A More Detailed Look at Stem-Cell Therapy for Diabetes

In mid-April, the popular press was full of reports on an exciting new paper published in the Journal of the American Medical Society on a stem-cell treatment for type 1 diabetes.

The phrase “stem cell research” has so many connotations that we thought it was worth taking a more detailed look at what exactly was in this widely-acclaimed paper. Published by Dr. Julio Voltarelli and colleagues from the University of Sao Paulo in Brazil, it reported the results from a small 15-patient trial that tested a method called autologous nonmyeloablative hematopoietic stem cell transplantation (AHSCT) for the treatment of new type 1 patients. The method is a complex three-step procedure that is already used to treat other autoimmune diseases like sclerosis, arthritis, Crohn’s disease, and lupus:

• In the first step, doctors collect a large number of hematopoietic stem cells (HSCs) from the patient’s blood. HSCs are the adult stem cells that normally reside in your bone marrow and that replenish both your red and white blood cells. Doctors have to collect a large number because at the end of the process, these pre-harvested HSCs will be re-infused in order to rebuild the patient’s immune system.

• In the second step, patients receive something called “immunoablative conditioning” in order to destroy their white blood cells. This is somewhat similar to the radiation therapy that leukemia patients receive when they prepare for bone marrow transplants, except that these patients receive an antibody that specifically removes their white blood cells without exposing their bodies to harmful radiation.

• In the third step, the HSCs are re-infused into the patient in order to rebuild a new immune system that (hopefully) no longer attacks their beta cells. Again, this differs from what happens in bone marrow transplants (and islet cell transplants, for that matter) in that patients are receiving their own cells, so there’s no risk of immune rejection, or any need for them to take long-term immunosuppression therapies.

In Dr. Voltarelli’s trial, 14 of the 15 type 1 patients were able to stop using insulin after they received this treatment and of these, all but one were still insulin independent at the time this paper was written, in February of 2007. Because this trial was conducted over the course of three years, at that time some of the patients had been followed for as long as 36 months and others for as little as seven.

Importantly, all of these patients had been diagnosed with type 1 diabetes within six weeks of their enrollment in this trial. There is some research that suggests that even people who have had type 1 diabetes for decades are still producing some beta cells, but the underlying autoimmune condition that is responsible for type 1 destroys these new cells as soon as they are created, perpetuating the disease. In Dr. Voltarelli’s trial, the idea was that if the autoimmune condition can be removed early in the course of disease, the remaining beta cells can be rescued and recovered, thus reversing the disease. Presumably this would be much less helpful in people with longstanding type 1 diabetes, who have few if any beta cells left and thus would not benefit from having the autoimmune condition removed.

The mechanism for how AHSCT restores beta-cell function is unknown. In an accompanying editorial to the Voltarelli paper, noted Miami endocrinologist Dr. Jay Skyler points out that while the goal of AHSCT is to eliminate autoimmune white cells and replace them with new, healthy white blood cells, this may not be the whole story. The process of AHSCT itself may somehow reset the immune system to be more tolerant of the body’s own beta cells. Alternatively, the re-infused HSCs may themselves be somehow growing into beta cells, or perhaps the treatment process mobilizes stem cells in the pancreas or bone marrow to become beta cells – this is a somewhat more controversial idea, but we simply don’t know enough about this exciting new technique to determine what exactly is happening.

Dr. Skyler identifies a few future directions of research. Ideally, doctors and scientists will want to see Dr. Voltarelli’s results replicated in a large, randomized controlled trial with a longer follow-up period to see if patients really do remain insulin independent in the long term. Having a randomized control group is particularly important because newly diagnosed type 1 patients often have a ‘honeymoon’ period during which they can stay relatively insulin independent, and it will be important to distinguish between the effects of the honeymoon period and the effects of the AHSCT procedure. Having a longer trial will also help because the honeymoon period doesn’t last very long, whereas we would hope that a “cure” for type 1 diabetes does. Finally, Dr. Skyler would like to see biological studies carried out to discover exactly how AHSCT works – whether it eliminates autoimmune cells or helps beta cells regenerate or acts through a different mechanism altogether. We agree, and we can’t wait to see more work done in this field!

Bottom line: There was a lot of hype in the press about a stem cell “cure” for diabetes in April. The study was exciting, though small and short, and it is important that more be done before we know whether this is meaningful. No embryonic stem cells were used, and no immunosuppression was required. Cells from a patient’s bone marrow were extracted, the patient underwent a sort of radiation therapy, and these cells were reintroduced. Indeed, most of the subjects of this small 15-person group did go off insulin, at least for a time.

Voltarelli JC, Couri CEB, Stracieri ABPL, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KCR, Foss-Freitas MC, Simoes BP, Foss MC, Squiers E, Burt RK. “Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus.” JAMA 11 April 2007. 297(14):1568-76. Skyler JS. “Cellular Therapy for Type 1 Diabetes: Has the Time Come?” JAMA 11 April 2007. 297(14):1599-1600.