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City of Hope Researchers Develop Potential Cure for Advanced Type 1 Diabetes in Laboratory


5/11/2012 9:44:54 AM

New combination therapy approach may have possible application in other autoimmune diseases

DUARTE, Calif., May 10, 2012 /PRNewswire-USNewswire/ -- City of Hope researchers developed a combination therapy to treat late-stage type 1 diabetes that appears to offer a potential lifetime cure for the disease without toxic side effects. The laboratory study is published in the May 9 edition of Science Translational Medicine.

"Our findings indicate that it is possible to cure late-stage type 1 diabetes by stopping autoimmunity and regenerating insulin-secreting beta cells," said Defu Zeng, M.D., associate professor in the Division of Diabetes, Endocrinology & Metabolism and Department of Hematology & Hematopoietic Cell Transplantation, City of Hope.

Type 1 diabetes is an autoimmune disorder that affects 20 million people worldwide. In a person with type 1 diabetes, immune cells mistakenly attack and kill the person's own insulin-producing islet cells. Individuals can take insulin to manage diabetes for many years, but many develop cardiovascular problems over the long term. A few types of treatments have reversed new-onset diabetes in the lab, but no treatment except islet cell transplantation has been effective for late-stage diabetes. Islet cell transplants are not easily available, nor last longer than an average of 3 to 5 years.

Other developing therapies for type 1 diabetes either target the autoimmune condition or look to replace the destroyed islet cells, but not both together. Studies have demonstrated only limited success with these approaches, because correcting only one problem lets the other problem continue.

"While transplanting islet cells from another person can provide insulin independence, the effect lasts only about three years due to chronic rejection of the graft cells," said Zeng, the study's principal investigator. "Additionally, there is a shortage of islet donors."

The research team's strategy strives to both block the autoimmunity to prevent continued destruction of islet cells, and to stimulate the growth of new islet cells to restore healthy insulin regulation. The combination therapy begins with timed doses of anti-CD3 and anti-CD8 antibodies that specially target the host T cells followed by an infusion of donor bone marrow to induce mixed chimerism in the patient.

Mixed chimerism is a condition in which a patient's immune system is made up of both the patient's own cells as well as new cells from the donor bone marrow. The patient's defective immune cells are replaced by the healthy cells, stopping the autoimmune condition. Unlike traditional bone marrow transplants, this approach does not require radiation or high-dose chemotherapy.

Because type 1 diabetic patients with chronic, unresponsive disease often have too few functional islet cells left to regenerate healthy cells, the researchers follow up the mixed chimerism with growth hormones that can augment the beta cells regeneration from progenitors as well as stimulate the remaining islet beta cells to expand via replication, reestablishing normal insulin production and management.

"We have shown that conditioning with our anti-CD3-based regimen allows for induction of mixed chimerism with no signs of graft-versus-host disease in late-stage diabetes lab models," said Zeng. "We have also shown that combination therapy of mixed chimerism with administration of growth hormone is able to reverse late-stage diabetes, although either alone cannot."

Zeng and his team were able to reverse late-stage type 1 diabetes in lab mice through this strategy, not only halting the autoimmune process, but also helping new islet cells grow. As a result, diabetes was reversed in 60 percent of the diabetic mice that received the experimental therapy, while none of the control mice recovered from their disease, said Miao Wang, M.D., Ph.D., first author of the study and a postdoctoral research fellow in Zeng's lab. The mice that received the therapy had 10 times higher islet cell mass, three times higher insulin levels and improved insulin sensitivity and islet cell survival compared to the untreated mice.

Zeng is pursuing additional preclinical studies of the combination therapy, with the goal of gaining approval for human clinical trials.

The collaborative study also included researchers from the University of Florida Diabetes Center of Excellence in Gainesville, Fla., University of Florida College of Medicine in Gainesville, Fujian Institute of Hematology at Fujian Medical University Union Hospital in Fuzhou, China, and Nanfang Hospital at Southern Medical University in Guangzhou, China.

About City of Hope
City of Hope is a leading research, treatment and education center for cancer, diabetes and other life-threatening diseases. Designated as a comprehensive cancer center, the highest honor bestowed by the National Cancer Institute, and a founding member of the National Comprehensive Cancer Network, City of Hope's research and treatment protocols advance care throughout the nation. City of Hope is based in Southern California and is ranked as one of "America's Best Hospitals" in cancer by U.S.News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation and genetics. For more information, visit www.cityofhope.org or follow City of Hope on facebook, twitter, youtube or flickr.

CONTACT:
Shawn Le
Phone: 800-888-5323
sle@coh.org

SOURCE City of Hope



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