One of the pleasures of writing for the Solving Diabetes Project is I get feedback on the thoughts of a group of interested diabetics in the world. It lets me know what is less than clear on our web sites. I recently received the following questions from MK:
Will the Islet Sheet be a cure for all diabetics?
We expect it will help everyone who requires insulin injections. This includes everyone with type 1 diabetes and many with type 2 diabetes. We use “functional cure” instead of “cure” to signal that you are dependent on this implanted thin sheet device to manage your diabetes. Sort of like a bioartificial heart valve replacement — its is not your own heart valve but it is safe and effective.
The Sheet will change management of diabetes from frequent BG measurements and injections to occasional (weekly?) assessment of sheet function. And the quality of blood glucose control should be much better.
Will the encapsulation protect the islets in type2?
It will work as well in type 2 diabetes as in type 1 diabetes because the immunological situation is similar. There is a difference in physiology in that the typical type 2 diabetic usually requires more insulin — sometimes much more — that normal type 1 diabetics. Thus a type 2 diabetic that needs .6 U/kg insulin will be treated as easily as a type 1 diabetic. A type 2 diabetic with a really large insulin need would be more difficult because of the large number of sheets needed to produce that much insulin. For these patients the Islet Sheet would be combined with interventions to get the insulin need down.
Will it cost $10,000 ?
Eventually it might be that low, when islets become cheap. It will be expensive in the short term for two reasons. First, tens of millions of dollars of capital will be required to bring this to market and investors will be repaid with initial profits (which is the case with almost all medical products). Second, the cost of islets will be high initially. Initially primary human islets will be used, which cost something like $40,000. Pigs islets will be less expensive. Eventually islets from human stem cells ought to be much cheaper but that will take many years.
Will it be a real cure or only restore the hypoglycemic awareness like the LCT product? If the funding is enough when can patients have it if it works? 5years?
LCT has already established that at a dose of 10,000 islets per kg their microencapsulated neonatal pig islets restores hypoglycemia awareness. I think that their product is medically justified for type 1 diabetics at risk because of hypoglycemia unawareness. Our goal with the Islet Sheet is to replicate LCT’s accomplishment in restoring hypoglycemia unawareness and go beyond to elimination of the need for insulin injections. This is a considerably more challenging goal. But it would justify therapy for essentially all type 1 diabetics if it is a safe as we project.
Funding of the Solving Diabetes Project is adequate so far. We anticipate our needs will go up within a few weeks. Preliminary metabolic studies are going well in rodents and we are planning the more expensive studies in large mammals. Assuming that funding remains adequate, a product is possible in five years. That time frame requires we have no major obstacles to overcome. Over the past two years we overcame a major obstacle that probably cost about a year. So we will need to be lucky.
But the main problem is the lack of islets. There are not enough for all patients. So for a real cure we must wait until doctors can proliferate islets in vitro or? (which companies/doctors make this research?)
There is no fundamental reason islets can never become abundant and reasonably priced. Initially insulin was very hard to make and limited in supply. Over time better methods were developed. The same thing is likely for technology to mass manufacture islets. Once we have the Islet Sheet perfected and proven our group intends to move into islet manufacture research.
I agree that porcine islets are a stopgap for a few years. I am concerned that the stem cell community has over-promised and their islets may take many years to be proven safe and effective. Most stem cell research efforts — including the California Institute for Regenerative Medicine — have targeted islet cells. We can only root for their rapid success.
Do you think smartinsulin will work?
I analyzed the prospects for Smart Insulin in an April column. The data the inventors have presented are not good enough. They say they have animal studies but I have been unable to find them. I have asked the company for more information without response. Unless they produce more information I must conclude that Smart Insulin will not contribute much to diabetes care.
And what do you think about CureDM and Exsulin?
CureDM is developing a peptide for islet regeneration. This is a promising approach and many research groups and companies have candidates. Their paper shows improvement in diabetic mice. This approach requires that the therapy do two challenging things: (1) stimulate islet regeneration and (2) greatly reduce islet autoimmunity. I hope CureMD makes progress.
Exsulin has similar goals using a peptide discovered many years ago called INGAP. They have refined it into the form named Exsulin and are in clinical studies. INGAP has a long history. I know some of the people and wish them the best in clinical studies.
Regeneration is a promising approach. The compounds appear to have low toxicity, so clinical trials are justified. I remain skeptical because of the autoimmune component of T1D. I hope I am proven wrong!
Do you think Diabecell/pig-islets could be a real cure for all
diabetics?
LCT is putting enough encapsulated islets into their patients, so the potential for a ‘real cure’ (I would call it a functional cure) is there. They have established safety and efficacy, but the efficacy is elimination of hypoglycemia unawareness, not euglycemia. They probably need improvements to their encapsulation system to get more insulin out of each islet.
Thank you MK for your questions and interest in our research.
I am not sure why you are considering using the miniscule amount of human cadaver pancreatic islets for your grafts. LCT has not cornered the market on germ-free pigs, and other providers, such as the Spring Point Project at South Dakota State University, would I hope be willing to contract with you to supply an adequate number of porcine islets.
It has been known for a long time that any increase to the surviving beta cell mass in diabetics helps with blood sugar control, so even a gradually dying encapsulated mass of porcine beta cells should be useful in blood glucose management. (S. Madobad, “Prevalence of Residual B Cell Function and Its Metabolic Consequences,” Diabetologia, vol. 24, p. 141 (1983)) Avoidance of hypoglycemic episodes might prove more difficult to achieve than the partial normalization of glucose levels would be, however, since some evidence suggests that it may be over-activity of the renin-angiotensin system in diabetics which plays a major role in causing the severe hypoglycemia of type 1 diabetes. (P. Kristensen, et al, “Vascular Endothilial Growth Factors During Hypoglycemia,” Metabolism, vol. 58, no. 10, p. 1430 (2009))
A major concern with the whole islet encapsulation approach is whether pancreatic islets can, in principle, function well and survive long following the stress of their isolation from the pancreas. Do they need to remain anchored in the pancreatic matrix to operate as they should? If so, then since there is no way to render an entire pancreas immunologically invisible inside an encapsulation, we are back to immunosuppressive drugs, which produce more damage than uncontrolled diabetes and so are therapeutically counter-productive. The relatively successful experience with whole pancreas transplants in contrast to the disappointing results with human islet cell transplants suggests that we isolate the beta cells at our peril. (R. Wang and L. Rosenberg, “Maintenance of Beta-Cell Function and Survival Following Islet Isolation,” Journal of Endocrinology, vol. 163, p. 181 (1999))
JP–
We will start with primary human (cadaver) islets for three reasons. First, Jon Lakey is setting up a human transplant program at UCI so such islets will be available there. Second, we will want to compare the Islet Sheet performance with the prevailing islet transplantation standard and different islets behave differently (for example, LCT’s neonatal islet take weeks to reach full function; primary human islets hours). Finally, and most important from the perspective of my for-profit company Cerco Medical, the FDA has approved clinical use of primary human islets, so we need only convince FDA that the sheet (not the islets inside) is safe. So the fastest route to clinical results is paved with human islets.