Islet Cell Regeneration and the gene INGAP, Part 5

Date: July 19, 2000 9:00 PM EDT
Moderator: Melissa Davis
Subject: Islet Cell Regeneration Update, Part V
Guest: Dr. Aaron I. Vinik, Director of Research, Strelitz Diabetes Institutes

Moderator:
Welcome everyone! Tonight we are very excited to welcome Dr. Aaron I. Vinik, Director of the Strelitz Diabetes Research Institute and Professor of Medicine at Eastern Virginia Medical School.

Dr. Vinik can you start by telling us about INGAP and any of the latest advances that you can share with us?

Dr. Vinik:
I would love to tell you about INGAP and some of the advances that have been made. When last we chatted, we had made recombinant INGAP as the entire protein in hamster tumor cells and used the whole protein in treating hamsters made diabetic with the drug streptozotocin. We were able to reduce blood glucose by 35 milligrams per deciliter for every log dose increment in INGAP concentration.

This was shown to occur in those animals that had new islets formed in their pancreases that were capable of making insulin. Thus we were excited that we had indeed cure a proportion of the animals with diabetes.

It turns out that there is another way to look at his. The FDA accepts any agent that is capable of lowering blood glucose by 35 mg/dl that translates to 1% HBA1c lowering as a potential treatment for diabetes. So we are doubly excited. There is a lot more to say, but I would like to see if I can field your questions.

Century:
I would like a perfect cure free of immunosuppressive drugs.

Dr. Vinik:
I think that an insulin free world without the use of immunosuppressive agents is Nirvana. The major difference between our approach and that of the islet transplanters or pancreas transplanters is that giving islets that are foreign will always require immunosuppressives, whereas our approach to stimulate the formation of new islets from one's own tissues is not accompanied by the need for immunosuppression necessarily since the islets may be recognized as self.

JR:
I believe that my daughter is still honeymooning. Would this be a time to wake up those cells before they're gone forever?

Dr. Vinik:
The window of opportunity for stimulating islet cell regeneration occurs at all stages of diabetes and is not necessarily confined to the honeymoon period. The cells that are the precursors (stem cells) survive the assault of autoimmune destruction of islets and appear to reside in the pancreas outside of the islet. Thus, do not fret when the therapy is ready for human consumption the opportunity will survive the honeymoon.

Pam:
Dr. Vinik, can you tell us about the islet cell regeneration, how it works, if it is for all types of diabetes type 1 and 2, and what age has this been done on thus far.

Dr. Vinik:
We think that islet regeneration will work for both type 1 and type 2 diabetes. Just as we know that agents that stimulate insulin secretion are effective in treating type 2 diabetes, we anticipate that if we can overcome the deficit in pancreatic insulin secretion, a must for the development of diabetes even in Type 2, then we will cure people with type 2 as well as type 1.

Marcia:
But if the person has islet cell antibodies and destroyed their own islet cells in the fist place, wouldn't they just do it again? Can you turn that process off?

Dr. Vinik:
INGAP will work even in the presence of islet or humeral antibodies. We have put that to the test in animal models of immune-mediated islet destruction, and it appears to be effective. The situation in humans may, of course, be different, but there is always hope with a number of possible situations. For example, many people with type 1 diabetes have antibodies in their blood at the onset of the disease, but this peters out so that after 10-15 years, only 5% have antibodies. We could use this late window for treatment with INGAP. We have also just learned from the Alberta people that there may be better forms of immunosuppression than we have had before, and this we consider a boon to our prospective program even for those who have an active ongoing immune process. We also think that the initial environmental trigger of the immune response may no longer be operative when it is time for INGAP treatment.

Sandy Donchess:
Dr. Vinik, I have been given an analogy for the INGAP/Iloptropin research: As long as INGAP/Ilotropin is given, the "bucket" of islets can be maintained. The islets will secrete insulin and C-peptide. However, in Type 1, autoimmunity is the "leak" in the bucket that kills/drains the bucket of islets. Would you say that this is a good analogy? If, indeed, autoimmunity in Type 1 continues to kill islets, how often and how would INGAP/Iloptropin need to be given?

Dr. Vinik:
I love the hole in the bucket analogy. My point has always been that one can fill a bucket if there is no hole in it. But, even if there is a hole, as long as one regenerated faster than the destruction, as it pours water into the bucket at a rate faster than there is a leak, the bucket will fill. The interesting thing is that one needs only about 2% of the total islet mass to be free of diabetes. Say we were to stimulate the formation of a reserve mass, that would be equivalent to plugging the hole in part. We could always go back to the well if necessary.

The process of new islet formation occurs from two sources, one is the pancreatic ductal system and the other one is the islets themselves. Islets account for less than 12% of the pancreatic capacity to regenerate and the ductal, or closely related cell the remainder. Even if the beta cell has taken a beating from the destructive forces, the stem cell, seems to escape. We really do want to target this cell rather than the failing islets.

Tim:
Dr. Vinik, I compare INGAP to Entremed's Angiostatin in terms of importance. Despite inconclusive results, NIH is rushing the Entremed product to human testing; only a year after achieving results similar to yours in mice. How receptive is NIH to doing a CRADA?

Thanks for your work.

Dr. Vinik:
The Enteremed analogy with Angiostatin may not be too far removed from what we are doing. Both operate as trophic factors targeting different cells. If we enjoy the same success in our animal studies, then hopefully we will receive the same accelerated consideration.

Babs:
Dr. V, you speak of your "prospective program." What stage have you reached in your research and when do you project your program to be available to the general population?

Dr. Vinik:
The next steps have in part been taken in some measures. For example, we wanted to know if we could achieve higher rates of cure. We were able to do this and increase the number from 30-40% to 75% simply be increasing the dose. We also wanted to know if INGAP would work in other animal models especially those with evidence of immune-mediated destruction. We now know this to be the case. We now would like to know what the best route of administration is and have designed such experiments. We would like to give huge excesses to be sure that there are no toxic or harmful effects. We have thus far not encountered any nor have we found that INGAP targets any other tissue apart from the pancreas.

Rebecca:
Dr. Vinik, do you work closely with the Alberta people (Edmonton Protocol)?

Dr. Vinik:
Strange as it may seem, the Alberta people are the ones who have just completed some of our animal studies in mice that develop an autoimmune form of diabetes when given the drug Streptozotocin. They and Dr. Rosenberg at McGill University have treated NODs with success as well, but these latter findings need to be made more robust with respect to numbers of animals and other variables.

Sandy Donchess:
Dr. Vinik, what other animals, other than hamsters, have been tested?

Dr. Vinik:
We are negotiating scaling up as we speak. We have found several parties that have the capability, but we need to be sure that the quality of the material is Global Medical Product's grade and that we don't lose any potency in the scale up process. We have unfortunately seen this happen with others trying this in the peptide sphere (not INGAP), and we will have to do some rigorous testing.

Bertie:
Dr. Vinik, how do you give (or cause) your lab animals immune mediated diabetes? What do you test for to determine their insulin production?

Dr. Vinik:
To establish that we have been able to induce beta cell production of insulin, we measure the islet insulin content and also the circulating insulin level. To show that there is recovery in someone who has taken insulin for years and may have antibodies to the insulin that would obscure its measurement, we can always measure C peptide a fragment of the insulin precursor not bound by antibodies to insulin.

Sandy Donchess:
Sorry for asking so many questions, but I'm a "Curious George" person…how often do your research animals have to be given INGAP/Iloptropin? Do you have an estimate on how often humans with Type 1 would need it?

Dr. Vinik:
It is premature for me to say how often we would have to dose people. We are able to induce a doubling to quadrupling of the islet number. If this is enough to alleviate the diabetes and there is no further destruction, it may be all you will need. In the Streptozotocin induced diabetic animals we have not had to retreat once the diabetes has been "cured."

Moderator:
Dr. Vinik, can I ask you about funding? How are you funded? If someone would like to donate, how would they do so?

Dr. Vinik:
You could search our website at the Strelitz Diabetes Research Institute. If you are considering supporting the effort then you would want to contact our Diabetes Institutes Foundation "Please See How You Can Help" page. We do get funding from different avenues for the work, but there are several components to the work. For example, with DIF funding we are actively trying to discover if there are ways and means of inducing the body to make its own INGAP. We are also actively trying to find the receptor which is like trying to find the lock into which the INGAP key will fit. These questions may become very important down the road as we unravel the INGAP status of people with diabetes.

Sandy Donchess:
Dr. Vinik, do you consider the STZ animals that have been used in INGAP research to be good models for human Type 1? Why or why not?

Dr. Vinik:
Sandy, I think the STZ model is excellent for studying the effects of INGAP on diabetes. Say, for example, we had chosen an animal model that had an active ongoing furious islet destruction process instead of the limited and predictive one that occurs with different carefully determined doses of INGAP, then we may never have recognized its potential for induction of beta cell growth. Now that we know that it can do this, we can address the issue of ensuring that these new islets are adequately protected from any further destruction.

Moderator:
Thank you again Dr. Vinik for joining us! Our hour is up but I would love to have you back again soon!

Dr. Vinik:
It has once again been a pleasure and thank you Melissa for inviting me. I detect that you are sensing the problem with regard to the Edmonton approach, and that is there may not be enough pancreases to go around to do more than say 1000 or so transplants, a mere drop in the bucket to use another analogy. What may turn out to be vitally important is to combine approaches, and we look forward to seeing more of this in the future. Take care, AIV.