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On May 18, at the final session of Transplant 2000 in Chicago, Dr. James Shapiro and colleagues at the University of Alberta in Edmonton said the keys to the success of the Edmonton Protocol are the avoidance of steroids and the delivery of sufficient islets. The findings will be published in the July 27 issue of The New England Journal of Medicine.
Doctors in other countries have tried such a procedure before, but with less promising results. An earlier report from the International Islet Transplant Registry, said only 12.4 percent of 267 islet cell transplant recipients were insulin independent beyond 1 week, and only 8.2 percent beyond 1 year.
The Edmonton Protocol, however, marks the first time patients have been completely freed from insulin injections.
According to Reuters Health, Transplant 2000 delegates in the audience gave Shapiro a standing ovation after his report. One delegate was heard to say, "This is what all of us have been trying to do."
Patients had Severe Diabetes
The Edmonton Protocol team, which included transplant surgeons Shapiro, Dr. Ray Rajotte, Dr. Jonathan Lakey and Dr. Greg Korbutt, as well Drs. Garth Warnock, Chris Bleackley, Allan Murray, Norm Knete-man, John Elliott and Alex Rabinovitch, successfully transplanted donor pancreatic cells into eight people who were between the ages of 29 and 53. The patients were from Alberta, Saskatchewan and Yellowknife. All of the patients had severe diabetes prior to the procedure, requiring up to 15 shots of insulin per day.
At Transplant 2000, Shapiro reported that the patients have been free of insulin for 11 months. One patient's graft has functioned for 14 months. In addition, the patients no longer need to monitor their diet. Up until now, according to Shapiro, fewer than 1 in 10 islet-transplanted patients have been insulin-free one year later.
A 15-Minute Procedure
Shapiro and his colleagues gave patients a new combination of three drugs, which include the genetically engineered anti-rejection drug Zenapax, and low-dose therapy with tacrolimus and Rapamune. Extracted cells were taken from the pancreases of dead donors, then kept alive and purified. They were then injected into the recipient's portal vein, which is connected to the liver. The mean islet mass transplanted was 11,547 islet equivalents per kilogram of body weight. The actual transplant takes about 15 minutes
The cells were then carried in the bloodstream into the liver, where they "nested." Even though they were in a different organ, they produced sufficient insulin to allow the patients to live without daily insulin injections.
Shapiro added that no episodes of acute rejection, elevations in lipid profile or serious complications have been evident in the patients thus far.
Rapamune-Eliminates the Need for Steroids
Rapamune, manufactured by American Home Products' Wyeth-Ayerst Laboratories, is also known by its generic name, sirolimus, or more commonly as rapamycin. It received FDA approval on September 15, 1999.
Rapamune eliminates the need to use steroids, which can destroy islets. Islet transplant recipients, however, are still required to take immunosuppressants.
In 1998, researchers at the University of Texas-Houston Health Science Center demonstrated that Rapamune significantly improved graft survival in two phase III clinical trials.
In one study, 576 patients participated in studies conducted in Australia, the United States, Canada and six European countries. In this study, the efficacy of 5mg and 2mg of Rapamune were compared to the effects of a placebo. Patients also received cyclosporine and prednisone.
Acute rejection occurred in 11 percent of patients who received 5 mg of Rapamune, 19 percent of those who received 2 mg of Rapamune, and 29 percent of patients treated with placebo.
Lead researcher Allan S. MacDonald, MD, of Dalhousie University in Halifax, Nova Scotia, said, "The incidence of rejection in these two studies is the lowest ever reported in large-scale clinical trials." MacDonald added that Rapamune holds promise for "modifying immunosuppressive therapies so they are significantly less toxic and result in greater graft survival."
While Rapamune is being touted as the key link to the succes of the transplant procedure, Albert Hayek, MD, of the Whittier Institute for Diabetes in La Jolla, California, thinks the positive results are due to the combination of the Rapamune, daclizumab and tacrolimus with the avoidance of steroids and cyclosporine.
"Steroids and cyclosporine have been found to be deleterious to islets," says Hayek.
Camillo Ricordi, MD, scientific director at the Diabetes Research Institute of the University of Miami, says another reason the procedure was successful is because transplants were performed with fresh islets.
"This avoids any culture period that we know is associated with some islet loss," says Ricordi.
You've Come a Long Way, Baby
Joanne Langner of the Alberta Foundation for Diabetes Research, which provided $1.8 million for the Edmonton Protocol, says the results are amazing.
"This is extremely exciting for diabetics everywhere," she says. "There's a definite improvement in the quality of life for these individuals."
Langner told The Edmonton Journal she has met most of the patients, and all have told her the best thing is being able to live normal lives.
"Even being able to sleep in late is a novel experience for them," she said.
Hayek says the discoveries of the Edmonton Protocol team are "the best results ever achieved in islet transplantation."
The Juvenile Diabetes Foundation International (JDF) says, "The new protocol is a very significant step forward in curing type 1 diabetes."
Bill Book, board chair for the Alberta Foundation for Diabetes Research, told the University of Alberta Express News he is not surprised with the response.
"These eight patients, who are now producing insulin on their own, can get back to the normal life most of us live every day," said Book.
Deb Butterfield of the Insulin-Free World Foundation says the consistent success in islet transplantation achieved by the Edmonton group represents a very significant advance toward the ultimate goal of curing diabetes.
"It is a major achievement like this that inspire scientists everywhere to look at an old problem in a new light," says Butterfield. "Edmonton has opened one more door that stood between us and a cure."
Bill Hartnett, spokesperson for the British Diabetic Association, told BBC News he agrees this procedure would greatly improve the quality of life for people with diabetes. He adds, however, that the new treatment could lead to massive demand from people with diabetes.
Ricordi says each patient in the Edmonton Protocol required islets from two different pancreases to become insulin independent.
"Currently, transplant surgeons cannot get enough islets from a single donor pancreas," says Ricordi, adding that a future goal of islet transplant procedures is performing one-to-one transplantation. "If we need two pancreases to reverse diabetes in one patient, there will be a lot of discussions and controversies on who should get the organs."
A normal pancreas has almost 1 million islets. According to Butterfield and Ricordi, there are approximately 5,000 pancreases available each year through the donor organ system. Only 75 percent are useable, and the rest go to waste. Because the allocation system is so slow, by the time pancreases could be offered for islet transplantation they are already too old.
"We accept pancreases with up to 12 hours of cold [preservation]," says Ricordi. "However, the best clinical results have been obtained with pancreases that were preserved for less than eight hours. There is an urgent and critical need to make sure that all pancreases are procured and allocated for either pancreas or islet transplantation. What we have now is not sufficient at all."
To be Continued
In addition to The Alberta Foundation for Diabetes Research other supporters of the Edmonton Protocol's research included:
The JDF, according to director of media relations Julie Kimbrough, has awarded a $14-million grant to support the extension of the Edmonton Protocol. The extension will be conducted in eight leading islet transplant centers across North America and Europe. The researchers will conduct at least 32 additional islet transplants. The $14-million JDF contribution is part of the $144 National Institutes of Health (NIH)/JDF Immune Tolerance Network grant.
The NIH awarded the Edmonton Protocol team $130 million of the $144-million grant.
Within a few months, NIH and JDF will name the eight hospitals that will participate in the new transplant study. For now, the Edmonton Protocol's transplant technique will only be tested in adults, not children.
Ricordi, who will be a co-principal investigator for the extension of the Edmonton Protocol, says if the study's results are confirmed, islet transplantation may have finally reached the same level of success of whole organ pancreas transplantation.
"This gives patients the option of the cellular transplant instead of the organ transplant, which remains a much more invasive, major surgical procedure," he says. "We will continue to work with the Edmonton group to make this new approach available to more patients at different institutions in North America and Europe, as well as to work to make islet transplantation possible from single donors and without the requirement for chronic recipient immunosuppression."
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