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Designing a Definitive Islet Sheet Study

April 2nd, 2012

Large-animal studies will demonstrate whether the Islet Sheet is ready for a clinical trial. In previous posts I have discussed the partnership doing this study: the Cedars-Sinai Diabetes and Obesity Research Institute, the islet transplantation group at UC Irvine, and our company Islet Sheet Medical. I have also laid out the study design. Today I want to describe how published research is used to help design a study such as this.

Although JDRF has chosen not to fund this research, one of its senior scientists, Albert Hwa (PhD from MIT, JDRF Senior Program Scientist in Beta Cell Therapies), is a good source of counsel for study design. As part of his job, Albert reviews proposals and previous research to help JDRF decide what research to fund in beta cell therapies such as the Islet Sheet. When I asked him to give me his opinion of the best published canine-islet encapsulation study, he immediately said the 2008 paper by Taylor Wang of Vanderbilt. So naturally we scrutinized this paper for procedures and concepts to use in our study. Click on the image for a PDF of the Wang study.

The basic idea of this study is the same as ours. A dog is made diabetic by surgical removal of the pancreas, and the encapsulated islets are implanted. The dog has continuing monitoring of its diabetic control, and the state of the capsules is assessed after the animal is sacrificed. One difference: Wang’s group used micro-encapsulation and we use the macro-encapsulation device we call the Islet Sheet.

Table 1 on page 333 shows other significant differences. Dr. Marilyn Ader of Cedars recommended using large animals so that the results are as similar as possible to human results. Our first Islet Sheet recipient (implantation is scheduled for this week) weighs 28 kg. In contrast, the average weight of the 12 dogs reported in table 1 is 8.6 kg, less than one-third of our dog’s weight.

Another significant difference is the proposed dose. Dr. Jonathan Lakey of our team is an author of the Edmonton Protocol, which demonstrated that in humans a dose of 10,000 islets/kg body weight could normalize blood sugar. We plan to use that dose for the dogs, which will require islets from one to two donors, as in human transplantation. Wang reports that the dose is 55,000 to 86,000 islets per kilogram (Table 1), or five to eight times our proposed dose. In the Wang study eight donors were used per recipient.

The metabolic monitoring of the animals is similar. The Cedars-Sinai group has been studying diabetes in dogs for 30-plus years and have their own protocols for the Intravenous Glucose Tolerance Test (IVGTT), but the the protocols are similar enough that they can be meaningfully compared.

Based on the difference in encapsulation technology design, we anticipate that our results will be somewhat different in several respects. Figure 4 shows that a healthy, normal dog’s insulin peaks in the first 15 minutes following glucose injection. Peak insulin for the four pancreatectomized and treated dogs show peaks from 45 to 90 minutes, consistent with capsules in the 700 to 1,000-micrometer diameter range. Islets is the Islet Sheet are mostly less than 125 micrometers from the surface of the sheet, so we anticipate an earlier insulin peak, closer to normal. We can make such a prediction from computer models of glucose and insulin diffusion through different device geometries, as well as from experimental data.

Of course, the big question for a person with diabetes must be: How long does an Islet Sheet work?  Table 1 in the Wang paper shows duration of normal blood sugar of 50 to 214 days with an average of 93 days. We do not have enough data to make a projection for the Islet Sheet, and this is perhaps the most important thing we will learn. We hope that Islet Sheet function will be more than 93 days.

 

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