Can Current Diabetic Research Replace the Edmonton Protocol

Were it not for the Sertoli cell, none of us would ever have been born. It is the testicular Sertoli cell which keeps the human body’s immune system from destroying a man’s sperm. This same cell might create an immunologically protective environment for transplanted pancreas islets and could provide new hope for Type 1 diabetics whose bodies reject those transplants.

Sernova Corp (TSX: SVA), which holds more than 20 patents related to the therapeutic use of Sertoli cells, is currently researching how to prevent islet cells from being killed off by immune-suppressing drugs. Current islet transplant procedures require the use of these anti-rejection drugs to prevent the body’s immune system from destroying the transplanted islet cells.

The first ray of hope for the million or more suffering from Type 1 diabetes came after a discovery in the year 2000 that certain immune-suppressing drugs prevented islet transplants from succeeding. Researchers led by Dr. James Shapiro at the University of Alberta in Edmonton, Canada began using a less toxic drug combo.

Known as the ‘Edmonton Protocol,’ because it was developed at the University of Alberta, the procedure offered hope for insulin-dependent diabetics, known as Type 1 diabetics. For the procedure, doctors collected about one million islet cells from two or more donor pancreas, purified them and injected them into the liver of the diabetic. Surgery amounts to a tube inserted into the hepatic portal vein where the islet cells are dripped into the liver. Seven Type 1 diabetics were transplanted with islet cells using this pioneering technique, which created excitement in this field.

But a new study, recently reported in the New England Journal of Medicine, showed transplants of insulin-making cells, using the Edmonton Protocol, failed to free Type 1 diabetics from insulin shots. After two years, only five of 36 patients – less than one in seven – remained insulin independent. While the procedure improved a patient’s blood sugar control, the transplants failed for ten of the 36 patients within a year of receiving islet cells from the pancreas of organ donors. The majority of patients were forced to return to insulin-dependence because one-half to three-quarters of the islet cells died.

During the study there were 38 serious adverse events, some of which required hospitalization. Patients are given immune-suppressing drugs after the islet cell transplants to block the immune system from identifying those foreign cells. Complaints from the medical profession criticize the anti-rejection drugs because the immune system fails to work the way nature intended. Patients are at risk of getting infectious diseases and other side effects.

Will Sertoli Cells Replace Anti-Rejection Drugs?

In unlocking the riddle of keeping the transplanted islet cells alive, the problem may be in the anti-rejection drugs. “We will have to develop strategies to educate the recipient’s immune system to tolerate the islet cells,” said Camillo Ricordi, M.D., chief cellular transplantation and scientific director of diabetes research at the University of Miami School of Medicine. “When we do this, we can treat all Type 1 diabetic patients, and also Type 2 diabetes patients who are dependent on insulin.”

Numerous researchers are searching for the unique anti-rejection drug which would prevent the body’s immune system from destroying the transplanted islets. Seung Kim, M.D., PhD, and assistant professor of developmental biology at the Stanford University School of Medicine recently announced that immune-suppressing drugs inhibit a protein called calcineurin. Dr. Kim discovered when the protein is inhibited, this hampers the beta cells from keeping blood sugar in check. When the beta cells fail to produce insulin, or too little of it, sugar stagnates in the blood and is not moved into the cells to produce energy for the body. In a nutshell, the anti-rejection drugs, surgeons have used to help islet transplants take hold, might be the culprit which unravels their procedure.

Sernova Corp is presently researching Sertoli cells as a replacement for anti-rejection drugs. “The recent New England Journal of Medicine study confirms that overcoming the body’s immune response to islet transplants remains the biggest hurdle to a successful treatment for Type 1 diabetics,” Sernova President Justin Leushner told StockInterview in a recent telephone interview. “The Edmonton Protocol is a great stepping stone as a proof-of-concept of what we are trying to do. It has now been demonstrated that by transplanting islets into a diabetic, you can restore the insulin-producing cells.”

Leushner calls Sertoli cells “Mother Nature’s anti-rejection drug” because of their immuno-protective property. He explained, “It’s been known for a long time that the testicles are an immune-privileged environment. Otherwise, our sperm would be attacked by our immune system.” It is on this basis Sernova Corp has moved forward in researching the impact the co-transplantation of Sertoli cells with pancreatic islets as a way to reverse Type 1 diabetes. “The Sertoli cells are the backbone of our company and our technology,” Leushner told us.

Several studies involving testicular Sertoli cells with pig islets transplanted into rats and mice have shown promise with this technology. A University of Alberta study, published in Diabetologia (2000, 43:474-480) demonstrated that testicular Sertoli cells can protect allogeneic islet grafts from rejection after transplantation into animals with chemically induced diabetes. Another study, conducted at the University of South Florida College of Medicine, which was published in the Annals of the New York Academy of Sciences in 2001 (944:420-428) also offered hope in cell transplantation therapy for diabetes using Sertoli cell-enriched tissue constructs.

Human Diabetes Reversal in Mexico City

In a recent controversy, the prominent Mexican transplant surgeon Dr. Raphael Valdes was given an unusual vote of no confidence by the International Xenotransplantation Society for his reversal of Type 1 diabetes in humans. Dr. Valdes had begun co-transplanting Sertoli cells with islet cells, both derived from piglets, into humans. Valdes has claimed to reverse diabetes in 31 Mexican patients. Although many of his patients stepped forward to defend Dr. Valdes, the Society censured him for skipping pre-clinical tests on primates. During a recent interview, Valdes said, “This procedure has worked well and we have never had any complications in any patients in five years.”

Valdes’ former professor at Cambridge University (UK), Dr. David White, is now conducting the mandatory pre-clinical research at the Robarts Research Institute at the University of Western Ontario. Dr. White is also chairman of the scientific advisory board of Sernova Corp, which is funding the research to develop a commercial product to reverse Type 1 diabetes.

Dr. White said of Valdes’ research, “Clinically, his work has extraordinary potential.” Previous attempts at xenotransplanting animal islet cells into humans failed because researchers could not get those cells to survive for long in a human body. Dr. White believes Valdes’ pioneering work could help him develop a revolutionary new therapy.

We spoke with Dr. White this past June at his offices in London, Ontario. He hoped to ‘back track’ Dr. Valdes work by starting with rodent studies and moving forward to primate trials. This would appear to satisfy the demands by the Xenotransplantation Society and provide a scientific basis for progressing to human clinical studies.

Dr. White told us he hoped his research would improve upon Dr. Valdes’ efficacy rate in helping patients become insulin independent. His challenge is to identify the most effective ratio of Sertoli cells to islet cells for the co-transplant process. He envisions diabetes reversal in the coming years without the use of anti-rejection drugs. White told us, “Immunosuppression drugs are very toxic to the human body.” He would know. As a young researcher at Cambridge University, Dr. White was part of the research team which helped develop Cyclosporin A, an immune-suppressing drug, to prevent the body from rejecting organ transplants. Perhaps his current research will lead to yet another breakthrough.

Sernova Corp’s proposed solution is under the working hypothesis presupposing that once islets and Sertoli cells are injected into a small vascularized chamber implanted below the skin, the islets can produce insulin in response to the body’s demands while the Sertoli cells protect the islets by masking their presence from the immune system. According to Leushner, “This ongoing research is built upon several proof-of-concepts experiments already completed by Dr. David White and others.”

Leushner concluded, “We hope to do xenotransplantation without the human recipient rejecting those cells. By using Sertoli cells from pigs and islet cells from pigs, and transplanting them into a human recipient, the islets can function normally without being rejected. And we hope to do this without the use of immuno-suppressive drugs, which have caused most, if not all, the negative effects of getting the islet transplants.”