Encapulsated Beta Cells and Sernova

This blog contains two parts.  The first is a general update on encapsulated beta cells as a possible cure for type-1 diabetes, and the second is some background and an update specifically on Sernova corporation's work on encapsulated beta cells.

General Update on Encapsulated Beta Cells
The basic idea, is that you take working beta cells and wrap them in some kind of barrier (called "encapsulation"). It must allow nutrients and sugar to flow into the beta cells, and insulin to flow out of the beta cells, but must stop the body's immune cells from getting to the beta cells.  So it must not be a complete (impermeable) barrier, but a "smart" or partial barrier.  The beta cells generate insulin in response to blood sugar.  Because they are encapsulated, the body's own immune system can not attack them.  This means both that the body's broken autoimmune attack does not kill off these beta cells, but it also means that the body's natural attack on any transplanted organ doesn't happen either.  These are both good things.

For more background, the Dec-2011 Countdown (a JDRF Publication) has a good article on Encapsulation: http://countdown.jdrf.org/Features.aspx?id=8589934725
Obviously, it focuses on JDRF's work, but it also contains a lot of the history, complexities and past problems of using encapsulated beta cells to cure type-1.  The discussion of past problems is important.  Many people seem to assume that since encapsulation sounds like a good and simple idea, it is a good idea and simple to implement.  However, different researchers have been working on this idea for over 20 years, and a cure has not been forthcoming.  So obviously, it is not as simple as it sounds.

Below I discuss status for all the encapsulated beta cell projects that I know of.  The basic summary is that one commerical company and two academic teams are in clinical trials now:  LCT is in phase-II trials and the others are phase-I, by my standards.  Sernova hopes to start clinical trials this year, but not on encapsulation directly, and the rest are in animals trials.

Status of LCT http://www.lctglobal.com/
LCT has completed a phase-I clinical trials in Russia, and has one ongoing in New Zealand.  They have also started a third clinical trial in Argentina.  At one time, they were hoping to have commercial availability in Russia in 2011, but that did not happen.  Results in people have been mixed.  A small number of people have been cured for short periods of time, and most people see improvement in their  BG control.

Status of AZ-VUB  http://clinicaltrials.gov/ct2/show/NCT01379729
This is academic research with human beta cells.
A 10 person trial, started in 2011 ends in 2013, but then patients will be followed until 2018.

Status of Université Catholique de Louvain http://www.clinicaltrials.gov/ct2/show/NCT00790257
A 15 person trial, started in 2008 and running until 2013.

Status of Sernova http://www.sernova.com/s/Home.asp
I discuss this more below, but Sernova hopes to start phase-I clinical trials in the first half of 2012 [d1].
They have already completed large animal trials.
Recent Interview: http://aheadoftheherd.com/Newsletter/2012/Ahead-Of-The-Herd-With-Sernova.html

Status of Cerco   http://www.hanumanmedical.com/  http://www.hanumanmedicalfoundation.org/type-1-diabetes-research.html
These guys are doing large animal studies now, and hope to start human trials in 2013 [d1].

Status of ViaCyte  www.­viacyte.­com
These guys are using putting embryonic stem cells into their encapsulation, which is different than the other research teams listed here, who are mostly using pig cells.  These guys have cured mice and are doing animal safety studies now, and hope to start clinical trials in 2013 [d1].
Interview: http://www.diabetesmine.com/2012/01/whats-up-with-diabetes-stem-cell-research-firm-viacyte.html

Status of Nuvilex    Cured In Mice! Nuvilex
These guys are "cured in mice".  We'll need to see what happens in people.

Background on Sernova

Sernova has a long and interesting history, which I summarize here:

It has been known for a long time, that the body's immune system does not have complete coverage within the body.  For example, the immune system is not good at attacking viral infections in the eye (for example)[d2].  One of the things that the body's immune system does not attack is your own sperm cells (or egg cells).  If you think about it, these two cells have a different genetic makeup then your body, and they might be identified as foreign invaders and attacked by the immune system.  However, this does not happen.   For sperm cells, the body has special cells, called Sertoli cells, that  are located next to the sperm cells and prevent the immune system from attacking them. [d3]

So, long ago (about 15 years) and far away (Mexico) a transplant surgeon named Rafael A Valdes-Gonzalez decided to implant into people a mixture of Sertoli cells and beta cells from pigs.  The Sertoli cells would protect the transplanted beta cells from the body's immune system. (See [d4] for discussion on pig cells, and [d5] for discussion on ethical apprvoals.)  Dr. Valdes-Gonzalez thought he was on the track to a cure, and published some promissing results [r1], but others were not so sure [r2].  Also, the standards for exotransplantation were still being created, and no where near as well formed as now.  So there was some controversy [r3].

So, when it was time to start a larger, more carefully controlled clinical trial, to resolve the doubts about the effectiveness of the treatment, the local trial review board did not give it's approval.  They pointed out that the current standard was that animal studies (preferably large animal studies) should be done prior to human studies (to assure a basic level of safety and a reasonable chance of success).  These studies had never been done.  Dr. Valdes-Gonzalez  was a transplant surgeon who was not focused on running animal trials.  As far as I know, the Mexican project has not made a lot of forward progress since then.  However, at one time around 2004, they were "open for business" at about US $35k for the operation[r4].  I don't know what the current status is.

Obviously, a lot of people were unhappy about the lack of forward progress.  One of these people was Dr. White, a Canadian researcher.   He decided to develop the Sertoli+Beta cell treatment, starting from animal trials, and worked with Sernova corporation to do so.

Sernova is working on two related projects.  The first is a pouch system which holds transplanted cells together in one place (but does not encapsulate them, there is no barrier involved).  The second is the Sertolin(tm) system, which is designed to use Sertoli cells to prevent an immune attack on the transplated cells.

Here is a quote from their web page:

Sernova, is developing two novel closely integrated proprietary platform technologies. The first is the Cell Pouch System™, a scalable device providing a natural "organ-like" environment for therapeutic cells such as insulin producing islets for diabetics and the second is Sertolin™, a cell-based technology providing an immune-privileged environment for donor cells, reducing or eliminating the need for anti-rejection drugs.

Also, their home page includes two video presentations and a power point presentation which describe what they are trying to do.

Sernova has announced that they hope to start phase-I trials for their Cell Pouch System in the first half of 2012[d1], so that is great news.  But it is limited news.  By itself, this provides no immune barrier, so it's not even part of an eventual no-rejection drug cure.  Is just a step in that direction.  Sernova has said that they are hopeful that if the pouch is successful, it means that in the future only local immune suppressive drugs would be needed.  Because the beta cells would be limited to one specific place, immune suppressive drugs would only be needed right there, also.  Since local immune suppression is safer and has less side effects than whole body immune suppression, but there's no way to know if the difference will matter.

Extra Discussion

[d1] When I use the phrase "hope to start clinical trials in ..." that means that the company or organization has said that publicly.  It does not mean it will happen; nor does it mean that I think it will happen.  Researchers in general have a strong tenancy to think they will start human trials much sooner than they actually do.

[d2] and some researchers at DRI are experimenting with transplanting cells into the eye, specifically to take advantage of this, but no human trials as yet.

[d3] After reading this, you might ask yourself, why bother with transplanting the beta cells at all?  Why not just put Sertoli cells right next to existing beta cells, and then they would protect the beta cells from the autoimmune attack.  People are working on that:
http://t1dcuredinmice.blogspot.com/2009/10/sertoli-cells-by-fallarino-at.html
but it has not progressed to human trials, yet.

[d4] The insulin generated by pig cells does work in humans.  For decades, humans injected pig and cow insulins as standard treatment.  It is only in the last 40 years or so that we have used human insulin from genetically engineered bacteria.  Prior to that, it was all animal origin insulin.

[d5] I've read several different accounts of the ethical approvals that this research had, and what it needed.  My belief is that it did have the proper approvals from the proper authorities at the time that it started, although some have claimed that the ethical approvals were lax.

References

Here are a link to PubMed references for all of Dr. Valdes-Gonzalez's work:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Valdes-Gonzalez%20R%22%5BAuthor%5D

[r1] The good results:
Three year follow up: http://axacell.com/uploaded/Publication%20Three%20-yers%20May%202007.pdf
Four year follow up:  http://www.eje.org/content/153/3/419.full.pdf+html
Long term follow up: http://www.ncbi.nlm.nih.gov/pubmed/20964645

[r2] I doubt this is a complete list of the doubters:
http://www.eje.org/content/154/6/917.full

[r3] This is not a complete list on the controversy, but enough to get you started:
http://www.ualberta.ca/~dcl3/Ref_2007-Aug-17/islet%20transplantation/islet_xenotransplantation_are+we+ready+for+clinical+trials.pdf
http://www.nature.com/nature/journal/v419/n6902/full/419005b.html
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)09285-1/fulltext
http://www.lancet.com/journals/lancet/article/PIIS0140-6736(02)09287-5/fulltext

[r4] http://eprints.qut.edu.au/3449/1/3449.pdf

Finally.....

I found this on the JDRF's "For Scientists" web site about encapsulation in general:
http://www.jdrf.org/files/General_Files/For_Scientists/MS2011/FY12_Encapsulation_Consortium_RFA_11.16.11.pdf


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.
My Blog: http://cureresearch4type1diabetes.blogspot.com
Mouse blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 Diabetes in the News (October)

Living Cell Technologies Starts Phase-I Study in New Zealand

LCT is developing an encapsulated pig cell cure for type-1 diabetes. They have completed a phase-I study in Russia which resulted in one patient being off insulin for a few months, and another for a few weeks. They finally got approval from the New Zealand government, and have now treated their first patient. This clinical trial is very similar to the one they completed in Russia, but half the patients will get twice the dose that the Russians started with, and the second half will start out with three times the dose. Eight people total. This trial is scheduled to complete in January 2011.

Commentary
This research has already shown that their encapsulated cells can have good effect for short periods of time. The big question they need to answer are these:
1. Will larger doses of encapsulated cells results in less need for injected insulin?
2. How long will the encapsulated cells continue to work?
This trial will directly address question 1. By using higher doses, they will see if they get more generated insulin, and a higher percentage of people who are off insulin entirely. Unfortunately, question 2 can only be answered by time. By following the patients from the Russian trial and from this new trial for a year or two. Although it may be that they'll learn more about duration by starting with a higher dose.

Another issue for me is this: is this a phase-I study or a phase-II study? That's a big difference because a phase-II study moves them closer to general availability, while a second phase-I study doesn't. Officially the study is "Phase-I / Phase-II". It's size is 8 people, and that's on the small size of phase-I. However, it's goal is to try different doses, and that's a phase-II type of goal. (Phase-I is more focused on basic safety.) The real measure is how the US FDA views it, and I don't know the answer to that question.

Sources
http://www.clinicaltrials.gov/ct2/show/NCT00940173
http://www.lctglobal.com/downloads/cms_latest_news/2009-10-06-LCT%20NZ%20Implant%207%20Oct%2009%20.pdf
http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10601771

LCT also issued their yearly report
which is here:
http://www.lct.com.au/downloads/cms_latest_news/2009-10-19-LCT%20Annual%20Report%202009.pdf

There are a couple of pieces of meaty news buried in this report.
On page 10 there is a list of KEY TARGETS. Nothing about any US trials, but (in addition to finishing their current trials) they list these two items:

• Commence pivotal trial in Russia.
• Commence DIABECELL® commercialisation [sic] – initially in Russian market.

And that makes it sound like whatever they are doing, they are going to do it in Russia first. They have a wholly owned subsidiary there, already.
Their clinical trials are described on pages 14 and 15.

Osiris Therapeutics Announces Preliminary Results For Prochymal Phase III GvHD and COPD Trials

Osiris is running two phase-III trials for their Prochymal treatment, for diseases other than type-1 diabetes. Both of these results are in and both were failures. They have several separate phase-II trials going on, and one of these does target type-1 diabetes. So having all their phase-III studies fail is bad news, but what really matters is the results of their type-1 diabetes clinical trial. Those results are expected in mid-2010.

press release: http://www.bioresearchonline.com/article.mvc/Osiris-Therapeutics-Announces-Preliminary-Res-0001?VNETCOOKIE=NO
http://www.clinicaltrials.gov/ct2/show/NCT00690066

Effects of Sitagliptin (Januvia) in Adult Patients With Type 1 Diabetes

This is a 20 person study which started in September and is expected to finish in December. It is trying a drug already in use for type-2 diabetics to see if it helps type-1 diabetics. This is aimed at helping type-1s use less insulin, not curing them. Based on my quick read of how this class of drugs works, I don't see why it's expected to work on type-1 diabetics. It helps the body create more insulin. I understand how that would help type-2s, but not type-1s. Anyway the proof is in the results, and we will not need to wait long. The research is being done at the Barbara Davis Center in Denver (which is top-of-the-line.) The good news is that we will have results very soon, and if they are positive, the drug is available right now.

http://www.clinicaltrials.gov/ct2/show/NCT00978796
http://en.wikipedia.org/wiki/Sitagliptin

Sernova's Animal Studies Continue

Sernova published results from some animal studies. You can read the links below for details. No date to start human trials was announced. This work is a follow on to Valdez's work in Mexico years ago, which was very controversial at the time it was done. He didn't do animal trials before going straight to people, and was eventually shut down by the Mexican government. It was also unclear if he was really getting as good results as he claimed. Sernova is trying to use the same ideas, but do the animal studies first, and then get Canadian or US FDA approval to do a clinical trial. So this treatment has been in clinical trials in the past, although not right now.

The basic trick was to get porcine beta cells, mix them with sertoli cells, and then implant the mix. Sertoli cells block the immune system, so the idea is that the immune system will not attack the new beta cells. So it's similar to encapsulated beta cells (LCT), but a little different.

http://www.genengnews.com/news/bnitem.aspx?name=65911061
http://www.benzinga.com/press-releases/m26601/sernova-s-cell-pouch-system-tm-and-sertolin-tm-preclinical-efficacy-presented-