By: Rebecca Borlaug
Islet cell transplants, a treatment that could reverse diabetes, is no longer a pipe dream. Success has been demonstrated in about 30 patients at a number of institutions worldwide.
Since 1974, 300 islet cell transplants have been given to humans using adult tissue from cadaver donors. “Now that we have learned about transplants, we have a better understanding of the problems and of the potential,” says Dr. Bernhard Hering, assistant professor of surgery and medicine at the University of Minnesota.
Islet cells are the cells in the pancreas that produce insulin. In people with type I diabetes, these cells are damaged or destroyed, disabling them from making insulin. As a result, a person with type I diabetes is required to take injections of insulin for survival. Over the past decade doctors all around the world have immersed themselves in work on islet cell transplantation. It is believed that if healthy donor islets could be introduced into a diabetic recipient, and not rejected or destroyed by the immune system, they would begin manufacturing insulin, thereby reversing diabetes.
Drugs Bring Disadvantage
A significant fact is that until now life-long immunosuppressive drugs have been required by the recipient of any transplant, including that of islet cells. Immunosuppressive drugs are toxic to the body and potentially harmful because they suppress the immune system, setting the stage for infections. Due to this risk, islet cell transplants have been limited to people who were already on immunosuppressive drugs from a previous transplant or to people who have an organ transplant simultaneously.
Islet cell transplantation is tricky business. Doctors have been exploring several different means of introducing donor islet cells to patients without having the immune system reject them, while trying to reduce the use of immunosuppressive drugs. Techniques to do this include, but are not limited to, gene therapy, encapsulation and induced body tolerance.
Pushing it to the Limit
There are a number of issues, aside from the use of immunosuppressive drugs, surrounding islet transplants. One of the most important is where the islets come from. Each year there are roughly 4,000 cadavers available for organ transplantation. Gary Kleiman, the executive director of medical developments at the Diabetes Research Institute at the University of Miami, explains that because islet cell transplantation does not stem from an immediately life-threatening condition, other transplants are given priority. More importantly, if islet cell transplantation is successful it will be impossible to meet the demand for islet transplants based on the few thousand available human pancreases. To solve this problem researchers are looking at the use of pig islets as well as cell proliferation (growing cells).
Research teams approach the issue of islet cell transplantation differently. While some private companies and academic institutions focus on one technique, others look at a variety of techniques.
Academic research institutions usually look at a number of different ways to transplant islet cells as opposed to focusing on a single technique, as private companies tend to do. This is not to say success will come easily to either. Most researchers agree that several areas of research need to be explored to insure the progress of islet cell transplantation.
University of Minnesota
In 1994, the Diabetes Institute for Immunology and Transplantation was established at the University of Minnesota by Dr. David Sutherland, the pioneer of whole pancreatic organ transplantation. Dr. Sutherland’s goal now is to make treatment for diabetes very simple: just one injection of insulin-producing cells that will last a lifetime and not require harmful drugs to prevent rejection.
Last year Dr. Bernhard Hering, a doctor from Germany, joined the Diabetes Institute for Immunology and Transplantation as the head of the islet transplant program. Dr. Hering has been practicing islet cell transplantation for a number of years. In one of his most recent trials, 12 patients received an islet cell transplant and a kidney transplant simultaneously (or very close together). The results were quite promising.
Nine out of the 12 patients showed evidence of ongoing production of insulin by the transplanted cells. This was associated with significantly improved blood glucose control and freedom from severe hypoglycemia. Four of the 12 became completely insulin-independent and remained so after a one-year follow-up.
Dr. Hering attributes the failure to consistently establish insulin independence to the use of steroids as part of the anti-rejection treatment. For decades steroids, used as one of two or three anti-rejection medication protocols, have been known to cause diabetes.
In a trial beginning this year, Dr. Hering and Dr. Sutherland will test the use of a low-risk, steroid-free, anti-rejection treatment.
“Immunosuppressive drugs are still required but they are getting safer. If a low-risk anti-rejection protocol can be developed in recipients of simultaneous kidney/islet grafts, islet cell transplants can then be offered to another subgroup of diabetic patients,” says Dr. Hering. People with brittle diabetes, those with frequent acute complications such as hypoglycemia and those who require frequent hospitalization or recurrent medical attention, could then become potential candidates.
The procedure itself is done with local anesthetics, and nearly without any risks, in 15 minutes, explains Dr. Hering. The islets are injected into the portal vein of the liver that branches into capillaries, where the islets can secrete insulin directly into the circulatory system to control blood sugars.
“Results are continuously getting better,” says Dr. Hering. “The goal is to make the anti-rejection treatment safer and to make islet transplantation available to more people early in the course of their diabetes.”
Joslin Diabetes Center
Joslin Diabetes Center is one academic institution researching two areas of study: macro-encapsulation and gene therapy. Dr. Gordon Weir, head of Islet Cell Transplantation and Cell Biology and professor of medicine at Harvard Medical School, believes he should “keep his feet in both camps.”
Macro-encapsulation and micro-encapsulation are two distinct procedures used to keep the immune system from attacking the transplanted islets. Macro-encapsulation involves the encapsulation of the islets as a group, whereas in micro-encapsulation researchers encapsulate the islets individually. Using mainly pig islets, Dr. Weir’s research team has routinely reversed diabetes in mice. Their next step is to test the procedure in monkeys.
Gene therapy is more complicated. It involves changing the genetic characteristics of a cell. “Our goal is to introduce new genes into the cell that may allow them to resist attack from the immune system,” explains Dr. Weir.
Introducing new genes into cells can be done in a variety of ways “which can change the characteristic of the cell and even make cells that can produce insulin,” says Weir. “This is still in the very early stages, but the power is extraordinary.”
In 1986 Dr. Patrick Soon-Shiong and his research team made a fundamental commitment to developing micro-encapsulation technology as a method for protecting islet cells. At this time other leading private research groups, like W.R. Grace, Cytotherapeutics and Neocrin, were exploring membrane technology rather than encapsulation. VivoRx remained the sole voice espousing the value of encapsulating individual islets with membranes.
“Our strong belief in this technology has now been validated by the decision of Neocrin to abandon their membrane devices and concentrate their efforts on micro-encapsulation,” says Dr. Soon-Shiong.
“By focusing our efforts on micro-encapsulation for the past six years we have explored all forms of isolating cells from the immune system using multi-fold raw materials including alginate (seaweed), polyethylene glycol polymer (a chemically defined substance) and a combination of both. We discovered that polyethylene glycol polymer resulted in inferior capsules which were not only less protective but also toxic. As a result, we concentrated our efforts on the alginate capsule, a naturally occurring non-toxic raw material.”
VivoRx has achieved a series of firsts in the long road to developing a bioartificial pancreas made of live tissue and artificial membranes. Among these, VivoRx was the first to achieve insulin independence in a man in 1993, using encapsulated human islets. The patient has now been followed for 43 months since the first procedure. VivoRx is also the first to receive Food and Drug Administration (FDA) approval to initiate encapsulated islet transplantation in man using proliferated (lab grown) human islets. The first patient to have received this procedure has shown encouraging results and evidence of islet function.
VivoRx also received approval by the FDA to initiate treatment with encapsulated porcine (pig) islets in patients with type I diabetes who have received a kidney transplant. Eight months ago Dr. Soon-Shiong, Professor Bob Elliott from the University of New Zealand and their research teams performed the world’s first encapsulated porcine islet transplant in a diabetic patient without the use of immunosuppression drugs.
“We are extremely excited by the results of this first transplant and have now shown evidence of porcine islet function even without immunosuppression using VivoRx’s encapsulation technology,” says Elliott.
University of Toronto
In 1994, Dr. Anthony Sun claimed he was “100 percent confident” he had a cure for diabetes. Since then, the Journal of Clinical Investigation has reported that Dr. Sun successfully reversed diabetes in diabetic monkeys. His technique: pig islets micro-encapsulated in a semi-permeable membrane prepared of sodium alginate and polylysine. The membrane protects the cell from the recipient’s immune system, is permeable enough to pass insulin freely but strong enough to keep out antibodies and other harmful elements. Sounds good, so what’s holding them back?
“The government has come up with guidelines for xenotransplants [cross-species transplants],” says Ivan Vacek, a microbiologist at the University of Toronto. Xenotransplants have brought a number of issues to the forefront. Some fear the risk of introducing pig diseases into the human body.
The FDA has had some discussion about the use of animal islets and has set up guidelines. Its main concern is xenograft complications, or the passing of cross-species diseases.
Dr. Edward Pope of Matech, a PhD in material science and engineering, does not share these xenotransplant concerns. Matech is a company in California encapsulating pig islets in a ceramic gel. So far, Matech has been able to reverse diabetes in mice.
“A lot of unjustifiable hysteria has been stirred up,” says Dr. Pope. “If there is anything we could catch from pigs, we would have caught it already.”
Alastair Gordon, the president of The Islet Foundation (whose main role is to create awareness of islet cell transplantation), says xenotransplants are much safer than human-to-human transplants. According to Gordon, any virus in a human donor can infect the recipient, but pigs can be raised in a pathogen-free environment. In addition, almost no pig viruses are capable of infecting humans, he claims.
Since 1994, Dr. Sun has helped prepare the grounds for future islet cell transplantation in humans in China. Currently, Dr. Sun and his research team are keeping monkeys with diabetes off insulin using their encapsulation technique.
Neocrin, a private company in southern California, has successfully reversed diabetes in rats and is currently testing primates with the help of Dr. David Scharp, a transplant surgeon and chief scientific officer at Neocrin. Like VivoRx, Neocrin has been using a polyethylene glycol polymer to micro-encapsulate pig islets.
“The polymer offers improved immune protection, a key advantage over alginate,” says Greg Dane, president and chief executive of Neocrin.
Unlike Dr. Sun in Toronto, Dane says the FDA guidelines are appropriate, and with minor modifications will permit the safe, commercial application of encapsulated cell therapy using non-human cells. Neocrin will continue its primate trial through 1997. The company hopes to file an application in 1998 for approval to test in humans.
“I think there is tremendous promise for diabetics, not only for type Is but all diabetics who use insulin regularly,” says Dane.
Diabetes Research Institute
The Diabetes Research Institute at the University of Miami has made great strides in its success with islet cell transplantation. Since its beginning in 1971, DRI has become a recognized world leader in diabetes research. Part of its success can be attributed to its collaboration with researchers and scientists worldwide. DRI has targeted programs and established specific research projects employing the services of doctors from around the world. Dr. Camillo Ricordi, DRI’s scientific director and chief academic officer, recently launched the Interinstitute, a virtual (on-line) institute to promote collaboration in the area of translational research (research aimed at taking basic research and applying it to humans).
“If we want to make a difference in the search for cures of disease states, we should be ready to abandon the concept of ivory towers and single-investigator-driven research and promote collaborations between investigators and institutions to verify basic findings towards applications that are relevant to the clinical setting [translational research],” says Dr. Ricordi.
DRI has come a long way since its first milestone in 1984: curing diabetes in dogs using islet transplantation and cyclosporine, an immunosuppressive drug. Today, recognizing the negative impact of immunosuppressive drugs, DRI is months away from a trial that, if successful, will reverse type I diabetes in humans with the minimal use of immunosuppressives.
The project, Human Islet Cell and Bone Marrow Transplantation Trials, will test the effectiveness of multiple infusions of donor bone marrow. The idea is that donor bone marrow will help make the recipient tolerant to the donor islet cells. Bone marrow contains “stem cells,” cells that are capable of producing every cellular component of blood. By injecting stem cells from the islet donor it is hoped that scientists will be able to fool the recipient’s body into using both its own immune system, and the one presented by the stem cells.
Clinical studies conducted by DRI and the Division of Transplantation at the University of Miami have shown that high doses of donor bone marrow infusions greatly enhance graft acceptance in organ transplant patients. Based on these encouraging results, along with evidence of long-term function of transplanted islet cells in patients requiring immunosuppression, DRI received approval from the University of Miami’s Institutional Review Board to begin the trial. This technique does not require the use of more than one donor per transplant.
“The process of recruiting patients is taking longer than we expected because we have to screen (candidates) very carefully,” says Dr. Rodolfo Alejandro, director of clinical research at the DRI Cell Transplant Center and professor of medicine at the University of Miami.
Once the trials do begin, who gets the transplant will depend on the best donor/recipient match. Considerations such as age and health conditions have to be taken into account before a match is made. After the islet cells are isolated and removed from the donor organ, they are then matched to someone on the list of acceptable patients. Fresh human islets can only survive for a few days outside of a body before they become useless. Therefore,
the processing of the islets needs to be done within 24 hours and the patient has to be ready to receive the transplant within three days.
For the first ten days after the transplant the patients will remain on high doses of immunosuppressive drugs. Then they will be tapered off of the drugs over the course of a year.
Islet cell transplantation is not a new idea, but it still has obstacles to overcome.
Organizational funding, or the lack thereof, is a common grievance of both private companies and academic institutions.
“Something has to account for the poor decisions being made by funding organizations,” says Alastair Gordon.
“One possible reason,” he speculates, “is the fear of a cure. Another could be the fear of failure.”
Before funding is approved by organizations, applications are peer reviewed. This means they are reviewed by other scientists in the field. It is possible that issuing a grant toward a feasible cure could overshadow a reviewer’s current and future research work. Reviewers know that once a cure is found there will be much less interest in funding projects that deal with basic mechanisms of the disease and its complications.
Fear of Failure
Failure of a research project could result in the loss of millions of dollars. With this in mind, funding organizations tend to focus on “safe” or incremental areas of research which promise no breakthroughs. If nothing is promised, then there is no risk of an embarrassing failure. Sadly, Gordon says, without risking failure there can also be no real progress, and diabetes will remain the scourge it is today.
“Our research is funded by grants and donations,” says the DRI’s Gary Kleiman. “Grants are limited. There are more researchers fighting for the same pool of money. The National Institutes of Health has reduced each individual grant because more scientists need money and there is no additional funding.” (Figures published by the budget office at NIDDK in 1994 report that the NIH spent $7,078,000 out of $280,000,000 on pancreas and islet transplantation research.)
For these reasons, Kleiman explains, the majority of funding organizations support less expensive research projects limited to test tube and mouse phase research. There is no substantial funding or incentive to do translational research – the only kind that will help those living with diabetes.