Islet Cell Regeneration and the gene INGAP, Part 3
Date: April 15, 1999
Melissa Davis, moderator
Subject: Islet Cell Regeneration and INGAP, Part III
Guest: Dr. Aaron I. Vinik, Research Director, Strelitz Diabetes Institutes,
Easter Virginia Medical School
Melissa Davis
Good evening Dr. Vinik. Glad you could come. Thanks for talking with us.
Sandy Donchess
Hi, Dr. Vinik. I'm glad you're doing this forum. I have more questions.
Wanda
Good evening Dr. Vinik. This is also my first forum I have been to on the web.
Aaron Vinik
Hi everyone, I am pleased to be back, and thanks to Melissa for inviting me. Happy to tackle any questions you might have.
Darlene
Hello Dr. Vinik. Thank you so much for coming to talk to us again. We really appreciate these chances to talk to you about your research.
Jen
Good evening Dr. Vinik. Thank you so much for the opportunity for us to learn more about INGAP. INGAP seems to be very promising. Have there been any new developments since your last forum? Are you still doing research in your own lab on INGAP?
Aaron Vinik
Jen, thanks for asking about INGAP. There certainly have been a whole lot of developments since our last chat.
Yes, we are continuing to do research in our own lab, and we are collaborating with a number of centers worldwide in our efforts to further our knowledge on INGAP and its potential.
Jen
Our 3 yr. old was diagnosed at 15 mos., and we're just now getting leveled out and on some sort of track. So forgive me my ignorance, but could you give us a short review of what you are doing.
Aaron Vinik
A short summary of what INGAP is all about: During the process of studying the ability of the pancreas to regenerate new beta cells that make insulin, we discovered a gene that was uniquely expressed only when the pancreas was stimulated to undergo regeneration of its beta cells from primitive stem cells that survive the assault of diabetes. These precursor cells seem to be resistant to the effects of autoimmune destruction that occurs in Type 1 diabetes and can be induced to differentiate into adult beta cells capable of producing insulin in a finely regulated manner, much like with those that occur during normal development. We have embraced this capability by seeking out the gene associated with the phenomenon and are seeking to employ it or its products in a cure for certain forms of diabetes.
Sandy Donchess
I'm intrigued about INGAP and want to know more. I have so many questions. Has your success rate gone up from the original percentage you first reported? Also, are you working with the Doctors in South Africa directly, or are they working off your papers?
Aaron Vinik
We are actively collaborating with scientists in South Africa, among others. Downunder they see many patients with chronic pancreatitis--a condition in which there is inflammation of the pancreas, and in many instances the pancreas appears to defend itself, thereby preventing the development of diabetes. We obtained a number of these human pancreases from our colleagues in South Africa, and low and behold, in the human pancreas, INGAP is expressed whenever the pancreas has successfully undergone islet neogenesis. Yes, INGAP appears in the human pancreas whenever regeneration occurs.
R.A. Harrison
Tacking onto Sandy's query, what animals has INGAP been tested on successfully? Is it just hamsters and mice, or have there been any large animal studies, including dogs and non-human primates? The South African stuff is interesting, but I presume the pancreases weren't attached to live human beings?
Jen
Am I right in my understanding that INGAP is being produced in the pancreas of persons with type I, only not in enough volume to overcome the diabetes?
Steve Santen
Has there been consultation/collaboration with the other companies involved in this area of research? Namely Ontogeny, Organogensis, and Ixion Biotechnology.
Aaron Vinik
Yes, there has been consultation with other companies, and the good news is that others are trying to produce INGAP by a variety of means. There has also been collaboration with the NIH, scientists in Finland, Argentina, Belgium and Canada amongst others. Much of this work will be presented at the National meetings of the American Diabetes Association in San Diego this June.
Ken C
Dr. Vinik, we will look forward to the June ADA conference. To re-iterate Joan's query - after all, that is the key. Is there a human trial on the horizon?
R.A. Harrison
Seconding Ken C's anticipation of the ADA presentation(s).
Ken C
Dr. Vinik, is the administering of INGAP contingent on the time since onset? i.e. must it be administered shortly after? Or can it be used after someone has had diabetes for years?
Sandy Donchess
Dr. Vinik, you said in a prior forum here that INGAP administration has cured 30 - 40% of hamsters/mice. Have you seen that percentage increase? How often is INGAP given? Is it given via injection, I.V.?
Joe F
What antibody to INGAP was tested to prevent its working? Was it a chemical or part of the bodies immune system?
Aaron Vinik
We have not yet administered INGAP to humans. When we saw that there was only a 30-40% response, we went back to the drawing board and re-examined the doses we had used in these first experiments. We then arbitrarily gave much larger doses to normal animals and now the response was almost universal--there was an approximated doubling of the normal islet number (60 - 80%)! Once the islets have been recreated, it seems that we will not have to continue giving INGAP if there is no attempt on the body's part to destroy our good work. If, however, the destructive process is still active at the time of treatment, then we would, in all likelihood, have to give repeated doses. We are doing these experiments in animal models of chronic active destruction of the pancreas.
Jen
This sounds too good to be true! But of course, I believe in miracles.
So, you are seeing up to an 80% success rate.
Ken C
Dr. Vinik, have you identified any side effects to INGAP? Is there any toxicity?
Leann
Of the 30-40%, has there been any destruction to date of the cells and how long has that been?
Sandy Donchess
Dr. Vinik, what kinds of animals are you working on? Large ones such as dogs and non-human primates? Also (and please forgive my ignorance), how will a Type 1's autoimmune process affect all of this? Seems like I'd need more and more INGAP to keep up with and out run my body's autoimmune destruction of my islets. Am I wrong here?
Melissa
Wow! That sounds like it's got a better response rate in the animals! Would human trials be next?
Aaron Vinik
Will INGAP be of use when the diabetes is well established? Yes. That is the important aspect of knowing that there are cells that are preserved even when the pancreas has been ravaged by autoimmune destruction. When one examines the pancreas of a patient with long-standing Type 1 diabetes, all the beta cells are destroyed and only < 2% remain. What does remain is a cell, that when appropriately stimulated by INGAP, will differentiate into an adult beta cell that makes insulin. So even when the diabetes has been present for a long time, there is still the possibility that the pancreatic beta cells can be regenerated.
Ken C
Thanks, Dr. V.
R.A. Harrison
What sort of "normal animals"? Hamsters, mice, dogs, non-human primates?
Aaron Vinik
The only studies we have done so far in large animals are in baboons where we have examined the expression of INGAP during normal development. Interestingly, INGAP is found at roughly gestational age 100 days at a time when the pancreas is developing from its precursors. This is in parallel with our studies in collaboration with a Swedish scientist in mice in which the expression of INGAP occurs at the exact time when the pancreas is beginning to form.
Jen
I was curious about that as well. For those that have type 1 for shorter time periods, it would seem the islet antibodies would still be kicking their heels in. Is there a different mode of treatment for newly diagnosed, versus those that have type 1 longer, due to the islet cell antibodies?
Aaron Vinik
For those with newly diagnosed diabetes, it is true that they have a higher frequency of antibodies to islets and particularly beta cells. What we have done is to give INGAP to animals that resemble this stage of diabetes, and it seems that as long as we stimulate the formation of islets faster than the body rejects them, then we have amelioration of the diabetes.
Jen
So the more recently diagnosed may require a more intensive therapy of INGAP versus the more established diabetes that is no longer producing antibodies?
R.A. Harrison
So would I be following you correctly in deducing that you have not actually administered INGAP to these creatures, but rather studied the natural expression within the animals? (slightly befuddled)
R.A. Harrison
With all respect to Dr. Vinik, how can it sound too good to be true without knowing even what sort of animal it has been tested on? Bear in mind that lots of mice have been cured of diabetes over the years. People still don't have a cure yet.
Aaron Vinik
It is true that mice are not men for the most part and cure of diabetes does not necessarily translate to curing humans with the condition? The exciting thing for us is that INGAP in humans appears to be remarkably like that in hamsters, and the antibodies that we have made to different portions of the INGAP molecule cross-react very well with INGAP in the HUMAN, MONKEY, CAT, DOG, RABBIT AND A FEW OTHER SPECIES. This is very encouraging and not like the problems thus far encountered with major difference in immune mechanisms for beta cell destruction between humans and other species.
Ken C
Dr. Vinik, to second R. Harrison's question, are you simply running models on the non-human primates and large mammals, or have you administered INGAP to these animals? Any sign of side effects related to INGAP?
Aaron Vinik
We have studied both the expression of INGAP in different species, but have only given it to small animals. We first had to know whether or not it was safe to administer and if there were any side-effects. In pharmacological doses we have seen no harmful effects as yet. The animals do well, thrive on the injections, and every organ that we have examined pathologically, has been free of any inflammation or cell proliferation. The only target appears to be the pancreas.
Sandy Donchess
Dr. Vinik, how often do you have to give a hamster, mouse, etc. INGAP? How is it administered and how often?
Aaron Vinik
It may be that if the process is active, as at the beginning of the diabetes, that we would have to treat more aggressively, more frequently or for longer. These are important questions to be answered.
Ron
All this is very interesting. But will there come a time in my life when I will be cured of diabetes? I'm 42 years old and I have had diabetes for almost 20 years.
Ken C
Dr. Vinik, can I assume that your last post regarding the pathological examination means you have NOT identified any side effects related to INGAP?
Jen
That's wonderful in that your research so far has shown INGAP not to be toxic to other cells which would raise a cancer/tumor concern and that it only affects the beta cells. Do you foresee this as what will be the human response as well?
Aaron Vinik
The antibodies we have used are ones we created in the laboratory. We have not yet found antibodies to INGAP in the human circulation, but have been working on developing an assay which will allow us to do just that. Soon we ought to know if the failure of certain persons to regenerate beta cells, when they need them, is due to the formation of antibodies to INGAP, just as there are antibodies to insulin as in a proportion of patients with Diabetes.
Curt
This is very kind of you to participate. I (we) appreciate it.
My question is, If one’s immune system is stimulated by the presence of beta cells that have grown back due to INGAP injections, would one feel ill continuously?
Aaron Vinik
I wish that I could say with absolute certainty that we will have the cure for both of you and your children and everyone else's children. That is our fervent prayer. There are still many questions to be answered. For example, we so far administered INGAP into the peritoneal cavity in the abdomen. We are now trying to find out the optimum route of administration. For all these years people have had to receive insulin shots and we have come to recognize the differences in rate of absorption from the subcutaneous tissue, muscle and intravenous routes of administration. This is the type of question we are trying to answer.
Ken C
Ron, Sandy - I agree, even though I've only been at it for 18 months. DR V. - is there ANY FORECASTING AT ALL FOR HUMAN TRIALS??????
R.A. Harrison
Sorry to keep hammering away at one point, but what "small animals" have actually received doses of INGAP? Hamsters? It concerns me that people are already anticipating having it available to humans when we both know that if you're only on small rodents presently, it may be awhile yet.
Ken C
Robin - yes, NOD mice are everywhere!
Melissa
How long does it take to go from rodents to humans, especially if the success rate is so good?
Aaron Vinik
We have treated NOD mice and they do well. We even outstrip the rate of destruction. Human trials are not immediately around the corner! We have worked closely with the scientists at Lilly which has allowed us to generate many of these new and exciting findings which have advanced our program far faster than we might have been able to do so working on our own. We are very busily trying to find out what other than wrapping of the pancreas would stimulate your own production of INGAP since that may be a better way to go than to have to give it by repeated injection.
Steve Santen
Dr. Vinik, wouldn't these questions be better answered with spontaneous IDDM autoimmune large animals like dogs, monkeys, etc.?
Jen
While it may be a while down the road, INGAP seems (to me, at least) to be one of the most viable, logical solutions to type 1 that is out there, so far. I'm thankful that Dr. Vinik is being so thorough in his research before putting it out for public use, a lot of researchers haven't been as kind.
Ron
Would you have to take anti-rejection drugs?
Leann
Dr. Vinik, I want to thank you for speaking with us and letting us know that someone is out there actively working for a CURE, and I hope it helps you to know that we are here pulling for you. I must say goodnight now, will read the rest in archive.
Dennis J
Dr. Vinik, with all due respect, "optimum route of administration?" There are people who are literally dying waiting for a cure, and you're telling us that this is one of the things holding up development? Who cares what the "optimum route" is, if it works, it works, regardless of route. Why put things off any longer than they have to be put off? Like Ron said, everyone's been waiting for about 30 years, being told for about 30 years that the cure is "5 years away." If this works (even 30-40%) let's go with it and save some lives!
R.A. Harrison
I think I know that one, Ron. The beauty of islet neogenesis is that it's your own insulin producing islets that your body makes. Sounds wonderful in concept, but Dr. Vinik has got a full plate trying to make it work in actual practice.
R.A. Harrison
Melissa, I hate to be a party-pooper, but a lot more products never make it out of rodent testing than do. I certainly hope that INGAP does, but there would be a full course to follow in the process - first rodents, then dogs or rabbits, non-human primates. If all those steps are successful (and they can take years), then humans.
Aaron Vinik
You are not a party pooper. I know that people have heard for many years that the cure is around the corner. I am telling you where we are now and the questions that have to be addressed before we can go into human trials. You have a perfect example of a major new diabetes drug that was rushed into treatment and "prevention" that is coming under very close scrutiny because of some untoward events. We would like to be secure in knowing that we will do no harm Primum non nocere!
Dorothy
Dennis, you're forgetting the United States is not big on allowing stuff to go out without thorough testing, and if this is "gene therapy" or even smacks of gene therapy, they're going to take their sweet time approving it.
Cheryl
Dr. Vinik, if you have more than 1 auto-immune disease, do you think even more INGAP cells would have to be repeatedly administered? Do you find diabetic's often have more than 1 auto immune disease?
Aaron Vinik
Hopefully the new islets you generate would be recognized as self and you would not have to take anti-rejection drugs. Even then that may still be a blessing compared with what one has to do currently.
Jen
Dr. Vinik, supposing INGAP pans out. Where does the INGAP come from? Will it be from donor cells or chemically engineered much the same way insulin is?
Aaron Vinik
We are going to have to prove that this is entirely safe and if it is going to be gene therapy we enter another arena of controversy. That is why we have done some of the most exciting work with our long-time collaborator at McGill University, Dr. Rosenberg, and have able to show that under very particular conditions, we can take human islets that have undergone a process of apoptosis (Death by suicide) and then added INGAP in the test tube and induced the remaining cells to grow into beta cells. Now this offers the prospect of using INGAP ex vivo and that would obviate many of the questions raised about in vivo therapy.
Joe F
What are your future plans and what milestones do you expect?
Sandy Donchess
Dr. Vinik, I am also sorry to keep on with the same questions. Tonight's forum is full of questions and I know you're working as quickly as you can to answer them. What animals have actually been given INGAP? How is it administered, and how often?
Aaron Vinik
Sandy, you have a lot of questions that seem to be on your mind. Let me see if I can answer some of these to the best of my ability. In the animals we have tested so far, we have given the INGAP by the intraperitoneal route once or twice a day. Originally we thought that you had to give the substance for several weeks before the process was initiated. Now we know that neogenesis occurs within a few hours. We would desperately like to know how little we need to give and for how long by what route. These are some of the questions we are currently working on. Any compound that comes to market as a drug needs to have this evaluated. We worked for 5 years on a drug that was supposed to reverse diabetic neuropathy and then discovered that it did not enter the nerve! We need to be a little more careful than that.
Sandy Donchess
Dr. Vinik, thank you for so far answering many of my questions. I really do appreciate it. The questions are in my mind because my son's welfare is in my mind.
Cheryl
Dr. Vinik, how long do you think before human trials take place, and what kind of other research is going on now at your center?
Sandy Donchess
Cheryl, I have rheumatoid arthritis, also. I understand that many folks with Type 1 have other autoimmune diseases -- thyroid stuff, most commonly. INGAP seems to be a very specific thing to the pancreas/islets.
Aaron Vinik
Yes, diabetes seems to cosegregate with a number of other conditions that are autoimmune. For example, adrenal insufficiency, hypothyroidism, pernicious anemia amongst others. I do not think that the presence of autoimmune destruction of the other tissues will compromise the action of INGAP on the pancreas. Yes, we have tested INGAP on nerve tissues grown in culture, and I regret to tell you that it is not going to be the cure for brain dysfunction.
Rich
Dr. Vinik, HOW CAN ANY OF US HELP?
Dorothy
Yes, is there a place we can donate money that we know will go specifically and totally for THIS TYPE OF RESEARCH?!
Melissa
I'm sure if you visit www.dif.org, the website of the Diabetes Institutes Foundation, you will find how to donate!
Sandy Donchess
Dr. Vinik, please tell us what you can about the research Lilly has been doing on INGAP.
Aaron Vinik
The work we have done with Lilly has really helped a great deal.
For example, when we started with them we had the gene but had not expressed the full length protein and a carrier system that allowed the protein to take up its natural state. This we did with them, and we have drafted a manuscript to describe these findings. We have also worked with them to show that we could cure diabetes with this product and have prepared another manuscript which we hope will be published shortly.
We, however, have been interested in finding the smallest molecule that could do the job and the nature of the target and the cells that make INGAP. This we have done at our Institution and collaborate with Dr. Rosenberg to show that the small INGAP peptide works in normal animals.
The solid backing of both our Universities and our foundations to assure that the program will go forth in all its strength.
Dorothy
Dr. Vinik, I can't thank you enough for your thorough response to the questions It has been MOST informative and exciting.
Joann
Thanks Dr. Vinik. We appreciate you taking the time to chat with us. Have a good night.
Terri
Thank you, Dr. Vinik, for all the information that you have given us.
Jen
God speed in your research, Dr. Vinik. Thank you for answering our questions.
Alan F. Bachrach, M.D.
Dr. Vinik, I've been "listening" for over an hour without asking any questions. Thanks again for coming. To many of us with diabetic children, you are a hero. Would you please outline the basic series of steps required to get us from here (small animal tests) to there (clinical use of the drug). Any time frame? There is no end to the detailed questions that MAY be asked before INGAP is ready for human use, but what are the essential question that MUST be asked? Thanks.
Aaron Vinik
Alan, I appreciate you being online for all this time and the direct questions you now ask. I have not begun to talk about the sophisticated scientific questions we are addressing. For example, what would a transgenic animal overexpressing INGAP or, underexpressing it look like? These are questions that need to be addressed for future directions with the work. Right now we need to know that the response we have now seen in normal animals at the higher dose occurs in diabetic animals. If this is effective in animals with spontaneous autoimmune diabetes and what the optimum route of administration would be. If all this pans out, then we can begin to think of phase 1 studies in humans i.e safety studies before going on to efficacy. Does that help?
Alan F. Bachrach, M.D.
Thanks, Dr. Vinik. Your comments are uplifting and really help me (and I'm sure others) to keep fighting the daily fight to keep our children as healthy as possible.
Ruth
Thank you, Dr. Vinik, for your intense dedication to finding a cure for diabetes and for answering our questions tonight. God Bless You Melissa’s Diabetes Chat.
MAR
Thank you, Dr. Vinik, for taking the time to connect with us. We march, we walk, we lobby, wrap gifts, wash dishes at galas and cry out for a cure. You are indeed a hero for fighting the good fight and giving us a light at the end of the tunnel. Without you and your colleagues, the only light at the end of the tunnel would be the oncoming train!
Melissa
Thank you, Dr. Vinik, for joining us again!
Brenda
My daughter has MODY 2 and is on oral meds....Please forgive me for barging in....I am just getting here...would it be out of line to discuss MODY (Mature Onset of Diabetes in the Young)?
Aaron Vinik
MODY is a unique form of diabetes that is inherited as an autosomal dominant. There are now several varieties that are associated with specific gene defects. We are working now with a group in Belgium to see if INGAP would be effective in their animals in which they have mimicked one of the forms of MODY. There is every reason to believe that in most forms of MODY, a defect in beta cell function, occurs and this would then be amenable to INGAP treatment. We will keep you posted.
Cheryl
How is MODY different from type 1?
Judith
MODY is essentially type 2 in young people.....
Melissa
Wow! That is just fantastic about MODY, Dr. Vinik! We really don't hear too much about MODY, and it's wonderful that that is being studied and a cure is being sought for that also! Just fantastic! (MODY is Mature Onset of Diabetes in the Young... or something to that effect... basically it's type 2 diabetes in kids.)
Aaron Vinik
Thank you all for participating in this chat session. I have enjoyed your questions and as you see we scientists are only too delighted to share with you all the good news that we have. I want to take this opportunity to thank the Eastern Virginia Medical School in Norfolk Virginia and the Diabetes Institutes Foundation and all the contributors for the support, financial and moral, that they have given us for these endeavors. They have been our source of funding and encouragement that has brought us to this point. Thanks to you, too, Melissa, for initiating these chat sessions. Take Care, Good Night all.
Robin (was R.A.) Harrison
Thank you, Dr. Vinik! You've answered a number of burning questions, and I enjoyed the discussion. Wishing you the greatest success!
Alan F. Bachrach, M.D.
Thanks for hosting this session, Melissa. It's really a great service for all of us.
Sandy Donchess
Melissa, you're great. Thanks for hosting this. Dr. Vinik, keep on going.
Kurt
Thank you Melissa, and thank you Dr. Vinik. I'm looking forward to the next "chat session" with you!!!!!!!!!!
Melissa
Thanks Alan and Sandy! It actually was very easy to arrange since Dr. Vinik is so willing to come and chat and for that, I'm very grateful.
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