Progress is rapid in islet cell transplants

Islet cell transplants are effective in both the short- and long-term in freeing patients with diabetes from insulin injections and have proven to be safe, said Bernhard J. Hering, MD. The use of embryonic pig pancreatic precursor tissue as the source of islets appears promising and would expand the number of transplant recipients, which is currently limited by number of potential donors.

Licensure for human islet transplantation is well under way, he said. Clinical trials have demonstrated dramatic improvements in glucose control before and after islet transplantation and "the problem of hypoglycemia is eliminated," said Dr. Hering, professor of surgery and director of the islet transplant program, scientific director of the Diabetes Institute for Immunology and Transplantation, University of Minnesota, Minneapolis. Fewer than 5% of patients experience severe hypoglycemia after transplantation.

Phase 2 and 3 clinical licensure trials are being performed. The primary endpoint of the phase 3 trials is the proportion of subjects with hemoglobin A1c levels lt;7% and no episodes of severe hypoglycemia at 1 year.

Long-term success with induction therapy is common; about 60% of transplanted patients achieve insulin independence at 1 year. Of these, 20% remained insulin-free at 2 years.

Islet autografts have been fairly durable; islet function at 1 year is 61% and at 5 years it is 48%. In pediatric patients, 40% retained insulin independence at 5 years. The decline in islet function over time may be related to immune-mediated injury from standard immunosuppressive treatment regimens. Another factor is that the immunosuppressants tacrolimus and sirolimus used for maintenance immunosuppression inhibit beta-cell regeneration, said Dr. Hering.

Studies of islet transplantation in type 1 diabetics with hypoglycemic unawareness using efalizumab, a humanized humanized IgG1 monoclonal antibody directed against lymphocyte-function associated antigen-1 (LFA-1), as a part of the immunosuppressive regimen are being conducted.

Pig islets being considered
Because of a shortage of human donor pancreases in the United States, and the large number of patients with type 1 diabetes who have hypoglycemia unawareness, pig islets are being studied as a source for islet transplantation. The islet quality would be consistently high and not compromised by age, comorbidities, brain death and cold ischemic injury, said Dr. Hering. Transplantation of embryonic pig pancreatic precursor tissue in cynomolgus monkeys receiving immunosuppressant therapy has resulted in normoglycemia for more than 2 months and a 90% reduction in exogenous insulin requirements. Genetic engineering of pig islets has improved transplant outcomes: adult islets isolated from transgenic pigs and transplanted in cynomolgus monkeys have resulted in normoglycemia for greater than 1 year.

Phase 1 and 2 studies of pig islets should begin in a few years. "Studies on human/pig islets will facilitate translational research on surrogate and stem cell-derived islets and possibly also progress on islet regeneration," he said.