Islet Cell Regeneration and the gene INGAP, Part 4

Date: April 6, 2000
Moderator: Melissa Davis or www.diabetesstation.org
Subject: Islet Cell Regeneration Research, Part IV

Melissa
Hello Dr. Vinik and welcome once again to my chat! I am so pleased that you could come tonight! Thank you!

Jerry
Look at all the people!!!! I hope there are enough seats.

Melissa
Dr. Vinik, I hear that you have been very busy since the last time we spoke! Can you update us on what you have been working?

Dr. Aaron I.Vinik
We have been very busy since our last chat. To update you on all would be quite a mouthful. I'm happy to answer any questions that you might have.

Steve
Dr. Vinik, can you give us a paragraph or so update on where your research stands and what it hopes to accomplish?

Jerry
Are you still working with McGill University in Montreal?

Dr. Vinik
We are still working with McGill University in Montreal. Also, if islet cell regeneration works, and we get to reverse diabetes before the complications set in, it is likely that we will prevent them from developing. Whether or not we will be able to reverse established complications is another matter.

Amy Jo
What are the main differences between regeneration versus transplantation? Why regeneration, and how does it work?

Dr. Vinik
The main difference between regeneration and transplantation is that regeneration allows one to regrow islets from your own precursor cells that are not foreign to the individual thus obviating the need for immunosuppressive therapy.

Jerry
When this works Dr. Vinik, what will determine the perfect candidate to try the procedure on? Will you have to try non-human primates first?

Dr. Vinik
We did that and hope to be able to tell you that we have now been able to give INGAP to normal animals and have induced the growth and development of adult islets capable to making the whole entourage of hormones needed for normal homeostasis. We have also recruited a new faculty members who is an expert at drug development to assist in the promotion of INGAP as a form of therapy.

The perfect candidate for INGAP therapy will need to be established. We believe that most people with diabetes, whether it is Type 1 or Type 2 or any of the secondary types will be candidates since, in all instances, there appears to be a deficiency of insulin.

Jerry
For those who are not familiar with INGAP - the INGAP gene stimulates regeneration and growth of insulin secreting islet cells from immature stem cells that survive the assault of diabetes. The INGAP technology overcomes these weaknesses by generating new cells recognized by the body as its own.

Dr. Vinik
I think a concern that one might not have the precursor cells has been answered. We have been fortunate to obtain pancreatic specimens from people who have had diabetes for close to 75 years and found INGAP to be present in cells associated with neogenesis. INGAP, it seems, acts up on these cells, even in long-standing diabetes in adults and stimulates them to transform into hormone producing cells.

Amy Jo
Sounds much better than transplantation, I'm sure you will agree.

Dr. Vinik
Does sound a whole lot better than transplantation. We have not found reoccurrence of diabetes in the models we are studying. We are also in the midst of experiments to see if relapses and remissions occur in models of Type 1 diabetes when the remission has been induced in animals that have an active ongoing auto-immunity.

Peggy
Does duration of the disease affect the cell regeneration? If complications have already begun, will this regeneration stop it?

Dr. Vinik
Duration of disease does not seem to matter. The reason appears to be that the assault on the pancreas is directed at the beta cell that makes insulin. The other hormonal cells such as those that make glucagon escape the attention of the antibodies and other destructive forces. Similarly, the precursor cells seem to be immune to the attack of self-destruction and appear to persist indefinitely. With regard to children and INGAP, we have done studies on neonatal pancreases and found INGAP to be expressed.

Jerry
So the possibility of the antibodies also sitting in the body is present? Even if that is true, it would seem to be but an inconvenience given this development.

Dr. Vinik
Antibodies may attack the newly formed islets, but as long as we can induce a rate of growth that exceeds the rate of destruction, then we should be okay. It's a little like trying to fill a bucket with holes in it. As long as you pour the water in fast enough, faster than it is draining through the hole, you will be able to fill it.

We are also exploring the ability to enhance regrowth of islets by using INGAP in combination with immunotherapy. Those experiments have only begun so it is premature for me to tell you how they are working out.

Amy Jo
What hinders these precursors from maturing into insulin making cells? In a healthy person, are beta cells regenerated all the time or are they like heart and brain cells that do not regenerate?

Dr. Vinik
Amy Jo, I love that question. I would like to tell you that all of diabetes will turn out to be due to a deficiency of INGAP and that the precursor cells are hindered from maturing because they do not have an adequate supply of INGAP, but I do not know this at this point in time. I do know from all the tissues we have studied so far that whenever one sees normal neogenesis, INGAP is there. When islets cease to grow, INGAP disappears - so it may be the clue. There are other parallels in nature that we could talk about.

Amy Jo
I love that answer. I'm still a little behind though. What exactly is INGAP?

Jerry
INGAP is the gene discovered by the research team at the Strelitz Diabetes Institutes, Eastern Virginia Medical School, under the direction of Dr. Vinik. Although INGAP sounds like a new pair of jeans, its name, Islet Neogenesis Associated Protein, actually implies regeneration and growth of islet cells stimulated by a protein.

Contrary to the current view that pancreas and islet transplantation will eventually succeed as the cure for diabetes, it is Dr. Vinik's belief that the cure for diabetes lies in finding a way to provide patients with the ability to generate new insulin-secreting cells from their own pancreatic cells. The INGAP gene stimulates regeneration and growth of insulin secreting islet cells from immature stem cells that survive the assault of diabetes.

Amy Jo
So, we just need to fill our pumps with INGAP!

Dr. Vinik
Maybe you could fill your pumps with INGAP or just use it once or twice! I hope it will be simpler than continuous use of a pump for delivery.

Tsmb
Hi Dr. Vinik!
What about "turning off" the regeneration process after the desirable amount of islets have been produced? Have you learned anything as to how this might be addressed?

Dr. Vinik
Nature seems to have provided us with a natural restraining mechanism. There is a clear balance between islet neogenesis and islet apoptosis, or the programmed cell death of islets, so that when islets reach a critical mass, a natural feedback mechanism comes into operation that restricts further growth. This has been one of the major distinguishing features between our work and that of others who have tried to engineer tumor cells to produce insulin and have then had to deal with unbridled growth and the reversion to their former state.

Dr. Vinik
Thanks Jerry, that says it very nicely.

Amy Jo
So it (INGAP) is the protein!

Dr. Vinik
Amy Jo, we have identified the protein that INGAP encodes for and have fully characterized it. We have also expressed the INGAP gene in a variety of different cell lines and have produced recombinant INGAP. We have completed a study with the recombinant INGAP and obtained reversal of diabetes in almost as many animals as we did with the original Ilotropin. We have now found that a peptide fragment of INGAP is fully capable of achieving all the effects of the whole protein if given in the right amounts. This means that we will likely be able to synthesize it in the laboratory for therapeutic purposes.

Melissa
How do you deliver INGAP? Is it just a large shot?

Dr. Vinik
To deliver INGAP, we have thus far only tried giving it as daily shots for a few weeks. We do not yet know how many shots will be necessary or how often, but that will come.

Melissa
Do you have an idea when you'll start clinical trials or is that still unknown?

Dr. Vinik
Melissa, our new partners are going to facilitate making this a reality sooner than we could have expected before.

Melissa
Is that right?! WOW!! How wonderful! Tell us about your new partners! You just announced it last month, right?

Dr. Vinik
Our new partners were signed on Valentine's Day 2000. They are Global Medical Products Companies, Inc. (GMP) based in Fort Lauderdale, Florida. The company has on board some of the smartest people you could ever ask to meet and a whole range of technology know-how that should telescope our activity into a period far shorter than we ever could have hoped for before.

Jill
Dr. Vinik, if trials are a success, how many years are we looking at until this cure is available to every Type 1?

Dr. Vinik
We still have a number of hurdles to go before we will begin trials.

Tmsb
What are the hurdles that must be cleared?

Dr. Vinik
Firstly, this type of research takes resources and financing. GMP has been more than generous in providing research grants to allow the work to proceed at a much more rapid rate. We had the experience a couple of years back when we were floundering with the original crude extract of Ilotropin and were progressing inordinately slowly in trying to find the active ingredient. Thanks to a significant injection of financial support from the Diabetes Institutes Foundation, we were able to upgrade the work and develop new techniques for going after the gene and thence to the protein. This whole process took us a mere two years, and we had been working on Ilotropin since 1983!! Having this sort of resource does help out a whole lot.

Melissa
Financing always seems to be the key!

Andrea
Dr. Vinik do you think there will be a cure of some sort in the next 5 years, 10 years, 20 years? Will any of them be affordable before a 50 plus year period. Will they only be for the rich and famous?

Dr. Vinik
I am the eternal optimist and hope to see a cure in my lifetime. I am also sensitive to the issue that if this transpires, it should be available to all the appropriate people.

Ruth
Thank you from the bottom of our hearts. We hope to fill your bucket (with the holes in) with support faster than hope can be diminished.

Mimi
Thank you, Dr. Vinik, for your time tonight and for your work on our behalf!

Dr. Vinik
Take care and thanks for having me again. Night all.

Melissa
Thanks again for your time Dr. Vinik! We hope to see you again soon!