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Design Protocol for Large-Animal Islet Sheet Study
January 30th, 2012
My last posting marked the start of trials at the new Cedars-Sinai lab to determine the efficacy of the Islet Sheet in large mammals—a long-awaited goal. It also talked about Professor Richard Bergman’s vision for his new Diabetes and Obesity Research Institute there. The fact that Bergman, known as a leader in type 2 research, has chosen the Islet Sheet as the Institute’s first project is exciting for those of us focused on type 1 research.
For those curious about the details of these studies, I offer a summary here. (The protocol for this experiment runs to 30 pages.) This protocol had a long gestation—in the end it was reviewed and approved three times: at UC Irvine, USC Medical Center, and finally (after Professor Bergman’s lab moved there) at Cedars-Sinai Medical Center. It’s time-consuming because licensed medical research facility are required to follow procedures to ensure the health and safety of laboratory animals, and to minimize pain and distress. Each institution is required by federal law to review proposals by an Institutional Animal Care and Use Committee (IACUC). Getting permission for animal experiments is generally considered to be as difficult as it is for human trials.
The work will take place at the Cedars-Sinai lab except where noted. Day Zero is when a recipient animal is made diabetic with total removal of the pancreas, but we begin with a key step four days earlier:
Day Zero minus 4: IVGTT #1 (recipient)
The Intravenous Glucose Tolerance Test (IVGTT) is a procedure in which the animal is injected with a known quantity of glucose and the amounts of glucose, insulin and other hormones are measured frequently, twenty-three times over 150 minutes. The Bergman laboratory is a leader in such metabolic studies. The data can be interpreted to show quantitatively the insulin secreted by the islets or the Islet Sheet, as well as the body’s response to the insulin (called insulin sensitivity). This first IVGTT is performed on the animal before the pancreatectomy to ensure that it has normal canine metabolism.
Day 0: Pancreatectomy (recipient)
The figure shows the canine pancreas, the removal of which is our method to make the animal metabolically diabetic. This is a very difficult surgical procedure, taking two skilled surgeons working together over an hour. The pancreas of a dog clings to the bowel, and compete removal without damaging the attached organs is a challenge.
Day 5: IVGTT #2 (recipient)
The purpose of the IVGTT is to determine whether the pancreatectomy was indeed compete. If insulin and C-peptide are undetectable then it was. After this IVGTT the dog is deemed diabetic and is managed with injected insulin.
Day 11: Pancreatectomy x 2 (donors)
Islets of Langerhans are isolated from pancreases obtained from two donors. The donor pancretectomies are performed at Cedars and the organs subsequently transported to UC Irvine for processing to purified islets. The islets are encapsulated to make Islet Sheets by Rick Storrs of Islet Sheet Medical, at Jonathan Lakey’s UCI lab.
Day 14: Islet Sheet Implantation (recipient)
The Big Lebowski. Islet sheets with enough islets to cure the animal are implanted.
Day 21, 22, 42 and 72: IVGTT #s 3-6 (recipient)
A series of IVGTTs precisely measure Islet Sheet function. We hope that the animal’s metabolism will return to near-normal over the course of these tests. Canine results can be used to project results in humans.
Day 77: Islet Sheet Explantation (recipient)
The Islet Sheet is removed along with some surrounding tissue. The animal remains alive and is expected to return to the diabetic state.
Day 80: IVGTT #7 (recipient)
The final IVGTT is very important because it will let us know if the animal has regenerated islets on its own. A frequent criticism of encapsulated islet experiments is that the recipient was not shown to be completely diabetic, and that the implanted capsules have not been proven to have provided the insulin. (We abandoned rat metabolic studies because we discovered islet regeneration in our preferred rat strain.) This final IVGTT will fully address that criticism because the Islet Sheets can be completely removed (unlike microcapsules and vascularized macrocapsules). We expect that insulin concentrations will be very low.
Progress and Plans
This study is complicated and expensive and requires coordination of disparate procedures. Some of the procedures—for instance, survival canine pancreatectomy—are difficult. Rehearsals have already occurred and more are scheduled. As I write, we expect that the first treatment of a diabetic large mammal with Islet Sheets will happen in March.
We plan to perform variations on this experiment several more times, investigating such variables as the number of islets required for efficacy and trade-offs in Islet Sheet implantation site. And with some future animals, we expect to wait longer than 77 days before explantation. For us, this study will provide a rich treasury of data that may persuasively show the Islet Sheet will work in human diabetics.
To all who hope that the Islet Sheet will improve diabetes therapy: Hanuman Medical Foundation has worked hard and succeeded is securing funding for the first six animals to be treated under this protocol. If it works, the foundation believes it will be able to get more funding. But large animal experiments are expensive, and right now—when the results are still unclear—a donation would make a big difference If you can give now, when we need funding most, please do. You will always know you make it possible!
