Depleting an enzyme called GM3 synthase with gene therapy may help diabetics heal wounds faster, according to recent research by Northwestern Medicine scientists.
Nearly 21 million people in the United States have type 2 diabetes. About 15% of them experience chronic wounds that heal poorly, especially in the feet.
“There are many factors that influence this poor wound healing, among them poor functioning of the nerves and blood vessels that supply the skin, issues related to poor sugar control, and resistance to the effects of insulin and other growth factors, which are important for how skin cells move and grow to close a wound,” said Amy Paller, MD, ’81, ’83 GME, Walter J. Hamlin Professor of Dermatology and chair of the Department of Dermatology.
In work published in the Journal of Investigative Dermatology, the Paller lab found that mice engineered to be deficient in GM3 synthase resist becoming diabetic on a high fat diet and have no trouble with wound healing, despite becoming obese. GM3 synthase is a key enzyme in making GM3, a molecule important in the function of growth factors.
The Paller lab then looked at whether GM3 synthase depletion in these mice had effects specifically on their skin cells.
“The skin cells that lacked GM3 synthase grew faster, moved more quickly in ‘wounds’ made in culture dishes and showed greater responses to insulin and insulin-like growth factor-1,” said Dr. Paller, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Next, they fed the cells high concentrations of sugar to mimic the environment of poorly controlled diabetes. While growth and movement in the cells with standard levels of GM3 synthase slowed dramatically, the cells missing GM3 synthase actually grew and moved even more quickly to heal the wound.
The direct effect on skin cells suggests the possibility of topical treatment to decrease levels of GM3 synthase at the wound site, a focus of ongoing research.
“Our subsequent work has been focused on two clinically-relevant questions in particular: One, can we replicate the reduction in GM3 synthase in the mouse with diabetes by applying a cream onto the skin at the site of the wound? And, two, is the effect of reducing GM3 synthase in the mouse fully or largely because of the changes in skin cells, or are there effects beyond the skin?” said Paller.
Working with Chad Mirkin, PhD, professor in the Department of Chemistry and Director of the International Institute of Nanotechnology, Paller is currently testing a gene therapy approach for diabetic wounds with spherical nucleic acids (SNAs), special combinations of genetic material and nanoparticles.
The Mirkin lab developed SNAs for topical application to skin, a topic the Paller and Mirkin labs described recently in the Proceedings of the National Academy of Science USA.
Applying GM3 synthase SNAs in a common moisturizer to the wounds of diabetic mice has led to promising early results. The scientists hope to ultimately transition this approach to human trials.
The published work was supported by the National Institutes of Health grants R01AR44619 and R21AR062898 and the Astellas Research Endowment and used Core resources provided by the NIH-funded Northwestern University Skin Disease Research Center.
