Update on Beta-Cell Replacement

Pig Islet Cell Transplantation

Two approaches to replace deteriorating beta cells in patients with type 1 diabetes were presented at the American Diabetes Association’s Scientific Sessions.

While pancreatic islet cell transplantation can successfully improve blood glucose control, temporarily reduce the need for insulin injections, and improve a patient’s ability to detect hypoglycemia, the procedure is still considered experimental. Only about 1000 surgeries have been performed in the last decade and with just 7000 to 8000 deceased human donors with viable pancreatic islet cells available in the US each year, there will not be enough islets to treat the estimated 1-2 million type 1 and 30 million type 2 diabetes patients.

David K.C. Cooper, MD, PhD, FRCS, Professor of Surgery, Thomas E. Starzi Transplantation Institute, University of Pittsburgh School of Medicine explained that genetically-engineered donor pigs mark the first time in transplantation that we are able to modify the donor instead of just treat the recipient. “That’s a very big change in our direction. That’s how we have to begin to think in this field of xenotransplantation – what can we do to the donor to make those islets less susceptible to the human immune response? – and the more we can do to the donor, the less we have to do to the recipient.”

This is particularly important in diabetes, Dr. Cooper said, because young patients with type 1 diabetes in need of transplants will have these islets for a very long time. Because all drugs have some detrimental effects, ideally transplant recipients should spend as little time as possible on immunosuppressant drugs. While researchers have not yet reached a point of engineering pig donor cells that are completely impervious to the human immune response, Dr. Cooper is confident this can be achieved.

There are two approaches to islet xenotransplantation. One method involves encapsulating the islets with various biomaterials to keep them from being rejected. This method has not yet been successful. The alternative is free insertion of islets, but this approach results in rejection by the human immune response.

Dr. Cooper’s group tested pig donor islet cells in monkeys induced with type 1 diabetes. The animals were followed for one year. When islets were inserted into the blood in the portal vein to reach the liver, the grafts failed. Results were promising when islets were inserted into the gastric submucosal space, just inside the lining of the stomach, with monkeys being able to maintain glucose control for the duration of the study. Researchers were able to confirm that these monkeys were producing porcine C-peptide.

“The transplantation of insulin-producing pancreatic islets from genetically-engineered pigs (whose number would be unlimited) could provide a cure for thousands of patients with diabetes mellitus,” concluded Dr. Cooper.

Universal Donor Stem Cells

Diabetes is a relatively simple problem, stated Chad A. Cowan, PhD, Associate Professor in the Department of Stem Cell and Regenerative Biology at Harvard University and Massachusetts General Hospital, Associate Member of the Broad Institute and Principal Faculty member of the Harvard Stem Cell Institute where he directs the Diabetes Disease Program and the iPS Cell Core Facility. “It’s the failure of one particular cell type in the human body that gives rise to the entire problem. . .We know at the end of the day insulin is the solution to this and an insulin-producing cell can also cure this disease.”

At the Harvard Stem Cell Institute, researchers are looking at using human pluripotent stem cells to treat diabetes. There are embryonic stem cells which are isolated from early stage embryos and induced pluripotent stem cells which can be made most often from blood cells. These cells can be divided in an unlimited fashion and the key is to teach the cells to do something. Because the cells are in the very early stages of development, they have the ability to become any cells in the body. “Our mission has been to teach them to become the insulin-producing beta cell."

It’s taken over a decade of work, but a mature, insulin-producing beta cell can be produced on a large enough scale that can treat people. “The challenge now is transplantation,” Dr. Cowan said. In type 1 diabetes patients, their autoimmune system would kill these cells. Universal donor stem cells are a biological approach to induce tolerance, such as what we see in pregnancy and cancer.

Through genome engineering, MHC molecules are removed to reduce the immune system’s ability to see the cells. Cells are also engineered to increase its ability to turn down the immune system response, such as in pregnancy. Finally, “checkpoint” inhibitors are added to stop the immune system from eliminating the cell, which would work for both type 1 and type 2 diabetes.

Through a universal donor stem cell, there is the potential to treat many other conditions in which you would want to replace cells, such as Parkinson disease which has one cell type that needs to be replaced. A universal donor could also offer protection from autoimmunity, such as in multiple sclerosis. “And thinking forward, probably the hottest thing to do right now for cancer is what people call immuno-oncology – using your own immune system against cancer.” Patients fighting cancer might not have enough immune cells, but the universal donor could be used to get around this barrier.