ATLANTA—Two of the most common and debilitating complications of diabetes are the subject of new NIH-funded studies at Emory University School of Medicine. Researchers are working to re-program cells taken from the bone marrow or peripheral blood of patients with diabetes to treat neurovascular complications such as peripheral arterial disease (PAD) and diabetic neuropathy (DN).

The National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (NIH), has awarded the research team, consisting of investigators at Emory, Georgia Tech, University of Alabama and University of California at San Diego, a $6.1 million grant.

Principal investigators of the study, called “Cell therapy for diabetic peripheral neurovascular complications,” are Young-Sup Yoon, MD, PhD, director of stem cell biology and associate professor of medicine (cardiology) in Emory School of Medicine, and Xiaodong Cheng, PhD, professor of biochemistry in Emory School of Medicine and a Georgia Research Alliance Eminent Scholar.  Andres García, professor in the George W. Woodruff School of Mechanical Engineering at Georgia Institute of Technology, is the investigator for Georgia Tech.

Patients with diabetes are frequently affected by PAD and DN, but despite the increase in incidence of diabetes, no current treatments effectively treat these conditions, notes Yoon. “Even after patients achieve glucose control, diabetes can lead to long-term complications,” he says. 

Patients with PAD experience blocked arteries in the legs and feet, which can lead to leg amputation in advanced cases. Because advanced PAD in diabetes frequently affects small vessels, conventional intervention and surgical treatment are ineffective in many cases.

DN, which damages the neural vasculature and neuronal cells, is the most common complication of diabetes, affecting 60 percent of patients.

Growing evidence has shown that cells taken from a patient’s own bone marrow, called bone marrow-derived endothelial progenitor cells (EPCs), can be effective in treating various cardiovascular diseases and diabetic neuropathy by repairing blood vessels. Thus far, however, EPCs derived from diabetic patients have been only modestly effective for these autologous (self-directed) therapies.

The Emory research team, based on earlier findings, believes epigenetic changes in the EPCs of diabetic patients may be at fault. Epigenetic factors direct genes to be either expressed or silenced, but they don’t affect the underlying DNA sequence of an organism. Epigenetic alterations in the chromatin of the EPCs of diabetic patients seem to be the culprit. Chromatin is the packaging mechanism for DNA in the nucleus of cells.

“We plan to investigate epigenetic chromatin changes in diabetic EPCs, and to reprogram or re-engineer these EPCs with small molecular epigenetic regulators and biomaterial to enhance or restore their function,” Yoon explains. “Other research has shown the ability of small molecules to induce chromatin remodeling of affected genes and alter gene expression, and we believe this is a promising approach.”

The research team will use animal models to test the therapeutic effects of the reprogrammed cells for PAD and DN. The next step will be a pilot clinical trial in human patients with complications of diabetes.

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