We focus on the bio-artificial pancreas because it is the largest opportunity in the bio-artificial organ segment of the medical device market, and because we all have diabetes in our family. There are other bio-artificial organ opportunities.
A bio-artificial pancreas has two components, living islets of Langerhans and the artificial device. Islet isolation methods are largely in the public domain. Therefore, the device component will differentiate products.
First, ISM must prove that the Islet Sheet bio-artificial pancreas cures diabetes, then the company must stay ahead of competitors as the bio-artificial pancreas improves. Considering devices currently in development, the UC-type alginate coatings are the best in our opinion; other methods in development seem to work well enough. These devices permit efficient use of islets, but are not retrievable. ISM intends to make the Islet Sheet the first proven retrievable bio-artificial pancreas. Other considerations aside, given availability of two devices with similar metabolic performance, the retrievable one will be preferred.
At this time increasing numbers of diabetes researchers are becoming aware of requirements for an ideal bio-artificial pancreas. A device that gives 10% greater islet life or 10% more function from islets, will reduce the cost of bio-artificial pancreas therapy significantly; a device that can be removed addresses safety concerns. ISM's short-term goal is to prove that the Islet Sheet is the optimal device. ISM's long-term goal is to commercialize the Islet Sheet and continue research in improving performance and lowering cost.
The experimental design is crucial to unambiguous conclusions. If results of model experiments cannot be extrapolated with confidence to the clinic, the experiments have very limited value (e.g., curing a nude (immune-incompetent) mouse means little!). There must be a predictable chain of decisions based on the findings in each of all possible suggested experiments which leads ultimately (and at reasonable cost) to a meaningful endpoint.
There are quite a few known issues which need to be addressed in developing a workable bio-artificial pancreas. And there continue to be some unanticipated issues which evidence themselves only when we undertook to cure an animal (see our experimental write-ups). To look at extremes, we could take many small incremental steps to reach a significant endpoint, or at the other extreme, we could make our best guesses and rely on luck, hoping to achieve a cure in the first experiment.
Data most relevant to the clinic will come from in vivo testing. Mice are routinely used as models because they're small and inexpensive. Unfortunately, mice are a bad model on account of possessing a very weak complement system and also on account of being small (it doesn't take long for a mouse to turn over all his blood). They develop diabetes but mouse metabolism is very different from human metabolism. In particular, almost none of the glucose uptake in a mouse is insulin-dependent. As a practical matter this makes curing a mouse very easy.
The model of choice is the dog, for historical, metabolic and immunological reasons. One of the experimental virtues of the Islet Sheet design is that it allows multiple, locatable, retrievable implants in a single animal. A single dog can be recipient to 100 small sheets; one each of 10 different formulations in each of 10 different implant sites. Thus, a single experiment can yield a wealth of highly relevant data on many parameters from a single dog.
Sheets of varying permeability, each containing between several and a couple thousand xenogeneic islets, can be implanted into a dog. The optimal thickness and permeability will be different in different sites, since both oxygen availability and aggressiveness of the humoral immune response will vary with site. Histological examination of retrieved sheets will quickly allow discrimination of successful sheet formulations.
Large Animal Studies Prove Safety and Efficacy
A very good Islet Sheet design that is probably close to optimal has been developed in research stretching from 1993 to 1999. In February, 2000 Islet Sheet Medical began studies to demonstrate safety and efficacy in curing diabetes in large animal models. We have established an experimental protocol for a well-designed canine study of juvenile diabetes that is intended to prove that the device has cured the disease.
Large mammal studies needed to justify animal studies are not extensive. First, type 1 diabetes research posses an excellent surrogate endpoint: we are certain the good blood sugar prevent the vascular problems that actually harm diabetics. Thus euglycemia without risk of low blood sugar and without immunosuppresive drugs is a cure for diabetes. Second, the sheet, unlike competitive products, can be easily removed. Thus the safety of the Islet Sheet is outstanding.
For our President's views views on the research environment in which Islet Sheet Medical finds itself, click here.
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