Friday, September 16, 2011

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:

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.
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Sunday, September 11, 2011

Results from a Phase-II Trial of Abatacept (Orencia)

Results from a Phase-II Trial of Abatacept (Orencia)

Abatacept is a treatment that prevents T-cells from becoming activated.  Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating.  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia.  It was just recently approved for home use via under skin injections (similar to insulin).  Previously it required an infusion, and this study used the infused form.  It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have less side effects than other immunosuppressives.

This study attempts to preserve beta cells during the honeymoon phase by giving newly diagnosed patients Abatacept.  This was a placebo controlled, double blind trial with 112 patients. About 2/3s (77 people) got the treatment and 1/3 (35 people) did not.  Three infusions the first month, and monthly thereafter for two years.  C-peptide production in response to a meal was the measured after two years.  The results where clearly better in the treated group.  Basically they produced 60% more of their own insulin at each point in the trial.  (Remember: C-peptide is a marker for insulin production.)  Also, the treated group had better A1c numbers.  The researchers estimate that this is similar to a 6-9 month delay in beta cell loss of type-1 diabetics at diagnosis.

Since Abatacept blocks some T-cell activation, infection was a worry, but the infection rates were the same in treated and placebo groups, as were injection site issues.  There were more mild side effects (things like headaches and nausea) in the treated group.

The researchers are going to continue to follow the patients to see what happens in the months after they stop getting regular doses of the drug.  They will see if the dosed patients stay ahead of the placebo group or not.

Next Steps

I'm not exactly sure what the next steps are in this line of research.  Are these results "good enough" so that you'd just move the same dosing into phase-III trials and then into the market?   Would you change the dose to try to get a better result?  (It looks like the researchers used the standard rheumatoid arthritis dosing for the trial.)  Would collecting data for a longer period of time, help planning the next move?  Belatacept is a follow on drug to Abatacept which was just approved in June 2011 (but not for type-1 diabetes), so would you move forward with Abatacept,  Belatacept, or both?

Another whole set of options involves combining Abatacept with another treatment.  The study chair for this trial is Dr. Tihamer Orban, who is also working on a B-chain insulin treatment (which already completed a phase-I trial, and which I've blogged on in the past), and he is interested in combining these two approaches. 

Previous blogging:
Clinical trial record: 
More News:
Related news:

This study was run by TrialNet.  Thanks to Dr. Tihamer Orban for providing me we a pre-print of the Lancet article.  And thanks to everyone who provided help and information for this posting.

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.
To Get as Email Join here: