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Under the Microscope

Interview with Luca Inverardi, M.D.

The discovery of a biological cure for diabetes will come from advances made in a broad range of research areas. At the DRI, scientific teams from such diverse disciplines as bioengineering, nanotechnology, immunology and stem cell research, among others, are working together as never before. Armed with important new findings from basic research and clinical studies, these researchers are now bridging cell-based therapies with powerful new technologies to restore natural insulin production in patients.

Heading one of these teams is Dr. Luca Inverardi, area leader for the DRI's Cell Products, Regeneration and Stem Cell Research programs. Dr. Inverardi also serves as director of Immunobiology of Islet Transplantation and is a Research Professor of Medicine, Microbiology and Immunology at the University of Miami Miller School of Medicine.

Dr. Inverardi and his team's programs address the need to develop an unlimited supply of insulin producing tissue – be it through regenerating a patient's own beta cells, using different types of stem cells or reprogramming the functions of other cells of the body. Below, he answers some important questions about some of the newest work underway in this key research area.

What are cell therapies?
This is an important question. We think of cell therapies as therapeutic approaches for the treatment of diseases that are based on the use of specific cell types, either by treating/manipulating them or leaving them untreated, to accomplish specific tasks. In our case, we are working with different cell types to restore natural insulin production. Using cell-based approaches offers a broad range of medical possibilities, including increasing the supply of insulin-producing tissue for transplantation, eliminating the harmful inflammatory reactions associated with islet loss and even re-educating the immune system to establish tolerance or the permanent “acceptance” of insulin-producing cells.

How are you pursuing the supply issue through cell therapies?
One of the sources we're looking at very carefully is stem cells. These are cells that have the ability to proliferate or multiply indefinitely. So, for example, we can obtain a few cells from a variety of different sources and then grow them into large quantities. Stem cells also have the remarkable capability to become any tissue or organ of the body and, therefore, have enormous potential to create an unlimited supply of tissue for transplantation. We are using many different types of stem cells, including embryonic, amniotic and umbilical cord stem cells.

Cord blood stem cells, as the name implies, are derived from newborn umbilical cord blood. These cells are multipotent and active, which means that they may transform (differentiate) toward most tissues and organs of the body, including pancreatic beta cells. Additionally, these cells are showing promise for potentially inducing donor-specific tolerance that could thwart immune attacks by re-educating the immune system to accept donor and recipient bone marrow cells as “self”.

What other types of cells are you exploring?
We have been investigating the co-transplantation of other cell types that can enhance cell survival and function. One particular group of cells that we are very interested in right now is mesenchymal stem cells (MSCs). These cells are a component of the bone marrow and have shown to be instrumental in repairing damaged tissue, stimulating the growth of blood vessels, and significantly reducing inflammation. In experimental islet transplantation studies, MSC's have demonstrated the ability to enhance graft acceptance and longer term viability of the transplanted cells. We believe this is due to their production of factors that help suppress the immune response to transplanted cells while also supporting new cell growth.

We are also looking at other cells of the body in an attempt to reprogram their function, an area of research known as transdifferentiation. We are working with Dr. Sarah Ferber from Chaim Sheba Medical Center in Tel-Hashomer, Israel, to test this strategy using liver cells. The liver and pancreas share the same developmental pathway and there is evidence that by inserting specific genes that are critical for beta cell development, the liver cells may be able to transform into insulin-producing beta cells.

Another approach is to reprogram a patient's own skin cells. Experiments are underway to reprogram these cells by, in a sense, wiping out the “computer hard drive” and installing new information. This could potentially overcome both the issue of cell supply as well as foreign tissue rejection since we would be using the patient's own cells.

What are the new technologies that the DRI is using to maximize the potential of cell therapies?
There has been a quantum leap in technology and, more importantly, in the ways in which we can apply these advances to our research. These new technologies range from improved methods for cell harvesting, cell culture and cell preservation, to the use of bio-artificial scaffolds and other biohybrid devices that protect cells from the body's immune response and inflammatory reactions. The use of bio-artificial devices also provides a more natural, nutrient-rich environment for housing the insulin-producing tissue.

For years, we focused on the isolation and function of the insulin producing islets and did not pay as much attention to their native environment. In recent years, much has been learned about the importance of replicating this environment to optimize the health of the insulin producing cells. In this regard, we have developed systems to provide the levels of oxygen needed for islet development and sustained function.

The use of an implantable, bioengineered device provides additional opportunities to deliver local immunosuppression and anti-inflammatory agents solely within the transplant environment. Instead of using oral or infused drug therapy, which affects the entire body, our team is designing a tiny “sprinkler-like” system to provide low-dose drugs directly into the device containing the insulin producing islets.

What is the status of the research?
As a translational research center, we are continuously moving the most promising findings from the bench to the small animal models and ultimately towards clinical application. For example, the biohybrid device is already in the pre-clinical stages, while other approaches are being tested in the lab and making their way up the translational ladder.

Luca Inverardi, M.D.
Luca Inverardi, M.D.


 

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