Mar 21 2007
A peptide developed by scientists at Weill Cornell Medical College may expand the availability and durability of islet cell transplant for patients with type-1 diabetes, which is characterized by a lack of these insulin-producing cells.
Right now, patients must obtain islet cells from two or three separate donors, and the transplanted cells are so weakened by transplant that most will eventually die off.
"However, our experiments in mice show that this small molecule, called SS31, is able to stabilize islet cells and help protect them from harm. The result is a dramatic increase in transplant success using cells from just one donor," says lead researcher Dr. Dolca Thomas, assistant professor of medicine at Weill Cornell Medical College and medical director of the Pancreatic Islet Transplantation Program at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
The findings were recently published in the Journal of the American Society of Nephrology.
About 5 percent of people with diabetes have the inherited type-1 form of the disease, where islet cells in the pancreas are lacking and fail to produce adequate amounts of insulin.
Islet cell transplant has always held promise in treating the illness, but because these cells are so fragile, one patient typically requires two or three cell donors to amass any real benefit.
"That's because the very act of isolating these cells easily sends them into apoptosis -- programmed cell death," explains the study's senior author, Dr. Manikkam Suthanthiran, chief of the Division of Nephrology and Hypertension at Weill Cornell Medical College and chief of the Department of Transplantation Medicine at NewYork-Presbyterian/Weill Cornell.
"Once the cells are in the recipient, certain weaknesses emerge that also cause a gradual dying off over time," Dr. Suthanthiran adds.
He and Dr. Thomas were looking for some type of compound that might "shield" these fragile cells, allowing them to survive and thrive during and after transplant.
SS31 -- an antioxidant peptide developed in the laboratory of Weill Cornell Professor of Pharmacology Dr. Hazel Szeto -- may provide just that kind of protection.
"SS31 is, first of all, able to penetrate islet cells, which clump together in tough-to-infiltrate clusters," Dr. Thomas points out. "It also stabilizes a part of the cell called the mitochondrial membrane. We know that keeping this area free from injury is key to preventing apoptosis."
In their experiments, the Weill Cornell team gave SS31 to diabetic mice, each of which had received islet cell transplants from just one donor mouse.
The mice were then studied for up to 45 days.
"Using SS31, we were able to quickly make 50 percent of these recipient mice insulin-independent or 'normoglycemic,'" Dr. Suthanthiran says. "And we did so by using just one donor. That's an incredible improvement over what we see in the usual human transplant model."
In contrast, mice who received the transplanted cells without SS31 remained diabetic.
Transplanted cells were much less susceptible to apoptotic death, and simply mixing the donor cells with SS31 prior to transplant seemed to be enough to provide the protective effect, the researchers say.
"The next step -- and our new studies are looking at this -- is to see if this protection lasts over the longer term," Dr. Thomas says. "Also, what happens if you treat more continuously -- say, over 10 days? Will that help boost the effect and prevent islet cells from dying? We hope to find out."
The researchers say the current study is merely "proof of principle" that SS31 treatment might improve islet cell transplant. But the results are encouraging.
"If it works in humans, this could greatly expand the number of patients eligible for transplant," Dr. Thomas says. "And it's also translatable to other transplant settings, because all organs sustain some degree of injury during harvesting. So, SS31 might be of benefit in those cases, as well."
This work was funded, in part, by the Juvenile Diabetes Research Foundation and the U.S. National Institutes of Health. Dr. Thomas is a recipient of the Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation.
Co-researchers include Drs. Kesheng Zhao, Craig Stauffer, Hua Yang and Vijay K. Sharma -- all of Weill Cornell Medical College.