Researchers from Johns Hopkins Medicine in Baltimore have developed a modified version of a protein known as TRAIL, which they have shown can effectively destroy cells that cause the hardening of the skin associated with scleroderma. “Because the TRAIL protein can cause cancer cells to die while sparing normal cells, it was originally pursued as a cancer therapeutic. But likely because cancers are varied in composition, TRAIL was never shown to have much success in changing the course of cancer in humans,” said Seulki Lee, PhD, an associate professor in radiology and radiological science and member of the Center for Nanomedicine at the Johns Hopkins University School of Medicine, in a press release. The new research, published in Nature Communications, follows up on findings from another research group at the Mayo Clinic, which 16 years previously found that TRAIL was effective against cells that cause liver fibrosis. “We came into this rather accidentally, but are very pleased to find that the human TRAIL protein analog we developed could potentially be a universal drug for all types of fibrotic diseases, of which scleroderma is a classic example,” said Dr. Lee. “And the vast clinical expertise at Johns Hopkins has allowed us many fruitful collaborations to thoroughly test the drugs that we develop to ensure we have solid results before going into clinical trials.” The TRAIL protein was of interest because it is naturally produced by the body in response to inflammation and wound healing, so is well-tolerated and unlikely to cause side effects, said Dr. Lee. In earlier research, Dr. Lee’s team overcame an initial challenge working with the TRAIL protein—it was difficult to work with and too unstable—and engineered a version of TRAIL, TLY012, that works similarly to the original but is more potent and remains in the body longer. Dr. Lee and their team first analyzed skin biopsies from scleroderma and non-scleroderma patients to see if the TRAIL protein and other proteins it associates with are present. While they found non-scleroderma skin biopsies contained low levels of TRAIL and other associated proteins, skin from patients with scleroderma contained much higher levels. The researchers then isolated human dermal fibroblasts from patients with scleroderma. As a next step, the researchers isolated specific skin cells called human dermal fibroblasts from patients with scleroderma to see if treating them with TLY012 would cause them to undergo apoptosis, similar to what was reported in the liver in the 2003 research from the Mayo Clinic. After six hours of TLY012 treatment, these cells started dying, but TLY012 did not affect human dermal fibroblasts from patients without scleroderma. “This was encouraging to us because it both confirmed that the skin and liver cells are equivalent and it showed us that treatment with TRAIL can cause these diseased cells to die while sparing healthy cells, at least when grown in a dish,” said Dr. Lee. Building on these findings, the team next tested TLY012 in two different types of mice. In one mouse model, the researchers medically induced skin inflammation. After three weeks, these mice showed signs of severe fibrosis similar to scleroderma. The mice were then treated every other day for three weeks with TLY012, and their skin was compared to that of fibrotic mice that had received no treatment. The research team found that cells not associated with fibrosis were fine, but cells in the areas of fibrosis were undergoing apoptosis. The second mouse model were genetically engineered to have the skin fibrosis associated with scleroderma but without the severe inflammation that produces the fibrosis. These mice develop scleroderma-like skin when they are four to five weeks old. At five weeks, the mice began treatment every other day for five weeks, after which their skin was evaluated and compared to that of untreated mice. Untreated mice were found to have thickened skin and collagen deposits similar to human scleroderma, whereas treated mice showed molecular signs of dying cells with significantly less skin fibrosis. “These data say to us that TRAIL could potentially reverse skin fibrosis to near normal skin,” said Dr. Lee. “We discovered that TRAIL plays a critical role in wound healing and fibrosis in the body, thus offering more attractive therapeutic opportunities for the treatment of fibrosis.”
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