Islet Cell Transplantation: Addressing the Underlying Defect in Type 1 Diabetes

In a presentation at the 76th Scientific Sessions of the American Diabetes Association held in New Orleans, Louisiana, David K.C. Cooper, MD, PhD, FRCS of the Thomas E. Starzl Transplantation institute at the University of Pittsburgh discussed xenobiotic islet cell transplantation, which may be a future therapeutic modality for patients with type 1 diabetes (T1D).

For the estimated 1.25 million patients with T1D in the United States today, an effective treatment modality in which the islet cells are replaced would correct the essential defect in the disease. According to Cooper, approximately 1000 such islet cell transplants from deceased human donors to patients with T1D have been performed over the past decade.

This method of islet cell replacement has a major drawback: the quantity of islet cells that can be harvested from deceased human donors would never be sufficient to meet the demand. Each year, only 7000 to 8000 deceased human donors could potentially provide islet cells for patients with T1D.

Instead of relying on human donors for islet cells, Cooper and colleagues are using genetically engineered donor pigs as a source of islet cells. To date, researchers have transplanted islet cells from a genetically engineered pigs to nonhuman primates with cases of long-term success. According to Cooper, “Monkeys with diabetes who received pig islet transplants and received immunosuppressant drug therapy experienced survival rates of more than 1 year with no need for insulin injections and no major complications.”

If successfully applied in humans, such transplants would be a major advance in T1D therapy, and could potentially correct the underlying defect of the disease. Regarding human trials of this strategy, Cooper noted, “We are getting closer to initiating trials of pig islet transplantation in human patients with diabetes in whom control of blood sugar is proving difficult.” These trials would benefit patients maintain normal blood glucose level without insulin injections. Ultimately, explained Cooper, “improved glycemic control from transplantation could help prevent later diabetes-related complications such as kidney failure.”

Pig islet transplantation is not the only line of research in treating the complications of T1D. As discussed by Chad A. Cowan, PhD, of the Harvard Stem Cell Institute, another approach to acheiving islet cells replacement would involve creating a new set of insulin-producing pancreatic cells from laboratory-grown stem cells.

Unfortunately, developing islet cells is a major engineering challenge. Specifically, developing beta cells outside the human body requires administering 150 combinations of 70 substances in a precisely regulated sequence that may be difficult to replicate outside a living organism. Researchers would also need a line of laboratory grown universal donor stem cells that compatible with a genetically heterogeneous patient population.

In addition to these challenges, use of islet cells would require a method of protecting the cells from the immune system. Proposed approaches to immune protection include physical methods, such as placing the replacement islet cells into retrievable macrocapsules or non-retrievable modified alginates. These physical methods would be used in combination with biochemical methods, such as using gene editing to remove major histocompatibility complexes from islet stem cells, or by harnessing some of the immune tolerance pathways that exist in developing fetuses and cancers.

With the ability to develop replacement islet cells that can stay in the body and escape destruction by the immune system, researchers may be able to treat T1D using regenerative medicine techniques. If these strategies are successful in T1D, researchers could apply the same techniques in other diseases, such as Parkinson’s disease, multiple sclerosis, and cancer.

Ultimately, concluded Cowan, “If successful, our proposed work could have an enormous impact on regenerative medicine. It could lead the way to rigorously tested universal donor stem cells that could be grown and differentiated into very large numbers of cells, made widely available to all medical institutions and used on demand to treat patients suffering from type 1 diabetes and a variety of degenerative illnesses.” Through gene editing and advanced methods for inducing immune tolerance, researchers hope to develop new therapeutics for a paradigm-changing shift, not only in the treatment of T1D, but also in the emerging field of regenerative medicine as a whole.