ISLET REGENERATION RESEARCH ACCELERATES

NEW DISCOVERIES POSE INTRIGUING NEW CHALLENGES

Procter & Gamble and GMP Companies have completed the Phase 2 INGAP clinical trials at 21 locations nationwide. In the basic science laboratories, researchers at the Strelitz Diabetes Institutes are working to understand the biological mechanism of islet regeneration and the important factors that will contribute to the success of this treatment for diabetes.

Scientists are being cautious. They speculate that human trials may reveal that INGAP Peptide therapy may not be a cure for all people with diabetes. In the Strelitz Diabetes Institutes laboratories, researchers are addressing possible contingencies by investigating several areas of concern. They opine that there may be multiple factors involved in the stimulation of islet regeneration, there may be insufficient progenitor cells for stimulation, and there may be factors present in any given individual that would prevent successful treatment.

Dr. Gary Pittenger , Director of the SDI's Protein Chemistry laboratory, comments, "To consider the relatively short seven year period that we've been working with the INGAP gene itself, it's remarkable how far we have come."

"The pace of our research has been swift, and our findings offer intriguing new insights into the regenerative process," says Dr. Aaron I. Vinik , Director of SDI Research. "Only a year ago, we needed to know what controls INGAP and what INGAP controls. Those answers now have provided new challenges to investigate."

One of the biggest leaps in scientific progress occurred last year when SDI scientists discovered the mechanism of INGAP production. They are now able to stimulate INGAP gene expression without the administration of the Peptide.

In research to find out what INGAP controls, SDI scientists discovered that the protein contains an active biological site of 15 amino acids that projects in a loop outside the whole molecule. Using only the small peptide, researchers were able to regenerate islet cells. With this new knowledge of what INGAP controls, SDI researchers are now looking for even smaller non-peptide molecules that bind to the receptor. In the future, these smaller molecules could render peptide therapy unnecessary and would open up exciting new therapies for islet regeneration.

Dr. David Taylor Fishwick , Director of the SDI's Cell and Molecular Biology laboratory, explains, "There are switches along the way to islet regeneration that we can turn on. INGAP may be used in combination with other factors, and as we identify these factors, we may find that they are good therapies in their own right."

"The creation of a small molecule(s) to activate the regenerative process may provide a viable treatment for people who have diabetes because of a receptor defect rather than an INGAP deficiency," adds Dr. Vinik .

As SDI scientists investigated cell signals, they discovered an important explanation for why there was no evidence of tumors or hypoglycemia in animals treated with INGAP Peptide. Their initial concerns about unbridled cell growth were put to rest when they found that nature has provided a homeostatic mechanism. They found that INGAP acts upon a transcription factor called PDX necessary for cell growth and proliferation in the pancreas. But, PDX in turn also suppresses the expression of INGAP.

Collaborative research with scientists outside the Strelitz Diabetes Institutes has led to important discoveries as well. In a continuing partnership with Dr. Lawrence Rosenberg at McGill University, SDI researchers have discovered an important possible application of INGAP to the treatment avenue of islet transplantation. They recently discovered that although adult islets harvested from donors for transplantation do not respond to INGAP Peptide , harvested "younger" pancreatic cystic structures treated with INGAP Peptide do undergo transdifferentiation and become insulin-producing islets. It now becomes feasible to expand islet mass in vitro (in the test tube).

"The ability to create, expand, and then harvest viable islets in vitro could solve the vast shortfall of islets available for transplantation," explains Dr. Vinik .

Targets for Future Research - The New SPIRIT Program

The Strelitz Diabetes Institutes has further accelerated islet regeneration research with the development of an expansive new SPIRIT research program. SPIRIT stands for "stimulation of pancreatic islet regeneration for Type 1 and Type 2 diabetes."

Using transgenic animal models, the new SPIRIT program will be investigating the creation and proliferation of islets, the protection of viable islets once they are created, evaluation of those people who may have antibodies to INGAP, and the development of new therapeutic targets for islet regeneration therapy.

Researchers have already developed three transgenic animal models. A recent transgenic study in which researchers inserted the human INGAP gene into mouse pancreatic acinar cells created islet regeneration that led to the formation of insulin-producing cells.

An abstract from this study and a concurrent study showing that INGAP works with a counter-regulatory hormone called glucagon to prevent hypoglycemia have been accepted for presentation at the upcoming American Diabetes Association International conference in June.

"This finding provides a very powerful tool," says Dr. Vinik . "We are poised to analyze any of the ancillary factors that may be important for initiating the growth and development of adult endocrine cells from proto-differentiated cells."

To further explore the creation and proliferation of viable islet cells, the SDI research team is also looking at the process of cell development. They are also searching for the presence of pancreatic precursor cells in the gastrointestinal track in an effort to expand the number of cells available for transformation into islets.

Research with transgenic models is also investigating the prevention of apoptosis – cell death – which could cause the destruction of viable new islets. Scientists are focusing on matrix metalloproteases or " MMPs ," chemicals that degrade cell makeup and are implicated in diabetes and the development of kidney diseases and retinopathy. Researchers are working on the creation of a cocktail that will protect and enhance the insulin producing capability of newly created islet cells by inhibiting MMPs .

Scientists at the SDI anticipate that the combination of cell development and MMP research will lead to the expansion of highly viable beta cell mass, reduce cell death, and increase the genetic markers that promote endocrine pancreatic development.

Researchers are also targeting INGAP's minute genetic structure, seeking to loosen the bonds that limit the malleability of the gene. New agents, called biotins, are available that loosen the tight bonds of the gene that have until now limited research access to proteins. Using biotins and and technological advances in mass spectrometry, researchers will be able to further investigate the stimulation of islet regeneration with INGAP and other factors.

These other factors may become very important when using islet regeneration treatment on Type 1 and Type 2 diabetes.

Because of the possibility that newly generated islets may be destroyed by persistent autoimmunity in people with Type 1 diabetes, SDI researchers are collaborating with groups in unique approaches to immunotolerance . Scientists seek to protect the newly formed healthy islets without the use of toxic compounds that have caused debilitating complications in the realm of pancreas and islet transplantation.

The factors are different with people who have Type 2 diabetes who have the problem of insulin resistance. One contingency with Type 2 diabetes is that the demand for new islet cells and insulin production could be exceeded by the resistance to the action of newly formed islets and their insulin. For this reason, the SDI research team is embarking upon studies to examine the combination of insulin sensitizers and factors which stimulate islet regeneration.

SDI scientists need to know who are the best candidates for islet regeneration therapy and are working with transgenic models in the effort to design predictive screens. These new investigations will show that if a person has a deficiency of INGAP, he will not have the appropriate islet mass, or with the excess of INGAP, he will overproduce it. Scientist will then be able to develop new ways to ascertain who is deficient in INGAP, who needs INGAP, who is likely to respond to INGAP, who has antibodies to INGAP and who is unlikely to respond to INGAP.

"The SDI research team is preparing for contingencies found by human trials," concludes Dr. Vinik . "Those trials will reveal if INGAP Peptide is a viable treatment by itself or if it must be used in combination with other factors. Pancreatic beta cells require multiple, very carefully coordinated and regulated signals in order to produce insulin. INGAP can stimulate the formation of islets, but that islet regenerative process may need a lot of refinement down the road to a utopian concept of a cure."

The SPIRIT program advances islet regenerative research beyond INGAP. The SDI's research program is tirelessly working toward a future with the assumption that islet regeneration in combination with appropriate immunosuppression in Type 1 diabetes and the reduction of insulin resistance in Type 2 will provide an effective treatment for certain forms of diabetes.