Hanuman Medical Foundation’s grant support for the Solving Diabetes Project began in the fall of 2008. From a standing start we are now getting interesting and significant results in treatment of experimental animal diabetes. Here is a brief report on these developments.
Over the past year Cerco Medical has developed an improved Islet Sheet with the physical characteristics, stability, and biocompatibility required for a successful implantable device. On May 13th we began a series of implants of Islet Sheets into diabetic rats. Thus we have completed first phase of the Project (improvement of Islet Sheet fabrication) and have started the next phase, small animal efficacy studies.
Phase I ran longer than planned. We had thought that the technology that was tested in 2000-2001 at Edmonton required only a few tweaks, but using rat and pig implant studies we discovered that the Islet Sheet encapsulation technology required fundamental changes. Our team led by chief inventor Randy Dorian rose to the challenge producing new methods at once similar to the older methods yet very different in at least two ways. We have not yet secured protection of the IP so for now I shall say only that rat studies show tissues adjacent to the new sheets give virtually no hint that there is a foreign object next door. Those of you familiar with the realities of implanted foreign objects will recognize that this is a remarkable achievement.
Of course, irrefutable success in islet transplantation is normal blood sugar. Ultimately only clinical success is proof, but large animal results can demonstrate likely clinical success. We plan to begin Islet Sheet implants into large diabetic mammals such as pigs soon. For the next few months we will focus on the less expensive diabetic rat model, which can teach us a great deal.
The graph shows injected insulin (yellow) and blood sugar (orange) of the second rat treated (Islet Sheet implant on chart day 0) and the first cured, so far for >30 days. We have treated one to two rats per week for the past month, and have seen similar success for rat and pig islets, and for sheets in the subcutaneous space as well as the peritoneal space. In a word, the Islet Sheet’s ability to normalize blood sugar in diabetic rats – based on very preliminary data – is robust.
We still have a long way to go. We need to demonstrate these metabolic results in much larger numbers of rats. Then we need to produce similar results in large mammals, and bolster them with IVGTT “stress tests.” And a commercially viable product will need a functional lifetime of months, so it will take months to prove. Nevertheless, to have such rapid and robust success so quickly is fairly encouraging.
Interest in the Islet Sheet encapsulation technologies is growing in the stem cell and islet replacement communities. We have been contacted by several commercial and nonprofit research organizations that have “islets” derived from stem cells. We are in discussions for animal studies combining their proprietary cells with the Islet Sheet.
We are increasingly hopeful that the Hanuman Medical Foundation’s grant support will lead to the demonstration that the Islet Sheet can normalize blood sugars without pharmaceutical immune suppression in pancreatectomized large mammals. We thank you for your ongoing support for the Solving Diabetes Project.
These are exciting times. Our team is engaged and will grow to meet the demands of an expanding and accelerating research program. We will learn in the coming months whether the Islet Sheet has the potential to be a major new therapy for treatment of type 1 diabetes.
“A commercially viable product will need a functional lifetime of months”? Does this mean that your encapsulated cells can be replaced as an out-patient procedure and that this would be extremely inexpensive? Living Cell Technologies is now estimating that their product will cost about $140,000 per insertion, and if topping up a failing encapsulated mass costs anywhere near the initial insertion price, it would seem uneconomic to have to intervene more often than every few years.
Lots of variables here, but “months” in minimal and probably marginal performance. We hope for “years” but it will takes years to prove that. If the site is subcutaneous you can make a case that months of euglycemia before replacement of supplementation of Islet Sheets is medically justified. More data are needed.
Dear Scott,
Encouraging initial results, but is there a technical justification as to why glucolevels started to fluctuate from day 22 onward? The Islet Sheet seems to have had a solid grip on the situation from day one, but sort of lost control afterward.
Probably just noise. Only time and a larger number of treated rats will clarify, as well as glucose tolerance tests over time. We are working on it. We have been treating two rats per week, and this week we are increasing the number treated.
Please keep us posted. I am very keen to see how this progresses.
Have heard in the past that the results in mice may not in all probabilties result in cure
in humans. Hope this one should not end in mice only. When do you think this line of
treatment start in human ??…scott, anyways you & lct are my only hope to cure my
son.
I am in Orlando for the ADA meeting and ran into a friend. She liked the rat results but was concerned that the implant was starting to fail around day 20. Since Samer wrote something similar, I want to assure you this is not the case.
This graph shows the results through yesterday. We are past 6 weeks!
So why does the control get worse then better again? This rat works for a living. We have done IPGTT stress tests to check how well the islets function. In this test, like a human IVGTT, the Islet Sheet is challenged with a glucose injection and the glucose level followed for a couple of hours (not shown). For instance the extraordinary BG around 400 was after one of these tests. So in lay terms we have stressed the Islet Sheet and the animal has always recovered.
We are treating more rats every week. We’ll say more when the picture gets clearer. (Don’t expect me to update the graph again!)
Scott King
Human subjects would be diagnosed as diabetic if they showed a blood glucose level above 200 mg/% two hours after a glucose tolerance test. You do not indicate how much glucose stress you subjected your mice to, or what the response of normal mice would be to a comparable stress, but it seems that the results you report indicate that even a short time after implantation the encapsulated islets are not functioning normally.
scott, have you read about the washington university researchers curing rats using pig islets, firstly with embronic pig cells & then with adult pig cells. Your comments on this please.
While awaiting Scott’s reply, perhaps I can suggest a perspective on the latest results out of Washington University. Normally transplanting tissue from animals to humans, or between any two different species, causes the most rapid and destructive form of rejection, called ‘hyperacute rejection.’ However, it has been known for a long time that embryonic organ tissue at very early stages of development has a minimal immunological signature while yet still having some of the function of a fully developed organ. This has led to the interesting result that embryonic tissue at an early stage of development, called ‘primordia,’ can be transplanted across species without triggering the hyperacute rejection that would be expected if fully developed organs were transplanted. Since most laboratory animals have much simpler or less sensitive immune systems than humans, implications for humans from experiments using mice or rats as primordia recipients have limited significance, but recently it has been demonstrated that such cross-species transplants can be effective even in macaques, which have an immune system much more like that of humans. (S. Rogers, et al, “Long-Term Engraftment Following Transplantation of Pig Pancreas Primordia,” Xenotransplantation, vol. 14, no. 6, p. 591 (2007)) In that study, only minimal immunological response to the primordia transplanted was found, such as might be found in an immunosuppressed human patient with a transplant, whose graft could function well though with a limited lifespan due to subtle immunological effects which constitute part of chronic allograft disease. Unfortunately, primordia transplants alone don’t seem to be effective in getting diabetic animals off of their requirement for injected insulin, such as could happen with mature pancreatic tissue transplants.
The Holy Grail of transplant immunology is to find a way to induce tolerance of the transplanted organ in the recipient so that toxic immunosuppressive drugs do not have to be used. This has so far proved to be an elusive goal, though it does occur spontaneously in some human organ recipients for reasons which are still unexplained. In the recent Washington University study, it was found that by xenotransplanting primordia first and then fully developed pancreatic tissue later, the primordia could in effect induce the recipients to moderate their immunological response to the later transplant so that toxic immunosuppressive drugs would not be needed and hyperacute rejection would not occur. The next step would be to try to replicate this result in the more subtle and sensitive immune systems of animals more closely related to humans, such as monkeys or apes.
However, since they are still at the stage of experimenting on non-human subjects, and the FDA clinical trial requirements for the introduction of any new treatment impose enormous delays, don’t expect any actual treatment for patients to emerge from this result for the next 12 to 15 years, even if everything from now on goes perfectly.
I agree with JP’s backgrounder and opinions. This is impressive work. I am not shocked this approach worked, but I am surprised. What I would add is that while embryonic cells are immune privileged, as they grow from undifferentiated cells to fully differentiated cells (meaning in the case of beta cells that they secrete insulin) they become fully immunogenic and are rejected. What may have happened here is that rat immune system became tolerant to the cells because they differentiated slowly.
I would predict that it will be very hard to replicate this in a large mammal, but if they can, it could lead to a major clinical advance.
Aren’t embryonic and umbilical cord stem cells extremely dangerous and pose a high cancer risk? Isn’t regenration therapy, altogether, risky in that respect?
I am assuming of course that implanted cells were not rejected, be it through immunosuppressant drugs or success in identifying those cells as ’self’.
There is not yet enough evidence to fully assess the safety of embryonic and umbilical cord stem cells. My guess is that the more they are manipulated in the lab the more dangerous they become. Our rule is to minimally manipulate the cells. In the case of primary islets, always less than a week. Some of the embryonic stem cells have been in the lab for years and worry me.
The news about researchers from washington is all over newspapers all over the globe…this view of yours will definately be a sad news for people looking for a cure !!!
I did not think I was that negative. I’m traveling now, but I’ll look into the Washington U paper in more detail when I get home over the weekend.