Research suggests path to more effective treatments created from a patient’s own skin cells.
BOSTON – (January 25, 2016) – In people with diabetes, a small skin wound can become a big problem, because wounds don’t heal as well as they do in people without the disease. Impaired healing is a particular concern in chronic diabetic foot ulcers, which lead to more than 80,000 lower limb amputations each year in the United States. Compounding this problem, “there are treatments for chronic wounds, but none of them really works for diabetic patients,” says George King, M.D., Chief Scientific Officer at Joslin Diabetes Center and Professor of Medicine at Harvard Medical School.
However, research in Dr. King’s lab has suggested a potentially more effective therapy that uses connective-tissue cells called fibroblasts. Described in a paper published today in the Journal of Clinical Investigation, the treatment would use a patient’s own cells, modified to lower production of a protein called protein kinase C delta (PKC-delta), which the scientists implicated in the slow formation of blood vessel cells in diabetic wounds.
“There’s not a lot known about wound healing in diabetes,” comments Dr. King. “This discovery is exciting because the treated fibroblasts are from diabetic patients and they work in an animal model. We also have a mechanism for why they work.”
Dr. King, lead author Mogher Khamaisi, Ph.D., and their colleagues looked at wound healing using fibroblasts from skin samples gathered from 26 members of the Joslin Medalist cohort (which is made up of people who have lived with type 1 diabetes for many years) with a median age of 79. They also studied a control group of seven people of similar age who don’t have diabetes.
The researchers found that, when stimulated by insulin, diabetic fibroblasts produced less of the VEGF (vascular endothelial growth factor) signaling protein, a key player in boosting the growth of blood vessel cells, than normal fibroblasts did. The researchers went on to determine that this abnormality was driven by the activation of PKC-delta.
Among their experiments, the scientists modified healthy fibroblasts to overexpress the PKC-delta protein, which converted the cells to behave like diabetic cells. Reversing the process, they found that suppressing PKC-delta expression in the diabetic fibroblasts converted the cells to behave more normally.
The Joslin researchers then transplanted these modified human diabetic cells into wounds in mice models of diabetes that also had suppressed immune systems so that they didn’t reject human cells. Earlier studies had shown that when normal cells are transplanted into such mice, they are quickly converted into a diabetic state. But the modified diabetic cells stayed normal for several weeks, allowing the wounds to heal.
If clinical studies show that this process also works in humans, “we could personalize the wound treatment,” Dr. King says. “We could take your own cells and treat them so they can’t become diabetic when you put them back into a diabetic wound.”
The transplanted fibroblasts would work not by growing into the wound but by making more nurturing products such as VEGF protein and thus boosting blood vessel growth. “The hope is that all you need is three or four weeks of these nutrients, and then the tissue will take over by itself and the wound will heal,” he says.
Importantly, research also indicates that the approach could prove effective even if patients are unable to maintain tight control of their blood glucose levels. While the study was done with cells from people with type 1 diabetes, similar results are expected for people with type 2 diabetes.
Such a therapy would require a safe way to modify the fibroblasts for medical use. Dr. King points out that a number of oral drug candidates inhibit PKC-delta and that it may be possible to suppress PKC-delta production with microRNAs (small RNA molecules that help to regulate protein generation). He emphasizes that these modifications would be applied to cells in culture, not delivered to patients systemically, thus potentially reducing the risks of side effects. The Joslin team is now setting up collaborations with surgeons to move the approach into clinical studies.
Joslin co-authors of the paper included Sayaka Katagiri, Hillary Keenan, Kyoungmin Park, Yasutaka Maeda, Qian Li, Weier Qi, Thomas Thomou and Amy Wagers. Other contributors included Danielle Eschuk, Ana Tellechea and Aris Veves of Beth Israel Deaconess Medical Center; Chenyu Huang of Tsinghua University Medical Center; and Dennis Paul Orgill of Brigham and Women’s Hospital. Lead funding for the research came from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
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