McGowan Institute for Regenerative Medicine faculty member Massimo Trucco, M.D. (pictured), Chief of the Division of Immunogenetics at Children’s Hospital of Pittsburgh of UPMC, and scientists there are involved in a research study where microspheres carrying targeted nucleic acid molecules fabricated in the laboratory have been shown to prevent and even reverse new-onset cases of type 1 diabetes in animal models. This innovative scientific approach is currently in a Phase 1 clinical trial at the hospital.
In type 1 diabetes, T cells from the immune system travel to the pancreas and destroy beta cells, which produce insulin. The scientists found that the microspheres reprogram dendritic cells to block the signaling mechanism that sends T cells to destroy beta cells.
“The microspheres prevented the onset of type 1 diabetes and, most importantly, exhibited a capacity to reverse hyperglycemia, suggesting a potential to reverse type 1 diabetes in new-onset patients,” said Dr. Trucco. “This novel microsphere approach represents for the first time a vaccine with the potential to suppress and reverse diabetes. This finding holds true promise for clinical testing in people with type 1 diabetes.”
In mice with autoimmune diabetes, the scientists injected the microspheres under the skin near the pancreas. The microspheres were then captured by white blood cells known as dendritic cells which released the nucleic acid molecules within the dendritic cells. The released molecules reprogrammed these cells, and then migrated to the pancreas. There, they turned off the immune system attack on insulin-producing beta cells. Within weeks, the diabetic mice were producing insulin again with reduced blood glucose levels.
Currently, Dr. Trucco and his colleagues are conducting a clinical trial of their leukapheresis-based dendritic cell approach in humans at Children’s. This Phase 1 clinical trial has been approved by the U.S. Food and Drug Administration (FDA). If the leukapheresis-based approach continues to show exceptional safety, the researchers hope to launch a national clinical trial that will assess the effectiveness of the dendritic cells in pediatric patients to prevent diabetes or reverse the disease right after it is clinically confirmed.
Leukapheresis is a process that allows for the collection of dendritic cell precursors from the patients in the study, which takes 2 to 4 hours. After the precursors are collected, they are treated in the lab with specific growth factors that turn them into dendritic cells. The growth factors are also combined with short DNA sequences that specifically block the expression of molecules that are found at the surface of dendritic cells known as CD40, CD80, and CD86. Once these reprogrammed dendritic cells are tested in the lab, they are injected back into the patient. They then orchestrate an anti-diabetic effect by suppressing the activity of T-cells which are responsible for the impairment and destruction of the pancreatic insulin-producing cells.
Type 1 diabetes is regarded as an autoimmune disease because a person’s immune system’s T cells attack and destroy the beta cells in the pancreas that produce insulin. Symptoms of type 1 diabetes usually develop over a short period of time and include increased thirst, frequent urination, constant hunger, weight loss, blurred vision, and extreme fatigue. People with type 1 diabetes require numerous daily injections of insulin to survive. Type 1 diabetes also is known as insulin-dependent diabetes mellitus or juvenile-onset diabetes. The National Institutes of Health (NIH) reports that more than 1 million children and teenagers (age 19 and younger) have type 1 diabetes. According to the NIH, 5 percent to 10 percent of diagnosed diabetes cases in the United States are type 1 diabetes.
Dr. Trucco, an international leader in the field of immunogenetics, has dedicated his life’s work to finding a cure for diabetes. He also is the Hillman Professor of Pediatric Immunology at Children’s Hospital and a professor of Pediatrics at the University of Pittsburgh School of Medicine. His laboratory team at Children’s John G. Rangos Sr. Research Center has pioneered numerous important studies and also maintains a federally funded national bone marrow HLA typing center.
Illustration: McGowan Institute for Regenerative Medicine.
Children’s Hospital of Pittsburgh of UPMC News Release (05/28/08)
The Pittsburgh Channel (05/14/08)
United Press International (05/28/08)
Pittsburgh Post-Gazette (05/29/08)
Pittsburgh Tribune-Review (05/29/08)
Science Daily (05/29/08)
Diabetes Health (05/30/08)
Abstract (Diabetes 57:1544-1555, 2008)
Autologous Dendritic Cell Therapy for Type 1 Diabetes Suppression: A Safety Study