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The Crucial Year for Islet Sheet is 2011
January 3rd, 2011
This is the year we will find out if the Islet Sheet works well enough to justify clinical trials.
How do I know that? First, my colleagues at Islet Sheet Medical have succeeded in inventing valuable medical technologies, so we know what success looks and feels like. Second, we are starting to get encouraging results from the diabetic rat studies. Third, we are experiencing growing interest in our work from parties attuned to changes in the zeitgeist. Finally, soon we will begin studies in diabetic large animals. And when done right they will be definitive.
The large animals studies will be done right because we are working with the best people. We bet on Prof. Jonathan Lakey, and he is building up his group at UC Irvine. Hiring the right people, training them, building experience in methods that require practical repition to work consistently, and acquiring and breaking in the equipment takes time. Jon came from the University of Alberta which has decades of leadership in islet transplantation research. He is reproducing many of the capabilities he grew up with and taking the opportunity to improve them. He expects to start UCI’s clinical islet transplant program this year.
We have learned many things from the diabetic rats (see previous report). We have also been frustrated by the difficulties and limits of the model. But at relatively minor cost we have learned about islet dosing in Islet Sheets, potential implantation sites, and stability of various Islet Sheet fabrication methods in several rat sites. We are ready to both extend rat studies and move on to another model.
The definitive experimental model is large animals (pig, dog, monkey) made diabetic with total removal of the pancreas. The rat is too small to study an Islet Sheet useful in a human. Instead we use a specially reduced rat-sized Islet Sheet. But a large animal can easily accommodate the 5 centimeter square human islet sheet.
Perhaps the most important difference between a rat and a large mammal is the metabolism. We who manage diabetes with insulin are aware that insulin causes glucose to drop in the blood. Insulin does this by causing tissues (especially muscles) to absorb glucose suger as long as insulin remains in the blood. We are less aware the glucose itself causes glucose to drop. In fact, in a human about half of glucose drop is caused by insulin — and half by glucose. In rodents almost all the insulin drop is caused by glucose. In rodents insulin does not directly control blood sugar.
So rodent studies are not helpful in understanding how well the islets are delivering insulin. Large animal studies are. In fact, most of what we know about how islets and insulin work come from studies in a certain large animal, the dog. That the pancreas is the source of the “anti-diabetes hormone” was discovered in 1889 when dogs who had had their pancreas removed were discovered to be diabetic. The identity of the hormone was not known for decades, and when found was named insulin. Dogs have continued to be essential in experiments to analyze metabolism and diabetes physiology.
In all other matters of importance to the Islet Sheet function, large animals, expecially dogs, are simlar to humans. Surgical aspects are similar, including the size and location of the pancreas. The immune system of the dog is similar to human, especially in the critically important foreign body reaction. Dog hormones can be measured easily, and the potency of dog insulin is essentially the same as human insulin.
Even statistically, dogs are like humans. That is, only a few diabetic dogs are needed to prove that a therapy is working. The reason is, like human autoimmune diabetes, spontaneous remission of disease is rare. So a few dogs – say 6 to 12 – is enough.
At the moment the Hanuman Medical Foundation is providing the funds we need, but now that we are on the verge of large animal studies expenses will start going up fast.
So this is the year we will find out if the Islet Sheet works well enough to justify clinical trials. Then we target clinical trials. This is the year that will let me predict when clinical trials can begin, and therefore when the Islet Sheet might be realistically available. Up to now the future has been a guess limited by resources and the vagaries of new technologies invention.
I hope the Islet Sheet is available soon. These things take time — there are many rules, there is FDA approval, it is expensive, and the funding challenges are very big. But I have been at this a long time — since 1980 — we’ll get there, if there can be gotten to!
It’s hard not to feel optimistic! Best of luck and a happy new year to all of you.
I wish you the best for this. You look to me like a very compassionate person let alone your deep knowledge about T1D. I will keep my optimism and finger cross so my daughter can have a cure one day
I am concerned about the negative implications for your own work arising from recent discouraging hints emerging from LCT’s islet implantations, which are similar though not identical to your own device, which seems to provide superior oxygen supply within the capsule. After finding that its own encapsulation of increasing numbers of porcine islets in differentially permeable membranes was not able either to produce a graft which could survive for very long or to control blood sugar very well in diabetics, LCT then suddenly announced that it was going to try implanting smaller, not larger, amounts of islets in what appeared to be a switch from trying to achieve independence from injected insulin to doing nothing more than helping the tiny subset of patients with hypoglycemic unawareness to overcome this coenaesthesis deficit.
Since proprietary secrets keep us from knowing exactly what is going on with LCT, I wonder whether they have found that increasing the number of islets to the point where they could theoretically control blood sugar levels in a human diabetic causes such a rapid loss of function in the islets through the ‘smothering’ effects of too many uncleared and toxic metabolic by-products getting stuck inside the capsules that insulin independence can in principle never be achieved by this or any analogous method. The decline in the rate of population growth of bacteria by self-intoxication through uncleared metabolic by-products is well-known, and eventually this can lead to a decline in population size, so if current membrane technology is causing the same sort of thing to occur with encapsulated islets so that they can never be provided in sufficient number for clinical success, then this is quite discouraging. Whether paying $150,000 every two years to re-implant a cluster of islets which have to be so limited in number that they can do nothing more than overcome hyperglycemic unawareness would ever be sufficiently attractive to enough patients to sustain an islet-implantation company seem doubtful.
JP, I think the ‘smothering’ concept is pretty unlikely to explain their decision because the capsules tend to spread through the entire peritoneal cavity, which is huge compared with the volume of the capsules. On the other hand, they have published micrographs showing capsules clustered like caviar. Until they publish more it is impossible to know.