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Study of Islet Sheets in Diabetic Pigs: Difficult but Promising
September 5th, 2012
After a long period of laboratory and small-animal studies, at last we have begun the crucial large-animal studies of the Islet Sheet’s safety and efficacy — second in importance only to clinical trials themselves. As I have discussed previously, large-animal studies are needed to determine whether the Islet Sheet will perform well in humans with diabetes.
After spending years on small animal and laboratory studies, the reality of large-animal studies is a bit shocking. We knew it would be expensive. We are learning that it is difficult. I cannot report the results yet, but I can tell you that we’re happy with our progress.
We are doing this study with Jonathan Lakey’s group at UC Irvine. The first step was to select the animal to be used. We had planned to use the canine model, which is the best metabolic model to compare with humans, and a good model for transplantation. Using dogs turned out to be even more expensive and complicated than anticipated, however, in part because of growing concerns about animal experimentation protests. So we have changed course and are studying the Islet Sheet in the pig model. All steps of the process can be performed at the University of California – Irvine, which helps simplify the logistics.
The pig is suitable for these studies for several reasons. Its metabolism is similar to that of humans (both species are omnivores), and its insulin requirements are similar, ~0.75 U/kg. Pigs are less expensive to use in a lab setting than dogs. And they can be easy to work with: after a relatively short time they become comfortable around humans, and even affectionate. Winston Churchill once remarked, “I am fond of pigs. Dogs look up to us. Cats look down on us. Pigs treat us as equals.” We’ve chosen the Yucatán minipig to be the subject of these experiments. It is smaller than a market pig with mature weight of 40 to 50 kg.
The process remains challenging. Type I (autoimmune) diabetes does not occur spontaneously in any large animal. You must make the animal diabetic through a procedure. There are two ways to do this: by administering the drug streptozotocin or by surgical removal of the pancreas. Dr. Lakey and his staff have mastered the canine pancreatectomy and now are working to develop a method for surgical removal of the pig pancreas. But other researchers report that, due to the vascular anatomy of the pig pancreas, total pancreatectomy often leads to serious complications. So in the meantime we are using the proven drug method.
Streptozotocin is toxic to the beta cells in the islets. As they die, the beta cells release insulin into the blood. The blood sugar drops; then, when the beta cell death is complete, blood sugar rises. Over the next couple of days the pig becomes frankly diabetic with high blood sugar. Then the use of insulin begins in an effort to control the pig’s blood sugar as well as we are able to control the blood sugar of a human with type 1 diabetes. The diagram below shows this process in pig 151:
Treatment with streptozotocin causes blood sugar to drop, then rise as the pig becomes diabetic
Now we enter a phase that will be familiar to you if you help your child manage diabetes with insulin, or manage your own diabetes, as I do. And that is getting the insulin dose right, twice a day. We are using both a short-acting and a long-acting insulin. (We don’t think the pig would tolerate a pump.)
Our team has learned to control the pig diabetes faster and better than I have ever seen done before. In addition to the regular stick BGs (green in the diagram), we are using Dexcom CGM (red in the diagram). For insulin dosing management we are using the tools developed by Dr. Andrew Drexler and Carolyn Robertson, CDE, of the Gonda Diabetes Center at the University of California, Los Angeles. This means that we can change the dose of fast-acting and long-acting insulin every two days toward our goal of stable blood sugar with injected insulin.
In addition to obtaining twice-daily blood sugars and the data from continuous glucose monitoring, the pig’s insulin secretions are evaluated with intravenous glucose tolerance tests (IVGTT). The first one is done before the animal has received any therapy; the next is done after diabetes is established. Then further IVGTTs are done after implantation of the Islet Sheets. The final test will be done after the sheets are removed, to prove that the animal has remained diabetic while Islet Sheets have been delivering insulin.
As I write this, one pig has received an implant of several Islet Sheets after being diabetic for weeks. A second pig has been made diabetic and its insulin administration is being fine-tuned. This animal is expected to receive its Islet Sheet implant later in September.
I must praise everyone’s devotion to this project. Management of a diabetic pig is as relentless as managing diabetes in a child. Dr. Lakey’s group members are coming in twice on weekends to measure BGs and administer insulin, as well as providing standard pig care and feeding. Robert Boock at Dexcom has been very helpful. Marilyn Ader, Associate Director of the Diabetes and Obesity Research Institute at Cedars-Sinai, is teaching best practices in metabolic procedures. We are all learning very rapidly. I am pleased to have a day-to-day role myself, helping to manage our little diabetic pig. Thirty years of managing the disease in a large omnivore (myself) is proving useful.
It is customary and expected among academic researchers that results will be reported at a scientific meeting before being released to the public. Dr. Lakey will present progress reports on these pig studies at scientific meetings over the coming months. With his permission, when he presents these interim results to his colleagues, Hanuman Medical Foundation will release them on this website.
Scott, This a great news. In a best case scenario. How long before this product could be brought to the masses after clinical trails began? Please notice I said best case. I realize, best case rarely happens.
Thanks for the softball – the best case! Clinical trials begin in 2013 and application for licensure in 2014, approval in less than 6 months, so Islet Sheet available somewhere (not USA!) in 2014-15. US FDA will take longer than almost any other place so initially you will need to fly somewhere. FDA approval in 2024.
Scott,
Any reason you guys couldn’t use monkeys in the trial? I’d love to go tell the FDA to go F themselves but I doubt that would help. Those Scumbags have us by the balls. I can’t get past the fact that we actually need approval from the FDA with something like this. It should be more like do it at your own risk. If I have to wait till 2024 for an effective treatment I probably won’t be around to wreak the benefit.
Gary, we may do NHP (nonhuman primate) studies, we have not decided whether they are needed. It depends on how well pig and dog studies go. I agree that Islet Sheet therapy is safe, and should be permitted to go to clinical trials quickly, but it’s not my decision. There are many places outside the FDA’s control (Singapore for example) that are working to make a welcoming environment for biomedical research.
I mention this before. What is the biggest risk with this type of “cure”. Potential allergic reaction to the sheets. Okay removal is an options if this happens. Worst case number 2, it does not work and a person will find this out quickly and they would need to go back on insulin. Not trying to make light of this or anything but from my perspective this would be worst case scenarios. This is why I know the FDA needs an overhaul, because they us a one size fits all approach to medical decision making. I believe the only exception maybe medical devices, which is what I feel this should come under. But hey I am a nobody
Islet transplants that have been done for years now even with toxic drugs have not killed anyone to my knowledge. Most islet recipients that had the procedure done had some side effects from the drugs and it varied from person to person. Most said the side effects from the drugs were much more tolerable then dealing with roller coaster sugars. Of course this procedure was never FDA approved but they did approve the trials. Islet transplants themselves are relatively safe (I think?). The only change here is the fact the cells are protected. In my mind anyway this should be safer then toxic drugs that were used in the Edmonton protocol. The bottom line is there should be no reason the FDA needs to drag these trials out for a decade to insure safety. LCT is already years into this type of treatment and so far there are no reports of safety issues.I would bet that a good solid two to three years of proof of safety and effectiveness in humans and there would be enough diabetics to fill up every football stadium in the country and then some to have the transplant done.
Minor point Gary: the CIT-07 trial (islet allo-transplantation) has been submitted to FDA and will probably be approved in 2013. Thirteen years after Edmonton protocol publication.
My blog on this:
http://www.hanumanmedicalfoundation.org/blog/2012/06/11/islet-encapsulation-is-the-best-hope-as-islet-transplantation-declines/
I’m just saying we as citizens should be able to have the option to pursue the transplant shortly after it proves safe. Its not going to take anywhere near ten years to prove that. We will never know the long term effects until someone has it long term. If I were a young teen with my whole life ahead maybe it would be justifiable to wait but nearing 40 years of this with not a lot of time left on planet earth I feel I shouldn’t have to wait for FDA approval to pursue this. The only way to get around FDA approval is to be a recipient during the clinical trials. Scott, I take it your at least a couple years older then me but its your company and I ‘m sure you aren’t waiting around till the FDA decides its safe enough to commercialize. I don’t blame you. It’s your life and the FDA has no business dictating your life or anyone else’s that has diabetes.
Hi Scott, Thank you so much for the work you are doing. I was just wondering if and when the islet sheet is proven safe enough for other countries to approve, I know the USA and Canada will be the last, would a person be able to go over to another country and pay to have the procedure done? I was also wondering what the expected life of an islet sheet is before it needs replaced?? Thanks
Brett, I’m not sure. I think it depends on the host country. Medical tourism is a growing service is some countries like India, and they actively encourage patients to come to India. We want to get the therapy out to everyone who would benefit.
So if I understood correctly you are hoping to start human clinical trials in 2013?
Katerina, Brian’s question specified “best case”. Trials could start next year with a run of good luck. I can actually think of two places where it could happen. Possible but not likely.
Can you explain more what do you mean with arun of good luck? Also estimation on a realistic (good) senario?
Thanks