Successful Case Study of New Encapsulated Islet Cell Device
Background
Encapsulated beta cells are one potential cure for type-1 diabetes. Beta cells are wrapped in a protective coating and are put in a person. The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunosuppression drugs (as you would for a normal beta cell transplantation).
Encapsulation research started in people in the 1990s. The current leaders in the field are LCT, in phase-II human trials, and University clinical Hospital Saint-Luc and The Sydney Project who have both done phase-I trials. Plus there is Sernova, the Islet Sheet Project, Viacyte (and probably several more) in animal research.
This Study
These researchers (who I will call "the Dresden group") have published a case study. A case study report on a single person, so it's not a clinical trial. For this person, they implanted some human beta cells (from a cadaver) encapsulated using their own alginate technology [d1], and added an oxygen infuser (which had to be reloaded every day) [d2]. The researchers implanted 2k cells / kg, which is about 1/5 of what they expect to need to cure someone. It is very common in phase-I trials to give a very small amount of whatever you are testing, in order to check for safety. They monitored insulin usage, and measured C-peptide levels every three months. After 10 months, they removed the capsule and ran some tests on it.
Results
C-peptides in Response to Carbs
One way to test the effectiveness of this device, is to give the patient some sugar, and see if they generate insulin (by measuring C-peptide levels) in response to that sugar. These researchers tested the patient once every three months, and the data is shown in the graph below:
Notice that all three response lines are pretty much the same [d3]. That is very positive news, because it means that the implanted beta cells worked just as well after 9 months as after 3 months. Previous encapsulated beta cell treatments have degraded over time, and the results after 9 months would be noticeably worse than after 3 months.
Insulin Usage Before and After
Prior to implantation, this patient used about 52 units of insulin per day. After the implantation he used 43 units. That's a drop of 17%. For the first human trial, with a dose much smaller than expected for a cure, that's a very promising result. It is especially interesting that by transplanting about 1/5 as many cells as they expect to need, the patient required almost 1/5th less insulin. That might be coincidence, or it might foreshadow more good news to come.
Fasting C-peptides
These measured about 0.04 nmol/L on average. The MedScape normal range (ie. non-diabetics) is about 0.26-1.03 nmol/L, so these guys were well below normal. But again, for a first case study, with a small dose of islets, this has promise.
Moving Forward
This research needs to move forward in three ways, and hopefully they can move forward in all at the same time. First, they need to run an actual clinical trial (ie. get more people treated). Case studies just don't attract the same attention as clinical trials, nor should they. One important next step for this research program is to implant this in 6-20 people and see what happens. The second step is to implant more beta cells, and the third is to find a better way to supply oxygen to the cells.
For this case study, they implanted about 2k/kg cells. They believe that about 10k/kg cells will need to be implanted to cure type-1 diabetes. If you look at the insulin requirements for the patient, they dropped just below 20% after implantation. So the next big question is, if you give more beta cells, do they generate more insulin, in proportion? If so, that is very important.
Discussion
These researchers are using human cadaver beta cells and a proprietary alginate encapsulation technology, but of which have been done before by others. However, they are also doing something unique, which is oxygenating the cells. They hope that providing extra oxygen will make the cells work better and survive longer. The trade off is that the oxygen generation system requires daily maintenance.
The obvious research to compare this to is LCT's "Diabcell". In LCT's most recent clinical trial (a Phase-II trial), they implanted a total of 10k/kg cells in 4 patients and 20k/kg cells in 4 patients. The higher dose group saw a 20% drop in insulin usage. LCT did not report on the durability of this result. So we don't know if they continued to use 20% less for months, or if the effect went away relatively quickly. So the most recent LCT results and the Dresden results are very similar, except that these researchers reported on durability and the LCT researchers have not, and the Dresden team used far fewer cells.
In addition to the possibility of being a cure by itself (especially if the oxygen supply issue can be solved), this research is also important for what it tells us about encapsulated beta cell longevity in general. If bigger trials show the same durability (that the cells continue to work for a long period of time), that strongly suggests that the problem that causes encapsulated beta cells to die over time is a lack of oxygen. So that means that everyone trying to create encapsulated beta cell cures will know to concentrate on the oxygen supply. Although this might not be new news to researchers: I remember David King (Islet Sheet developer) talking about the importance of oxygen supply years ago.
News articles: http://health.usnews.com/health-news/news/articles/2013/10/28/scientists-report-transplant-advance-for-type-1-diabetes
http://idw-online.de/pages/de/news558740
General link on encapsulation: http://en.wikipedia.org/wiki/Cell_encapsulation
Extra Discussion
[d1] Alginate is a general term that covers all (or almost all) of the recent encapsulation techniques.
[d2] One important question is: how long is the oxygen generator used? The paper makes it sound like it was used for the whole 10 months that the device was in use. However, one of the researchers was quoted as follows:
and that implies the oxygen generated is only needed for a short time. Since the generator needs to be refilled each day, and that is a hassle, this duration is important. I did ask the researchers how long the oxygen generated was used for, but had not heard back at the time I finished this posting.
[d3] Different people view this data differently. I tend to see them as all being about the same, but at least one person (Celsus, on islet.org) thinks that the 3 month is stronger, because it ends stronger. However, when I look at the whole graph, I think they are all similar. The official way to make the comparison is AUC "area under the curve", and I don't think the researchers did that math.
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 Tidepool 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
C-peptides in Response to Carbs
One way to test the effectiveness of this device, is to give the patient some sugar, and see if they generate insulin (by measuring C-peptide levels) in response to that sugar. These researchers tested the patient once every three months, and the data is shown in the graph below:
Notice that all three response lines are pretty much the same [d3]. That is very positive news, because it means that the implanted beta cells worked just as well after 9 months as after 3 months. Previous encapsulated beta cell treatments have degraded over time, and the results after 9 months would be noticeably worse than after 3 months.
Insulin Usage Before and After
Prior to implantation, this patient used about 52 units of insulin per day. After the implantation he used 43 units. That's a drop of 17%. For the first human trial, with a dose much smaller than expected for a cure, that's a very promising result. It is especially interesting that by transplanting about 1/5 as many cells as they expect to need, the patient required almost 1/5th less insulin. That might be coincidence, or it might foreshadow more good news to come.
Fasting C-peptides
These measured about 0.04 nmol/L on average. The MedScape normal range (ie. non-diabetics) is about 0.26-1.03 nmol/L, so these guys were well below normal. But again, for a first case study, with a small dose of islets, this has promise.
Moving Forward
This research needs to move forward in three ways, and hopefully they can move forward in all at the same time. First, they need to run an actual clinical trial (ie. get more people treated). Case studies just don't attract the same attention as clinical trials, nor should they. One important next step for this research program is to implant this in 6-20 people and see what happens. The second step is to implant more beta cells, and the third is to find a better way to supply oxygen to the cells.
For this case study, they implanted about 2k/kg cells. They believe that about 10k/kg cells will need to be implanted to cure type-1 diabetes. If you look at the insulin requirements for the patient, they dropped just below 20% after implantation. So the next big question is, if you give more beta cells, do they generate more insulin, in proportion? If so, that is very important.
Discussion
These researchers are using human cadaver beta cells and a proprietary alginate encapsulation technology, but of which have been done before by others. However, they are also doing something unique, which is oxygenating the cells. They hope that providing extra oxygen will make the cells work better and survive longer. The trade off is that the oxygen generation system requires daily maintenance.
The obvious research to compare this to is LCT's "Diabcell". In LCT's most recent clinical trial (a Phase-II trial), they implanted a total of 10k/kg cells in 4 patients and 20k/kg cells in 4 patients. The higher dose group saw a 20% drop in insulin usage. LCT did not report on the durability of this result. So we don't know if they continued to use 20% less for months, or if the effect went away relatively quickly. So the most recent LCT results and the Dresden results are very similar, except that these researchers reported on durability and the LCT researchers have not, and the Dresden team used far fewer cells.
In addition to the possibility of being a cure by itself (especially if the oxygen supply issue can be solved), this research is also important for what it tells us about encapsulated beta cell longevity in general. If bigger trials show the same durability (that the cells continue to work for a long period of time), that strongly suggests that the problem that causes encapsulated beta cells to die over time is a lack of oxygen. So that means that everyone trying to create encapsulated beta cell cures will know to concentrate on the oxygen supply. Although this might not be new news to researchers: I remember David King (Islet Sheet developer) talking about the importance of oxygen supply years ago.
News articles: http://health.usnews.com/health-news/news/articles/2013/10/28/scientists-report-transplant-advance-for-type-1-diabetes
http://idw-online.de/pages/de/news558740
General link on encapsulation: http://en.wikipedia.org/wiki/Cell_encapsulation
Extra Discussion
[d1] Alginate is a general term that covers all (or almost all) of the recent encapsulation techniques.
[d2] One important question is: how long is the oxygen generator used? The paper makes it sound like it was used for the whole 10 months that the device was in use. However, one of the researchers was quoted as follows:
For that reason, the current version of the device had an oxygen port on the outside of the body attached via tubing that had to be refilled daily by the patient for as long as a month or two, Block explained.Source: http://health.usnews.com/health-news/news/articles/2013/10/28/scientists-report-transplant-advance-for-type-1-diabetes
and that implies the oxygen generated is only needed for a short time. Since the generator needs to be refilled each day, and that is a hassle, this duration is important. I did ask the researchers how long the oxygen generated was used for, but had not heard back at the time I finished this posting.
[d3] Different people view this data differently. I tend to see them as all being about the same, but at least one person (Celsus, on islet.org) thinks that the 3 month is stronger, because it ends stronger. However, when I look at the whole graph, I think they are all similar. The official way to make the comparison is AUC "area under the curve", and I don't think the researchers did that math.
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 Tidepool 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.
Joshua, that is one problem they are also tacking with the BIOHUB. They have away to keep the cells or are looking into ways to make sure the cells get oxygen. As always thanks for your work
ReplyDeletehello,
ReplyDeletethx a lot for this blog, my daughter was diagnosed a year ago with type 1 Diabetes, she is 8 years old right now. I always follow your blog.
As a Scientist (formulator chemist & microbiologist), I am impressed by your comments and analysis on possible cures.
GBU
Fadi
This comment has been removed by a blog administrator.
ReplyDeleteThanks Joshua
ReplyDelete... very useful information
This comment has been removed by the author.
ReplyDeleteHi Joshua,
ReplyDeleteHere's a recent news report from Nature about encapsulation that should be interesting for your readers.
http://www.nature.com/nm/journal/v20/n1/full/nm0114-9.html
As always, your research is much appreciated!