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Gene Expression Changes Found in Wound Healing Therapy

Apligraf disk

Apligraf disk (Organogenesis Inc.)

4 January 2016. A clinical trial to reveal the mechanism of a cell therapy to treat venous skin ulcers found the therapy works by altering the gene expression activity of treated cells to resemble healthy tissue. The trial testing Apligraf treatments, developed by Organogenesis Inc. in Canton, Massachusetts, is reported in today’s issue of the journal Science Translational Medicine.

Venous skin ulcers are shallow wounds that result from poor circulation in the veins that do not return blood back to the heart, a condition known as venous insufficiency. The sores normally occur in the lower leg, between the ankle and the calf. Venous ulcers can take months to heal, and account for 80 percent of all chronic wounds, according to National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the National Institutes of Health, that estimates treatments for the condition cost the U.S. health care system more than $1 billion a year.

Apligraf treats venous leg and diabetic foot ulcers with living cells and associated proteins to encourage healing of the chronic wounds. The treatments are applied in two layers, with the top layer consisting of human keratinocytes, or outer skin cells, and a lower layer of bovine collagen — a protein found in connective tissue, such as skin and cartilage — and human fibroblasts, cells that combine with collagen to repair injured tissue.

Apligraf is applied as a circular disk, 75 millimeters (3 inches) in diameter. The lower layer of the disk generates more structural proteins that encourage keratinocytes in the top layer to multiply and then differentiate to resemble the structure of the tissue being repaired.

FDA first approved Apligraf as a treatment for venous leg and diabetic foot ulcers in 1998. But the agency asked Organogenesis to conduct a study following its approval to better understand the treatment’s mechanism of action. The study was a clinical trial of 30 individuals having venous leg ulcers, with participants randomly assigned to receive Apligraf or standard foam compression dressings for comparison.

Marjana Tomic-Canic, a dermatology professor at University of Miami medical school in Florida, led the team. (Organogenesis helped fund the study, but the team otherwise had no connection to the company.) The researchers looked primarily at changes in gene expression in the wounds, specifically tissue at the edges of the wounds both before the treatments and 1 week later. The tissue samples were taken in biopsies, then analyzed for changes in messenger RNA transcribed from genes in the cells and proteins produced.

The results show cells treated with Apligraf expressing RNA and proteins similar to wounds in healthy healing tissue rather than the chronic, non-healing tissue from before the treatments. These expression patterns include protein signals sent by the cells, such as inflammation and growth factor signals, and activation of keratinocytes in the healing process. “Our findings show,” says Tomic-Canic in an Organogenesis statement, “that Apligraf can shift the gene expression profile of a chronic, non-healing ulcer to resemble a profile similar to that of an acute, healing wound.”

In addition to confirming the mechanism of Apligraf, the results offer a road map for developing further wound healing therapies. “This is important,” adds Tomic-Canic, “as we now can use this as a guiding tool to understand healing of a chronic wound and mechanisms by which therapies can work.”

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