diabetes issues which are important to me.  It is more than half type-1 and less than half other issues.   I try to keep LinkedIn very strictly for work related stuff, and Facebook for family and friends.  So if you are linked with me either on LinkedIn or Facebook, but only care about diabetes news, then you'd probably do better to either sign up for emails from my blog or link with me on Twitter.

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Results from a Phase-II Dual Stem Cell Trial

Back in 2011, when this clinical trial was registered, I was not careful about blogging on all the new research.  Somehow I completely missed this study. So this is my first blog posting on this research.

The Clinical Trial

This trial was testing the impact of giving two different stem cell treatments at the same time.   The people in this trial had long established type-1 diabetes.   No long term immunosuppression was used. The study was randomized and controlled, but was not blinded. The researchers and the patients both knew who was getting the treatment and who was not.  A total of 21 people were treated and they were compared to 21 people not treated.  This paper reports on data gathered for a year after treatment.

The people were all adults, and had been diagnosed (on average) for 7 to 10 years.  Everyone had type-1 diabetes for at least 2 years when the trial started.  The clinical trial record describes it as phase-I / II, but the paper calls it a "pilot trial".  Based on size I'm calling it a phase-I trial.  But it's large for a phase-I trial.

The treated people were given two types of stem cells:

• Stem cells harvested from the umbilical cord.  Everyone got stem cells from the same umbilical cord.  These are called "umbilical cord mesenchymal stromal cells" (UC-MSCs).

• Stem cells "self donated" from the patient's own bone marrow.  These are called "autologous bone marrow mononuclear cells" (aBM-MNC).

The Results

The following two graphs include the most important results, from my point of view.  The F graph shows fasting c-peptide levels. The A graph shows c-peptide levels 3 hours after a meal.  In both cases, higher numbers are better.  C-peptide is generated when the body produces it's own insulin, so these graphs show the body generating about twice as much insulin in two different situations.

In addition, they measured A1c and insulin usage, plus some psychological measurements of happiness and number of low BG instances.

Discussion

The results here are much stronger than the positive results that I've seen in other trials, and the fact that these results are seen in long established type-1 diabetics makes them all the stronger.  The treated patients generated about twice as much C-peptide at the end of the trial as at the beginning. For an oversimplified comparison to other clinical trials done on long established type-1 diabetics:

• This study:  100% more C-peptide
• Stem Cell Educator: very roughly 100% more C-peptide
• TOL-3021: 28% more C-peptide
• BCG: 22% more C-peptide

It's important to remember that since all of these people were established type-1 diabetics, they were generating very little C-peptide of their own to start with, so twice a small amount is still a small amount.

The treated group's insulin usage dropped about 30% (while their A1c levels dropped also!).   You could argue that these researchers are 30% of the way to a cure, although that does oversimplify things.  Again, an oversimplified comparison to other clinical trials done on long established type-1 diabetics:

• This study: 30% less insulin
• Stem Cell Educator: 25% or 38% less insulin
• TOL-3021: not measured.
• BCG: not measured.

All of this is good news, and similar to Stem Cell Educator results, which (up until now) have been the absolute best results seen in long established type-1 diabetics.

Conference Abstract:
http://conference.idf.org/IDF2015/CM.NET.WebUI/CM.NET.WEBUI.SCPR2/SCPRfunctiondetail.aspx?confID=05000000-0000-0000-0000-000000000003&sesID=05000000-0000-0000-0000-000000001276&absID=07000000-0000-0000-0000-000000008843
Paper Abstract: http://care.diabetesjournals.org/content/early/2015/11/29/dc15-0171.abstract
Full Paper: http://care.diabetesjournals.org/content/early/2015/11/29/dc15-0171.full.pdf
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01374854


Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Mesenchymal Stromal Cell Results From a Phase-I Trial

Mesenchymal Stromal Cells (MSC) are the stem cells in your bone marrow.  Stems cells can grow into beta cells, and some researchers think they can modulate the immune system (they generate one or more chemicals that cause the immune system to stop attacking beta cells).  So it's possible that stem cells might resolve both cure issues at once.  They might be able to regenerate beta cells and stop the autoimmune attack.  That is what these researchers hope.

Results From a Phase-I Trial

These researchers, at Uppsala University Hospital in Sweden, ran a phase-I trial, randomized and with a control group, but not blinded.  There were 10 people in the treated group, and 10 in the control group.  MSCs were harvested from a patient, treated externally, and then put back in that same patient.  No immunosuppression was used, and I don't think the people were ever hospitalized (the work was done in a clinic).  Data was collected on insulin usage, A1c, fasting C-peptide, and post meal C-peptide, among other measures.

Fasting C-peptide measures how much insulin your body is generating as background. It's measured while fasting, usually first thing in the morning.  This is your natural basal insulin. Post meal C-peptide measures how much insulin your body is generating in response to carbohydrates.  It's measured after eating a meal with a known carbohydrate content. This is a body's natural insulin bolus.

My summary of the results are as follows. In all cases the paper is comparing data measured 10 weeks after the treatment (which the paper considers starting or baseline data) to data measured 1 year after treatment (which the paper considers resulting data):

1. Fasting C-peptide, A1c, and insulin usage did not significantly change for either group, and there was no significant differences between the groups.
2. Post meal C-peptide levels for the untreated group dropped about 12%.  Dropping is bad, but it's also normal during the honeymoon phase.  In the treated group, C-peptide numbers rose 5-10%, and that represents improvement.  The difference between the two groups was statistically significant.
3. There were no safety issues.

Discussion and Opinions

Confirming that the procedure was safe is a good thing, of course, and is the official goal of a phase-I trial.  But this is a procedure that's been done for decades to treat other diseases (especially cancer), so no surprise that it is safe.

I was a little surprised at how consistent the insulin usage, A1c numbers, and fasting C-peptide numbers were.  I assumed that A1c would still be high from diagnosis and would drop, and that insulin usage would rise to the end of the honeymoon, and that fasting C-peptide would drop.  None of that happened during the course of the honeymoon.

The important results are the post meal C-peptides.  For this data, higher numbers are good, because they mean the body is generating more of it's own insulin.  In untreated people those numbers dropped about 15%, which is normal for the first year after diagnosis.  The treated people saw a rise in their C-peptide.  There is no doubt that is good news, but it did not have an impact on the treated people. Specifically, they were still injecting the same amount of insulin, and their A1Cs did not improve.  So it's a small effect.

My memory is that I've seen this level of result several times, for several different drugs, over the last two years or so.  I think I was much more excited about them in the past.  Part of my lack of excitement is that the treatments with these results that I saw a few years ago have not progressed. They don't give better results in more recent studies.  That might be because the research is taking longer than expected, or it might be that getting a small result is much easier than getting a useful (to patients) result.  But in any case: I haven't seen forward progress in other treatments with similar initial results, so I've become less excited about these kinds of results, in general.

So in general, these results go in my "good start, but more is needed" category of results.

This study was published on line Sept-2014 and on paper in Jan-2015:
http://diabetes.diabetesjournals.org/content/early/2014/09/05/db14-0656?papetoc
http://diabetes.diabetesjournals.org/content/64/2/587?etoc

Clinical trial record: https://clinicaltrials.gov/ct2/show/NCT01068951

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

A Cautionary Tale from Dr. Melton's Lab At Harvard

The soundtrack for this blog posting is the blues: Ball Peen Hammer sung by Joe Bonamassa:
http://grooveshark.com/#!/s/Ball+Peen+Hammer/2pulWL

This is a cautionary tale of research from Dr. Doug Melton's lab at Harvard.  I considered carefully if I should blog on this subject.  It is certainly a lot more fun to blog about successes, and new opportunities, than it is to blog about failures and mistakes.  However, I think it is critical to include both good news and bad news.  At the very least, so that people following type-1 research understand that mistakes get made, and that one of the strengths of the scientific method is the ability to recover from mistakes.

This posting is about Betatrophin, which I did not cover in my blog when it was first announced. The research was all done on animals, and I focus on human trials.  However, now that this research has gone full circle, I think it makes a useful scientific morality tale.  Obviously, lots of scientific research doesn't pan out for one reason or other.  Usually it dies a quiet and obscure death.  But this research was a little higher profile, and therefore it's death was a little higher profile as well, so more about it's life and death is known, than about your average research dead-end.

History

In early 2013 Dr. Melton's lab at Harvard released a "big news" research paper. They had identified a natural human hormone which caused beta cells to naturally regrow.  This one hormone, which they named "Betatrophin" had a huge impact in beta cell regrowth.  The research had been done in mice, and was published in Cell (a prestigious scientific journal).  Two big name pharmaceutical companies (Evotec and  Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson) paid millions of dollars for the rights to Betatrophin.  The lead author of the paper (Dr. Peng Yi) was hired by an important diabetes research center (Joslin) to do research, including future clinical trials focused on Betatrophin.

But about 18 months later, it all collapsed.  A research group working for Regeneron Pharmaceuticals found that Betatrophin did not cause beta cells to regrow, and submitted a paper to that effect.  When the paper was sent to Dr. Melton for peer review, he endorsed it, and wrote a "Perspective" stating that his own lab had been unable to reproduce it's own previous findings.  It now appears that the conclusion in the first paper was incorrect.  I want to stress that no one has suggested that there was any fraud or mistakes in the research; it is just that the conclusion turned out to be wrong.

Discussion of Fallout

Betatrophin was the big news from this lab in 2013, but what about the big news in 2014?  In 2014 Dr. Melton's lab released a "big news" research paper showing that they could grow large amounts of functional beta cells from embryonic stem cells.  (Again, I did not blog on this, because it was not yet being used in a clinical trial.  However I was asked about it specifically on CWD, and posted some comments.)  How does the failure of the 2013 news, affect how we view the 2014 news?  This is the question that should be in the front of the mind of everyone following research aimed at curing type-1 diabetes.  Does the collapse of Betatrophin suggest that the beta cell breakthrough might collapse?

There is no way for me to have any insight into that question.  A pessimist would say that a lab that is wrong with one thing, could easily be wrong about the next thing;  that whatever caused the first incorrect conclusion could still be there for the second one.  An optimist would say that testing Betatrophin is a very different technology than transforming embryonic stem cells into beta cells, and the fact that the lab was wrong about one does not mean it is wrong about the other.

Of course, this brings up this question: if a world class scientist, working at one of the most highly regarded universities in the world, publishing in one of the most prestigious journals in the world, can still be wrong, how are we -- everyday people affected by a disease, but without extensive scientific knowledge -- to know what is correct and what is wrong?  How will we ever know?  (I discuss this in the conclusion section.)

Discussion of Peer Review

One of the interesting "side issues" that this brings up is conflict of interest in peer review.  When the scientific journal Cell got the paper showing that the research done in Dr. Melton's lab was wrong, they sent it to Dr. Melton as part of peer review.  I was a little shocked by that; but it makes sense in a pure-science sort of way.  Dr. Melton is a world expert on Betatrophin (by virtue of being "senior author" of the paper discovering it's function) so it makes perfect sense to ask him to peer review this paper.  However, from a human point of view, it seems nuts to have a person peer review a paper that directly undermines his own paper.  Even if there is not a monetary conflict of interest, there certainly is an intellectual one!  We were all well served by Dr. Melton's ethical actions after he was asked to be a peer reviewer.  But the opposite can happen as well.

This policy, of having papers which contradict previously published papers (in the same journal) reviewed by the authors of the previous paper, appears to be common in scientific journals.  At least it used to be.  The big name journal Nature did this in the 1990s.  More shocking, it then did not publish the second paper, based on a bad review from the author of the first paper.  Two other reviewers gave the second paper good reviews. You can read the sorry tale here:
http://retractionwatch.com/2013/06/19/why-i-retracted-my-nature-paper-a-guest-post-from-david-vaux-about-correcting-the-scientific-record/

Corporate vs. University Research

There is the growing trend to ignore corporate research in favor of academic research, often under the guise of "conflict of interest".  Obviously, some of this is a well earned reaction to various corporate attempts to manipulate scientific research (nuclear, tobacco, and pharmaceutical industries, just to name the ones who have gotten caught at it).

However, it is important to not take that attitude to extremes.  There are pressures to deliver in academia and the non-profit world as well.  In this case the wrong results were from university research and the right results came from industry.  I think it is important to remember that, in the face of a growing "corporation = evil" narrative.

The Original Paper Has Not Been Retracted

An interesting question (at least it's interesting to me) is should this paper be retracted?  It hasn't been, and it doesn't look like it will be.  It is certainly wrong in it's conclusions, but is that enough to retract it?   There are two schools of thought here.   One says that publications should only be retracted if they are "in error", meaning there was an error in design, data collection or analysis, or if there was fraud or ethics problems.  The other school of thought says that being wrong is enough.  If the authors / editors / publishers are sure it is wrong, then it should be retracted.

This sounds like a good topic of debate in a college level ethics class, with a scientific bent.
But one of the existing complications, is that there is no global standard.  Each publication is free to make their own decisions about retractions, and even in one publication, they don't have to be internally consistent, if they don't want to be.

My Summary

First, the press:

I have a very low opinion of how "the press" (ie. mass market news web sites) covers science and medicine.  Among their other sins, I think they over hype certain medical news, based on buzz words in press releases.  Although these "over hype triggering buzzwords" change slightly over time, a good PR firm or savvy researcher keeps up to date, so they can use the trendy buzz words to manipulate the press coverage.to get more than their research deserves.

For the last decade, I think "stem cell" is one of those triggering buzz words, and I think "Harvard" is one, too, and reports from big name universities are generally over hyped, in relation to universities with less name recognition.

Second, how to determine that science is correct:

This incident reinforces my belief that the only way to be sure a scientific paper is correct, is to follow it's research for a period of years after the paper is published, to see what happens.  There is no way to look at a freshly printed paper and know that it is correct.  I know that a lot of people try to take short cuts, and they say (or think) things like "it is a peer reviewed paper [so it must be right]", "the researcher is one of the most famous people in the field [so it must be right]", "the researcher is at an ivy league calibre institution [so it must be right]", "it was published in the leading journal in it's field [so it must be right]", "the researcher's family is affected by the disease so he's totally committed to the research [so it must be right]", "he is so personable, so articulate, and the description of what is happening makes perfect sense [so it must be right]", "the researcher has a great history and a great reputation [so it must be right]", and so on.

For Betatrophin, every one of those statements was true, and yet the research was flat out wrong.

This case is a clear example where the only way to see if research was correct, was to wait and see what happened to the research over time, as people tried to capitalize on it, to build on it, and to productize it.  The take home point is simple: there is no short cut.  There is no way to know quickly if research is correct.  Only the passing of years will tell us with certainty.

Now, I certainly don't claim perfection in this regard. I'm sure I've fallen into this trap myself. But it still is a trap, and something to be avoided.  I do stress peer reviewed results in this blog, almost to the exclusion of non-peer reviewed results, but that is different than implying that peer review means the research is good.  I consider peer review to be a necessary component of good research, but not sufficient to prove good research.  Put another way: if research is not peer reviewed, then it is not worthy of serious consideration.  But even if it is peer reviewed, it still might be wrong.

Some people, optimists, might look on this example as a fluke, but I think that's a mistake.  Most research does not pan out.  Most phase-I clinical trials do not lead to a marketed treatment. Therefore, the failures described here are quite common.  Maybe even normal.  I'm posting about this particular case because it made a bigger than usual news splash.  I get emails from people asking "remember research project X from years ago?  Whatever happened to that?  Did the money making, type-1 conspiracy suppress it?".  Nine times out of ten, the answer is that the research just didn't pan out at the next level.  Like Betatrohpin, the first publication was in error, and nothing could be built on it.

I'm always very nervous about the number of people who assume because they have not heard of it, that means it was really successful, and was therefore suppressed.  It creates a mindset where failure is taken as evidence of conspiracy.  In a world of research, where most new ideas do not pan out, this is spectacularly dangerous logic.

To join the two parts of this conclusion, notice that news organizations have an impossible conundrum: they are judged on how quickly they get (incredibly superficial) articles about scientific research out on the web, yet the only way to know if those articles are accurate is to wait, often months or years!   Yet as long as we reward news sources for speed, and ignore their accuracy (the current situation) this is the news we are asking for.

More Reading

Betatropin news at the time:
http://news.harvard.edu/gazette/story/2013/04/potential-diabetes-breakthrough/
http://jdrf.org/blog/2013/discovery-of-new-hormone-may-impact-t1d/

The papers:
Harvard paper: http://www.cell.com/abstract/S0092-8674(13)00449-2
Regeneron Pharmaceuticals: http://www.sciencedirect.com/science/article/pii/S0092867414011763
The Perspective: http://www.cell.com/cell/abstract/S0092-8674(14)01177-5

Discussion and fallout:
Retraction Watch: http://retractionwatch.com/2014/11/10/i-kind-of-like-that-about-science-harvard-diabetes-breakthrough-muddied-by-two-new-papers/
Blog: http://www.ipscell.com/2014/10/the-betatrophin-blues/
Pubpeer: https://pubpeer.com/publications/8EAC9ED889CC6E498199B11B1BC135 and also https://pubpeer.com/publications/0F7B9DF45743305575A36FDBA7FC9A
Money issues: http://seekingalpha.com/article/1730632-companies-race-to-develop-the-next-novel-blockbuster-diabetes-drug-part-2

A note on titles: In the past I have not been consistent about it, but in the future, in this blog, I will attempt to refer to anyone with a doctorate (PhD, PharmD, DVM, etc.) or a medical degree (MD) as Dr. X Y the first time they are named, and Dr. Y thereafter.   (Sorry lawyers, on this blog, you're not doctors, no matter what your degree says. :-)

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Background on Four Types of Stem Cell Research

This blog post contains general background information on four types of stem cell research.  I'm writing it because the term "stem cells" is used to describe several different lines of research, and it is important not to mix them up.  Good news from one type of "stem cell" research should never be used to suggest that a different type of "stem cell" research is going to be successful.

Quick Summary
Here is a very quick summary of four types of stem cell research:
1. "Burt"  Reboots the body's immune system to stop the autoimmune attack.  First, the patient is given very powerful drugs to shut down their immune system, then they are given drugs which causes the body to mobilize it's own adult stem cells to rebuild the immune system, without the autoimmune flaw.  Has resulted in the best cure results of any research to date, but is also the most dangerous.
2. "Zhao"  Patient's immune cells are removed and stem cells from the umbilical cord used to help retrain them   to stop the autoimmune attack.  The immune cells (without the stem cells) are then put back in the patient.  Good results and appears to be much safer than Burt.
3. Several companies (example: Viacycte) are attempting to grow new beta cells from stem cells.  They are taking undifferentiated stem cells and trying to find the recipe to cause those stem cells to differentiate into beta cells.  None of this work is in human trials right now.
4. Many stem cell clinics (example: Xcell) will infuse bone marrow stem cells in the hopes that this will cause the patient to regrow beta cells and improve their type-1 diabetes.  Although many clinics will provide this service, I have never seen a peer reviewed study showing that it improves type-1 diabetes.

How They Are Different

Burt
Burt's research does not use external stem cells.   Rather, the patient is given a drug which "mobilizes" their own internal stem cells.  People have several different forms of adult stem cells in their body.  Part of Burt's protocol is to give the patient a drug which is well known to cause them to generate more of their own bone marrow stem cells, and cause these cells to be released into the blood stream.

Zhao
Zhao's research is very different from the rest, because he is not trying to grow beta cells from the stem cells.  Instead, he is using them to train the immune cells not to attack beta cells.  (This is sometimes called "curing autoimmunity".)

You may ask, "why should stem cells cure autoimmunity?"  It's a very good question, and I don't know the answer.  But I'm not an immunologist, and for me it is far more important that a treatment work, than that I understand how it works.  Many treatments are used for years before we understand exactly why they work.  (Aspirin is a 100+ year old example.)

Beta Cells from Stem Cells
There are several companies working on ways to differentiate beta cells from stem cells.  Generally, they differ from each other two ways.  First, in the kinds of stem cells they start with (embryonic from an embryo, embryonic from cord blood, or different types of adult cells or adult stem cells that have been treated in some way to make them undifferentiated).  Second, in the recipe they use to transform these undifferentiated stem cells into beta cells.

Stem Cell Clinics
These guys harvest bone marrow stem cells from a person, and then put them back into that person or a different person.  They differ in exactly how they put the stem cells back in (in the blood or directly in the organ that needs them), and also in what processing or separation is done to the bone marrow cells before being put back.

My opinion of the stem cell clinics is very low.  They are a cash up front business without evidence that they help anyone.  For example, to approve a new drug, the US FDA requires four clinical studies to show that it works and is safe.  Currently, there is not one stem cell clinic, that has published even one peer reviewed study (that I have found), that shows that it works.

Most of these clinics are in third world countries, but there was one, called Xcell in Germany.  Years ago, Xcell said that they were running two studies to show that their treatment would help type-1 and type-2 diabetics, respectively.  Neither of these studies were ever published in a peer reviewed journal, and last year the German government shut down Xcell after an 18 month old baby died of complications from a stem cell treatment at the clinic.  (And this after a 10 year old boy almost died after the same procedure!)

I often see these clinics cite Burt's work as peer-reviewed, scientific research that suggests their clinics are on the right track. But this work is wildly different from the work done at these clinics and the success of one does not support the treatment of the other.  As an example: Burt uses three drugs in his trial.  These clinics sometimes use one of those drugs, and sometimes none at all.  They never use all three of them, and never get close to the same procedures that Burt uses.  My guess is that you will see these guys citing Zhao's work soon as well, even though Zhao is using a totally different type of stem cells and not even putting in the patient.


Other Terms to Understand

Adult vs. Embryonic
These are the two types of stem cells that we have heard about for the longest, and the loudest.  Much of the arguments about stem cells (especially in the US) are phrased in terms of Adult vs. Embryonic.  However, I have come to believe that, while this difference is critical religiously, politically, and socially, that it is not important in terms of research aimed at curing type-1 diabetes.

The confusion comes from the fact that in the early days of stem cell research, embryonic stem cells were the only undifferentiated stem cells known.  So when people talked about the power of embryonic stem cells, they were often talking about the power of undifferentiated cells.  However, now we can get several different types of undifferentiated stem cells from adult sources, and from different embryonic sources.

Differentiated vs. Undifferentiated
A better way to talk about stem cells, is undifferentiated (and if so, what is their source) vs. differentiated (and if so, how were they differentiated). Differentiated stem cells are those which have already specialized into a specific type of cell. For example, a beta cell. Undifferentiated stem cells have the potential to do this, but have not yet done it. With the current research results, it appears that undifferentiated are not useful for growing beta cells in the simple minded way used by the current clinics. However, both Burt and Zhao have had success using them in other ways, and undifferentiated stem cells have not yet been tested (in people) as a source for growing beta cells.
A lot of the recent news in stem cell research is reporting on different ways to create different types of undifferentiated adult stem cells.  These different type stem cells might have different properties and be good or bad at different things, but we really don't know yet.

Another type of research news that we have gotten recently, but is not as common, is success in turning different types of undifferentiated stem cells into beta cells.  It is especially important to turn them into beta cells that generate insulin when presented with sugars.  The has been some success at this, but none of it has progressed into human trials (that I know of) as yet.  Even if they did, we would still need to either encapsulate them or cure the autoimmunity before they would be a cure for type-1.

Self vs. Others
Any kind of stem cells can be gotten from the person being treated (self) or from someone else (others).  This is true for both embryonic stem cells, and adult stem cells.   You can get embryonic stem cells (for example, from the cord blood) and use them on the person you got them from.  Or you can get adult stem cells from that same person.   Self stem cells are going to have fewer immune issues than those from others.

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/

Zhao et al (Tianhe) Publish Successful Phase-I Results (in non-honeymoon diabetics)

In my opinion, this is big news.
It's the result of a phase-I study, published in BioMed Central's Medicine Journal (which is peer reviewed) by a group of researchers working at the University of Illinois at Chicago and in China.

What Did These Guys Do?

This trial was done on people with established type-1 diabetes.  Each person had a blood draw, and then a particular kind of immune cell was separated from the blood and specially processed.  The processing phase used umbilical cord stem cells, but not the patient's own umbilical cord.  (This was generic umbilical cord stem cells, not from the exact person being treated.)  The immune cells were then put back in the person.  The stem cells did not go into the person; they were only used for the external processing.

The goal was to teach the body's immune system to stop attacking beta cells.  The researchers refer to this as "education", and refer to the processing device used as an "Stem Cell Educator".

The treatment was done once and I think it took about 10 hours.  Patients were in the hospital for 2 days, but it's not clear to me if that was due to an over abundance of caution (this was a phase-I study, after all), or if it was really needed.  This trial was done at the General Hospital of Jinan Military Command (Jinan, Shandong, China).  The lead author of the paper is Yong Zhao, is an Assistant Professor at the University of Illinois at Chicago.

The patients averaged about 29 years old, and had had type-1 for an average of about 8.5 years.  Patients were followed for a total of 40 weeks, but most of the results data was gathered at 4, 12, and 24 weeks after the procedure.

The researchers divided their patients into three groups.  Group A (6 people) had some insulin production before treatment. Group B (6 people) had no measurable insulin production before treatment, and Group C (3 people) also had some insulin production  before treatment, but they got a "sham" (or placebo) treatment. 


What Results Did They Get?

There were no significant safety issues during the trial.

Average Daily Insulin Usage:
Group A's insulin requirement was down 38% at 12 weeks (from about 36 to 22 units/day).
Group B's insulin requirement was down 25% at 12 weeks (from about 48 to 36 units/day).
Group C's insulin requirements didn't change.

Note: earlier version of this blog had a typo in Group B's starting insulin units/day.  Fixed here.

Average A1C levels:
Group A started at 8.73 and dropped to 7.67 at 4 weeks and to 6.82 at 12 weeks (almost 2 points overall).
Group B started at 12.2 and dropped to about 10.5 at 12 weeks.
Group C started at 9 and was at 8.7 at 12 weeks.
Note: I consider a drop of 1 to be important, although some researchers consider even a drop of 0.5 as important.  Here we have drops of over 1.9 and 1.7.

Fasting C-peptide (ie. Body's ability to generate "basal" insulin at background levels)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts at about 0.35 and ends at about 0.8 at 24 weeks.
Group B: Starts at about 0 and ends at about 0.5 at 25 weeks.
Group C: Stays at about 0.4 at 4, 12, and 24 weeks.
Note: Non type-1 diabetics generally have a fasting C-peptide level between about 0.5 and 2.0.  The paper's authors felt that 0.6 was the lower bound of normal C-peptide in the population being studied.  So it is possible that Group A has moved into the bottom of the normal (for non-type-1 diabetics) range.

OGTT C-peptide (ie. Body's ability to generate "bolus" insulin in response to food)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts out generating 1 after a meal, at 4 weeks generates about 1.6, and at 12 weeks about 1.7.
Group B: Starts out generating about 0 after a meal, at 4 weeks generates about .05, at 12 weeks about 0.35, and at 40 weeks about 0.6.
Note: I don't know what "normal" is for this test, so can not compare either group to non type-1 diabetics.

The paper also contains data on immune system changes which the researchers felt showed significant improvement in autoimmunity.    I can not evaluate those results.

Also interesting, the researchers are very specific in saying that they think this study shows that beta cells do regrow, in people, if the immune system stops attacking them:

Notably, our clinical data provide powerful evidence that reversal of autoimmunity leads to regeneration of islet β cells and improvement of metabolic control in long-standing T1D subjects.

My take on all this data is that there is no question that the body is generating more of it's own insulin after this treatment than before.  And that happens in people who have had diabetes for a long time, and who are not generating any of their own insulin before treatment.  That's huge.  The results are large enough so that type-1 diabetics would see the improvement in their insulin usage and A1C numbers.

Discussion

Obviously, there is a lot of issues to discuss here:

Possible Conflict of Interest

I hate to start off with discussion of a conflict of interest, but in this case, the situation makes me nervous, so I'm discussing it first.  In the paper's pre-publication version, it says:

Competing interests 

The authors declare that they have no competing interests.

However, the unique and specialized equipment that they used in their clinical trial was manufactured by Tianhe Stem Cells Biotechnology.  This equipment was central to the clinical trial.  However, that company is connected to three of the authors (including both first and last authors).  Here is a quote from the University of Illinois web page:

Tianhe is a stem cell biotechnology company commercializing the inventions emanating from the labs of Drs. Zhao, Mazzone and Holterman within the Departments of Medicine and Surgery at the University of Illinois at Chicago. With operations in both Illinois and overseas, the Company is pursuing the application of stem cells for the treatment of autoimmune diseases.  Tianhe is initially pursuing the treatment of Type 1 diabetes through a clinical system which extracts the patient own stem cells and utilizes them to re-educate the patient’s faulty immune cells to prevent future immune response to the patient’s own insulin producing cell.    [from http://otm.illinois.edu/sites/all/files/files/otm-annual-reportseptember-1final.pdf]

Obviously, I don't know the exact financial details involving the University, Tianhe, and the three researchers, but I would like to see more details before I accepted the claim that the authors had no competing interests!  It certainly sounds like the researchers are testing equipment that they will make money off of, if it works.  On the other hand, if this relationship gets this research to market quicker, and the research helps people with type-1 diabetes, then I'm all in favor of it. :-)

Missing Data

There are a couple of obviously missing data points.  For example, Group A's 40 week post-meal C-peptide numbers are not reported.  And 40 week fasting C-peptide data is not reported for any group.  The trial design only collected insulin use and A1C data at 12 weeks, which is too bad.  I would have like to see it at 24 or even 40 weeks as well.

There are also a few other odditites.  For example: in Groups A and B (treated), about 2/3 of the patients are women, but Group C (placebo) is all male.  Also, the Group B A1C before treatment averaged 12.2, which is a lot higher than you would see in the US (I hope!)

None of this is particularly unusual for a phase-I trial; and none of it makes me nervous about the results.  It just makes me want to see data from a larger phase-II study.

Next Steps To Market

Getting a cure to market requires three things:
1. Scientific success.
2. Engineering and corporate success.
3. Regulatory approval.

This study is a solid, successful phase-I clinical trial.  No doubt (in my mind) about that.
Plus, it is the first time this has been used in people, as far as I know, and there are obvious ways to improve it.  More blood could be put through the machine.  The blood could spend more time in the machine.  It could be used repeatedly, etc.  The classic goal of a phase-II trial is to figure out the best dosing, and I think these guys are well positioned to do that.

There is a clear engineering path to market.  The "Educator" equipment is produced by Tianhe corporation, and I would expect that once the equipment is for sale, many doctors would be able to use it.  It sounds to me like there is a clear way to make money off this, and so I would expect that (if it works scientifically) Tianhe will have no problems getting funding and getting the corporate structure required to build a business around using their equipment to treat/cure type-1 diabetes.

As for regulatory approval, I think there are two paths forward.  The normal path to approval is a phase-II trial, and then two phase-III trials.  The already completed phase-I trial took about a year, I would expect the phase-II to be about that long, maybe a little longer, and phase-III to be still longer.  However, if they are successful and well funded, these guys could get to market in less than 10 years.  Of course, the next question is, what will they make it to market with?  Will the thing available be a treatment?  A cure?  A temporary cure?  Fewer long term complications?

There is a second, much faster, path to approval, called the "surgical procedure exemption".  I do not know all the details, but the FDA does not require that surgical procedures be proven "safe and effective" before a surgeon uses them.  Under this exception the FDA does allow some treatments to be sold without full approval, if those treatments involve taking something out of the body, processing it in some simple ways, and then putting it back in.  I don't know if this "educator" process would qualify or not.

I know some people are nervous about research done in China, and especially at a Chinese military hospital.  I think this is my first detailed blog post on research done in China.  I do want to point out that this trial has ethical approval from the review board at the University of Illinois at Chicago, and that it looks to me like the researchers followed US FDA standards in the trial, and international standards where applicable.  I don't have detailed knowledge of FDA requirements, but it does look to me like, even at this early stage, these guys are working to eventual US FDA approval.

News Coverage: http://www.medscape.com/viewarticle/756691?src=emailthis
Clinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT01350219
Full Paper: http://www.biomedcentral.com/content/pdf/1741-7015-10-3.pdf

Some general information on C-peptide values:
http://www.diabeteshealth.com/read/2000/09/01/2020/interpreting-your-c-peptide-values/

A Personal Note
2011 was an awful year for following clinical trials aimed a curing type-1 diabetes.  We lost three phase-III clinical trials, and started zero new ones.  In phase-I and phase-II trials, the successes seemed small; the failures, great.   These results are a wonderful way to start 2012.

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.
Blog: http://cureresearch4type1diabetes.blogspot.com/

Stem Cell Research Checklist (and recent uterine stem cell news)

Whenever I see stem cell research published, I always ask myself the following questions, in order to evaluate it's importance:

• What animal was used in the research?
• Humans are the best animals to use, obviously.
• NOD mice, and other animals that have autoimmune diabetes are good to use.
• Animals that have artificially produced diabetes are not so good.
• Animals that don't have diabetes at all are the least promising.
• Were the cells created true beta cells?
• Sometimes people announce that they create "precursor" cells, or some other cell on the way to a beta cell, but not there yet.  
• Making a complete beta cell is good, but not enough.
• The best result, is making a beta cell that generates insulin in response to sugar in the blood.  That's what a real beta cell does.
• What sort of immune suppression (if any) was used.
• Any stem cell from another person (adult or embryonic) may trigger an immune response, so the first question is did they use the animal's own stem cells?
• What sort of drugs, treatments, or encapsulations were used to prevent rejection of the stem cells?
• Did it work in actual animals?
• Some research just measure what the cells do in petri dishes or cell cultures, but the true measure of a beta cell, is what it does in a real animal that needs insulin.
• Did the researchers measure C-peptides?
• Did they need less insulin, see lower A1c and lower BG (especially after meals)?
• The best would be no need for external insulin, and no bad side effects
• How long did it work?
• Obviously, longer is better (and remember to scale based on the lifespan of the animal involved).
• It's always better if the experiment ended before the effect ended, rather than the other way around.
• What's the plan for preventing the autoimmune attack from destroying the new beta cells?
• Many stem cell researchers have a "that's someone else's problem" attitude, which I don't think is a good one.
• A few stem cell options come with an integrated solution to the autoimmune attack, and those are a lot more interesting to me.

(As I look back over this list, I think most of it could be used for any research which claims to be curing type-1 diabetes.  First ask yourself: what animal?  And so on.) 

Applying the Checklist to a recent headline:

Uterine stem cells used to treat diabetes in mice

A press release is here: http://www.nih.gov/news/health/aug2011/nichd-30.htm

Here are the first few paragraphs (we've all read this stuff many times before):

Researchers funded by the National Institutes of Health have converted stem cells from the human endometrium into insulin-producing cells and transplanted them into mice to control the animals' diabetes.

 

The endometrium, or uterine lining, is a source of adult stem cells. Normally, these cells generate uterine tissue each month as part of the menstrual cycle. Like other stem cells, however, they can divide to form other kinds of cells.

The study's findings suggest the possibility that endometrial stem cells could be used to develop insulin-producing islet cells. These islet cells could then be used to advance the study of islet cells transplantation as a treatment for people with diabetes. If the transplantation of islet cells derived from endometrial cells is perfected, the study authors write that women with diabetes could provide their own endometrial tissue for such a transplant, sidestepping the chance of rejection posed by tissue from another person. Endometrial stem cells are readily available and can be collected easily during a simple outpatient procedure. Endometrial tissue could also be collected after hysterectomy, the surgical removal of the uterus.

How do I apply my checklist/questionnaire to that research?   Like this:

What animal was used in the research?
Two quotes from the abstract: "mice having a laboratory-induced form of diabetes" and "mice had few working beta cells. But the paper and in email from the author, things were a little more explicit: SCID mice were used, and their diabetes was triggered by giving them SZ toxin, which kills their beta cells.  SCID are "Severe Combined ImmunoDeficiency" mice.  These mice did not have autoimmune diabetes.  This creates some complexities, which I discuss below.

Were the cells created true beta cells?
Two quotes from the abstract: "The researchers found that some of these cells also produced insulin." and "the researchers exposed the mature stem cells to glucose and found that, like typical beta cells, the cultured cells responded by producing insulin." And the paper makes it crystal clear that the new beta cells did generate insulin in response to BG, and worked the way real beta cells are supposed to work.

What sort of immune suppression (if any) was used?
Nothing is mentioned in the abstract or paper.  SCID mice were used and they don't have a fully functioning immune system anyway.  In email, Dr. Taylor (lead author) said that he expects that a biopsy from one person would create enough stem cells to treat one person.  Discussion below about why that is important in terms of immune suppression, or lack of it.

Did it work in actual animals? 
Pretty well, but not perfectly.  The paper says that the mice had BG levels between 250-300, and were not given insulin.  This stayed pretty constant (my eye-balling of the data) during the weeks that the mice were followed. Obviously, the current standard of care is closer to 140, but remember that until the 1980s, BG levels around 300-400 were pretty standard.  So in this very first mouse experiment, they achieved better standard of care than the first 70+ years of human treatment.  And I expect they can refine their procedures to do much better.

How long did it work?
The abstract says "the animals continued to produce some insulin for six weeks, until the researchers ended the study." And the paper has more details on this.  The fact that they ended the study before the effect ended is promising as well.  It suggests that the effect will last longer.

What's the plan for preventing the autoimmune attack from destroying the new beta cells?
So far, there isn't one.  Since the mice in the experiment did not have autoimmune diabetes, the researchers didn't learn anything about what a type-1 diabetic's immune system would do to the new beta cells.  (Type-2 diabetics would not have this problem, of course.)  See below for some discussion about this.

What does all this mean?

My one sentence summary is: this is good research; very promising that it might be available in people in 15-20 years.

I know that a lot of people are staring at their screens right now screaming silently "how can it be good research yet still so far from general availability? Good research should give me a cure, quickly!"  And the answer is that if it were not good research, it would be even farther away.  Just because we want a cure quickly, does not mean we are going to get it that quickly.  Human research takes 10-12 years to make it from start to general availability, so I'm assuming that this research starts human trials in 3-10 years.  Because this research was done in severely immune compromised mice, I would expect that they would need to do some experiments in NOD mice or similar before trying it in type-1 diabetic people.

(Although the 10-12 year approval process is for drugs and devices, not surgical procedures, but this difference is too complex for me to describe here.  The much oversimplified version is: this research might take slightly less than the normal 10-12 years, but don't bet on it.)

Why is this research good?
Mostly because they made true beta cells that generated insulin in response to blood sugar and actually worked in real animals.  That's huge.  Even better, it continued to work for the length of the experiment.

What about this research needs more work?
It needs to run longer, for the whole life of the mouse.   It needs to be done on animals or people who have natural autoimmune diabetes.   Finally, it needs to be done in people.

What about this research is complex?
The type of mouse used combined with the lack of immunsuppression is the complex part of this research.  The mice used were SCID and these mice have seriously broken immune systems.  That's why they are used in transplant studies; they can't really reject foreign cells they way normal animal could.  So the researchers didn't have to give the mice an immunsuppresive drugs, because the mice were already immunsuppressed.  That all sounds pretty bad, in terms of applying this to people.

But maybe not.  Dr. Taylor has told me that he is hopeful that a single biopsy would provide enough uterine stem cells to treat one person.   If so, perhaps a person's own uterine stem cells could be used to treat themselves.  In that case, no immunespressives would be needed, because it would not be a foreign transplant.  Finding doners would not be a problem, either.  At least not for female diabetics.

The only issue remaining, and it is a big one, is this: would the body's own autoimmune attack kill of the new beta cells same as the old ones?  I would think they would.   However, the stem cell harvest / implanting process is simple (could be done in a clinic), so even if the new beta cells were attacked by the autoimmune process, maybe they could be replenished at every endo visit?  Or maybe every couple of endo visits?  That is why the researchers chose these particular stem cells to use: they are plentiful relatively easy to get, and are naturally replenished every month in women.

I'd like to thank Dr. Hugh Taylor (lead author), for his information., and for giving me a copy of the paper.

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.
Blog: http://cureresearch4type1diabetes.blogspot.com
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