Targets for the Future – The New SPIRIT Program

The SPIRIT Program
New Developments and Future Targets

Today, the Strelitz Diabetes Research Institute’s scientific team is aggressively pushing ahead in the laboratories to further understand the mechanism of islet regeneration and to ascertain the factors that will contribute to the success of this treatment for diabetes.

International scientists and the biotech and pharmaceutical industry are engaged with the Institutes in collaborative efforts in regeneration research to promote and find solutions to complex diabetes issues embracing this therapeutic approach and bringing it to fruition.

Basic science research in the laboratory furthers the understanding of islet regeneration and escalates research development on all levels.

In the laboratory, new discoveries produce new understanding; new understanding creates a need for further new discoveries. Each discovery is like an excavation- as one layer is revealed, it leads to digging deeper for other clues to the mysteries of factors essential to enlist islet regeneration as a therapeutic modality. Everyday, scientists bring us closer to a cure that will heal people’s lives.

An expansive new SPIRIT research program for the Stimulation of Pancreatic Islet Regeneration In Type 1 and Type 2 diabetes is under development at the Strelitz Diabetes Institutes. Incorporating transgenics, the new program will work within the cell and molecular biology laboratory to continue to explore the biology of islet regeneration and to discover the other components which compliment INGAP action and may be required to bring islet regeneration cure research to fruition.

SPIRIT is making significant investigational milestones in the following areas of understanding.

1. Molecular mechanism(s) involved in the process of islet neogenesis for the creation and proliferation of islets.
2. Exploration of tolerization (strategies to prevent INGAP antibody resistance and reduce immune destruction or programmed cell death of newly developed islets).
3. Feedback mechanisms in regeneration that regulate cell production and prevent unbridled cell growth.
4. Downstream signaling pathways that may provide an opportunity for the development of surrogate molecules to stimulate islet regeneration.
5. INGAP’s role in the transformation process of precursor cells into viable pancreatic islets.
6. Use of transgenic animal models (animals in which the human gene is inserted) to unequivocally demonstrate the dependency of pancreatic islet mass to INGAP expression.
7. Exploration of partnering insulin sensitizing agents with INGAP that will help the body more effectively use the insulin that is created.

1. Molecular mechanism(s) involved in the process of islet neogenesis for the creation and proliferation of islets.

After discovering the INGAP Peptide, scientists immediately began to investigate how the Peptide worked to create islet regeneration. They discovered that the Peptide projects in a small loop outside the whole molecule. This knowledge allowed scientists to look for even smaller non-peptide molecules that may do the work of the Peptide by binding to the receptor. Some people may develop diabetes not because of a lack of INGAP but because of a problem with the receptor. Smaller molecules may address the receptor issue. They could also render Peptide therapy unnecessary and create new therapies for islet regeneration.

2. Exploration of tolerization (strategies to prevent INGAP antibody resistance and reduce immune destruction or programmed cell death of newly developed islets.

Concurrent transgenic research is investigating the prevention of apoptosis (cell death). Scientists are focusing on matrix metalloproteases or MMPs 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 (possibly combining DiaPep277 with INGAP) that will inhibit MMPs. The inhibition of MMPs may have a stabilizing affect on insulin levels and allow for greater function of newly created islet cells.

SDI scientists expect that the combination of Notch-1 pathway research (see #5) with MMP investigations will lead to the proliferation of highly viable beta cell mass, reduce apoptosis, and increase the genetic markers that promote endocrine pancreatic development.

The expression and translation of gene action is now closely linked to the nuclear chromatin structure, which is tightly bound and restricts access between proteins and genes. New agents are now available which loosen the structure and allow better access of gene products to their targets. We propose to combine this approach to the stimulation of islet regeneration with INGAP and other factors.

3. Feedback mechanisms involved in the regenerative process that regulate cell production and prevent unbridled cell growth.

The Institutes’ research team has also discovered why there has been no evidence of tumors or hypoglycemia in animals treated with INGAP Peptide. They were initially concerned that administration of the Peptide may cause unbridled cell growth. Experiments have revealed that the body has a homeostatic mechanism that controls INGAP cell production. INGAP acts upon a transcription factor called PDX that is necessary for cell growth and proliferation in the pancreas. Cell growth is controlled because PDX in turn suppresses the expression of INGAP.

4. Downstream signaling pathways that may provide an opportunity for the development of surrogate molecules to stimulate islet regeneration.

To further explore the creation and proliferation of viable islet cells, the SDI research team is presently investigating the process of stem cell development from totipotent stem cells to pluripotent endocermal cells – the precursor to pancreatic progenitor cells. This work is being done through the investigation of Notch-1 pathways. SDI researchers posit that inactivation of Notch-signaling with INGAP administration or expression will enhance INGAP’s biological effects.

5. INGAP’s role in the transformation process of precursor cells into viable pancreatic islets.

Scientists searching for the presence of pancreatic precursor cells in the gastrointestinal track to expand the number of cells available for transdifferentiation into islets.

6. Use of transgenic animals models to unequivocally demonstrate the dependency of pancreatic islet mass to INGAP expression.

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. This finding provides a very powerful tool whereby researchers are poised to dissect any of the ancilliary factors that may be important in initiating growth and development of adult endocrine cells from proto-differentiated stem cells

7. Exploration of partnering insulin sensitizing agents with INGAP that will help the body more effectively use the insulin that is created.

One contingency in people with Type 2 diabetes is that the demand for new islet cells and insulin production would be exceeded by the resistance to the action of newly formed islets and their insulin. For this reason we are embarking upon studies to examine the combination of insulin sensitizers and factors which stimulate islet regeneration.

Summary

The SDI research team is preparing for contingencies found by human trials. 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 refinement as it develops into a successful treatment for diabetes.

As with the discovery of insulin in the 1920’s, which opened a door for research into a new field, so the discovery of INGAP has generated an explosive new biology enticing scientists worldwide into exploring its exciting possibilities for a cure.