Islet Cell Regeneration and the gene INGAP, Part 10

Date: May 29, 2003
Moderator: Majorie Hunter
Subject: Islet Cell Regeneration Research Progress
Guest: Dr. Aaron I. Vinik, Research Director, Strelitz Diabetes Institutes, EVMS
Appearing on: www.diabetesstation.com

MARJORIE -Welcome to Diabetes Station! I am pleased to inroduce as our guest Aaron I. Vinik, MD, PhD, FCP, FACP, Director, of the Strelitz Diabetes Research Institute, Scientific Director, Department of Medicine and Professor of Medicine, Eastern Virginia Medical School who will speak on progess in Islet Cell Regeneration.

DR. VINIK - Delighted to be here with you again.

MARJORIE - Dr. Vinik plays a key role in the Strelitz Diabetes Institutes' quest to cure diabetes. Dr. Vinik spearheaded the discovery of "ilotropin," a chemical substance that can re-awaken the potential of cells to produce insulin, and the INGAP gene, a protein responsible for this reawakening. INGAP has just moved into the first phase of clinical trials with 62 people being recruited to participate at three medical institutes around the country: the Texas Diabetes Institute at the University of Texas in San Antonio, the Diabetes Care Center at the University of North Carolina at Chapel Hill and the MedStar Research Institute in Washington. In humans, doctors will inject a small, specialized section of a protein, called a peptide into study participants' muscles once a day for 35 days.

MARJORIE - In tests on animals, researchers found that the peptide travels to the pancreas, where it apparently "wakes up" inactive adult stem cells. Once stimulated, the formerly sleepy cells give birth to beta cells, which are responsible for manufacturing insulin. The peptide also seems to trigger the creation of companion cells in the pancreas, which begin making glucagon and other hormones needed to regulate blood sugar.

MARJORIE - Welcome back, Dr. Vinik! We are excited to hear of the progress you are making in islet cell regeneration. Can you give us the latest update on the progress of your research and the clinical trials?

DR. VINIK - Marjorie, as you know and have described so aptly in the introduction, the phase 1/2a trials were designed purely to establish the safety of administering INGAP peptide to humans in escalating single doses and in repeated doses. These studies were initially to be carried out at three centers in the USA and a fourth center was added in San Diego. This study has now been completed.

GARY - Any good news doc???

DR. VINIK - Lots of good news Gary. The mistake people ought not to make is to think that working towards changing the biology of diabetes is like taking a shot of insulin. When Banting and Best first gave a shot of insulin the reduction in blood glucose was instantaneous and when the insulin disappeared from the circulation then the effect disappeared. When trying to re-awaken sleepy cells in the pancreas, the process takes longer, but when they are turned on, they retain the capacity to fight diabetes. Our studies now in several different animal models show that this holds true. What we need to learn is the right dose, the route of administration and for how long, in humans to achieve the effects seen in the animals tested.

KURT - Can you share with us the results of those trials?

DR. VINIK - The results of the trials are not in.

MARJORIE - Was the data encouraging? Will you proceed to further Phase 2 studies?

DR. VINIK – The data is being analyzed, but you must remember that we were seeking primarily to learn if the peptide was safe to give to humans. We cannot yet talk about the trends toward efficacy since the data lock has not yet occurred, and the analysis will not be available till later in the year.

SHAN – Would this mean no other anti-rejection meds?

DR. VINIK - We have high hopes for not having to use anti-rejection medicines. There is, however, some new data in the NOD mouse being studied by Alex Rabinovitch in Alberta, which suggest that in that model with very intense rejection that a combination of INGAP and immunosuppressives may be the answer in certain situations. In people who have no autoimmune response or in people with type 2 diabetes, it is unlikely that they would need concomitant immunosuppressive drugs.

SHAN - What are the most common side effects of INGAP?

DR. VINIK - Shan based upon the animal studies there were no real side effects.

MARJORIE - Where are the data being collated?

DR. VINIK - The data will be collected and collated by GMP companies.

RUTH - What process is involved in collecting the data? Who collects this data? What is the role of the FDA? Do you need the approval of the FDA to progress to the next stage of clinical trails?

DR. VINIK - We cannot second guess the FDA. When all the data is in, it will be presented to the FDA who determines if and when you can proceed with the next phase. We are, however, in the planning phase of these studies now that the phase 1 and/2a have been completed.

NHKATZ - Dr.Vinik, is there any connection between the work you are doing and the work of the Canadian company Transition Therapeutics?

DR. VINIK - We have a close collaboration with McGill and Alberta in addition to the four sites in the US. We do not have collaborative arrangements with other companies in the US or Canada.

CAROLE - You entered this stage of testing quite optimistic based on what you learned in the animal studies. Did you uncover anything unexpected?

DR. VINIK - Carole, I ought to tell you of some recent findings in humans that would peek your interest. A patient in Minneapolis underwent a pancreas transplant and the blood glucose fell to low levels. When they biopsied the pancreas the patient had received, they found many of the precursor cells had grown and formed these neoislet structures, and all could make insulin. Wherever these cluster were found, INGAP was expressed. We published this paper in the Journal of Clinical Endocrinology because it strongly supports our animal findings that INGAP is necessary for the growth of islets in humans.

ANNA - Dr. Vinik, there is a lot of exciting work going on in islet neogenesis right now. Can you explain simply, the collaborative efforts that SDI researchers have with others in islet regeneration?

DR. VINIK - Anna, when we started this work it was considered heretical, but now it is traditional and mainstream. Many laboratories have now shown that islet neogenesis is feasible from stem cells - our laboratories work with adult stem cells. Our collaborative work with other research teams speaks to the difference between stimulating adult stem cells versus finding the link to embryonic stem cell differentiation. The problem with this approach has been the inability to get the cells to make large quantities of insulin. It seems that the resident precursor cells in the pancreas are still the best source, and we have collaborative arrangements with Lawrence Rosenberg at McGill, Alex Rabinovich at Alberta, Ralph DeFronzo in Texas, Bob Henry in San Diego, John Buse in North Carolina and Bob Ratner in Washington. We also have many international collaborators.

NORA - How is the research in Europe going compared to the US and Canada?

DR. VINIK - There are laboratories in Europe interested in this phenomenon, in Spain and Belgium predominantly. While they have contributed greatly to our understanding of the process, none has yet identified a material that could be used in human studies such as the INGAP peptide.

AMY - Does anyone know the chemical equation of insulin?

DR. VINIK - The chemical equation of insulin is known, and the molecule has been synthesized and won for several the Nobel Prize.

SHAWN - Have any of the diabetics in the clinical trial seen any benefit from the INGAP received?

DR. VINIK - In the safety trials, we maintained the patients current treatment with careful attention to changes in insulin or oral hypoglycemic agent dosage. This will be one of the variables measured to see if indeed there were changes in the trend towards efficacy component when the data are analyzed.

MARJORIE - Dr. Vinik, is INGAP only found during developmental stages or are there other uses postulated for this protein?

DR. VINIK - Marjorie, our early observations taught us that INGAP was expressed early in the development of the animal at a time when the pancreas had just formed and was compatible with a role in islet development. We also did not find INGAP in the adult pancreas except when provoked to undergo neogenesis by wrapping with cellophane. Dr. Gagliardino in Argentina published two papers to show that if the mothers were overfed, then the offspring developed islets earlier, and that INGAP was involved in the process. We have now created transgenic animals that express INGAP in the acinar tissue of the pancreas or in the islets, and the most striking and exciting news is that it is produced in the acinar tissue as the gene, and then the protein travels in the pancreas to these cells around an islet in a sort of halo to transform them into islet cells.

GARY - Dr. Vinik, what's your outlook on the islet transplant?

DR. VINIK - Gary, my outlook on islet transplants is that they are a proof of principle but not an answer to the gigantic problem we have with diabetes. For me personally, the most exciting thing to emerge from the islet transplant work is that an islet likes to remain in contact with its environment, otherwise it tends to commit Hari Kiri, that is to say undergo apoptosis (cell death). We believe that the surrounds contain INGAP that protect the islet from this destruction. Also, we have shown that when these islets in isolation undergo cystic degeneration, treatment with INGAP in the test tube can regenerate a viable islet. That suggests that a role for INGAP may be the protection of islets from destruction in an unfriendly milieu.

NHKATZ – Dr. Vinik, do you think some diabetes treatments would make subsequent treatment with INGAP more effective than others?

DR. VINIK – NHKatz, that is an interesting question and one that we are addressing in the laboratory. Whereas, we used to think that to regenerate an islet requires a pushing signal, it now is becoming apparent that it can be done or enhanced by removing a restraining signal. Imagine how much better we could be at regenerating islets if we could push and pull at the same time. We have some new important clues as to how to do this.

SHAN - Would INGAP happen after you already go through the process of an islet cell transplant?

DR. VINIK - Shan that is a possibility, but it could be done in vitro before the islets were administered, and it could be used in capsules or encapsulated islets or the endogenous INGAP concentration could be elevated to accommodate the need of the islets. We have just published a paper by Dr. David Taylor-Fishwick which shows that we now know what the regulators of INGAP expression are, and it may be feasible to use these regulators to turn on the production of INGAP to do the job.

CAROLE - When you inject a substance into the body with the intent of manufacturing new cells there can be the risk of producing too many of these cells. From this first phase of testing can you tell if this is a concern?

DR. VINIK - High dose INGAP was given without toxicity to animals. We have now given huge doses to animals both large and small for protracted periods in preparation for the large-scale studies that will be required for testing efficacy.

MARJORIE - Your point about the difference between insulin and INGAP is well taken. Have you performed further laboratory studies that might answer some of the other questions you mentioned?

DR. VINIK - The clues relate to the interaction of INGAP with both the positive side of the stimulatory arm and the negative side of the inhibitory arm. When we have nailed the whole pathway, I will be happy to disclose all the details.

MARJORIE - Does INGAP promote regeneration of all other islet cell types, e.g., more than just the beta cells?

DR. VINIK - Marjorie, the key to INGAP effect is that it is promoting the formation of an entire complement of islet cells including beta, glucagon, PP and somatostin. This excites us because it means that the counter regulatory response to hypoglycemia which is dependent upon glucagon will not be impaired in treated people. In a paper by Malik presented at the ADA last year, we showed that the neoislets make insulin as well as glucagons, which for us was very reassuring that our goal of recreating ontogeny might be fulfilled.

CAROLE - Were the participants in the first phase a mix of type 1 and type 2 and if yes, were there any differences in how they reacted to INGAP?

DR. VINIK – Carole, the participants in the 1/2a trials were a mixture of type 1 and type 2 patients. We look forward to examining this data in detail because we feel that it will shed light on how much C-peptide needs to be produced to have a biological effect. Strangely this is one piece of information that nobody seems to know with certainty.

SHAN - If you could guess a positive time of this coming to the answer for the cure, do you suppose we are about10 years or sooner from an effective cure in your opinion?

DR. VINIK - Shan I hesitate to give opinions on a time line. All I would ask you to think of is that we licensed INGAP to GMP Companies in March of 2001, and here we are 2 years later with the phase 1/2a trials completed. When it was first suggested to me that we would be in human trials in one year from licensing, I thought this was crazy, but kept my opinion to myself. I would hate to second guess the people who are trying so hard to make this a reality sooner than later.

TIM - Dr. Vinik: Couldn't you speed this work by running more trials concurrently? It is almost two years since the start of trials was announced. Thanks for all your work.

DR. VINIK - I think the trials are going as well and as fast as they possibly can with the attention to detail, meticulous care and concern for the welfare of the participants and care not to make mistakes that have been made with compounds that have the ability to change biology. There are some excellent examples out there of trials of nerve growth factors that claimed that the drug failed, but what really failed was the study. Remember, it was not long ago that growth hormone was hailed as the elixir of life based upon flawed studies, and these had to be retracted, and I could go on and on. Bart, the President of GMP, likes to say we will do it right, and I do believe that is what is being done now with the entry of Procter and Gamble making the whole thing feasible.

MARJORIE - Dr.Vinik, you have been so wonderful to share with us this evening. You can tell that we are anxious to have you return once the results are published. In the meantime, do you have any last thoughts or hopes for us?

DR. VINIK - Thank you all for being here, and it was a pleasure to exchange dialogue with you once again. Thank you too for all your support and good wishes, and I fervently pray that good will come out of this program to help those in need. Take Care.