A counterintuitive discovery by a post-doc may open doors for eventual clinical trials testing the effectiveness of a synthetic peptide called ‘E4’ in fibrosis-related ailments. Individuals who suffer from fibrosis—a condition in which overproduction of the protein collagen leads to tissue thickening, scarring and, ultimately, organ damage—currently have no drug treatment options. Those lucky enough to get on an organ transplant list must impatiently wait.

“I think this study is intriguing,” says Paul Noble, a pulmonary specialist at Duke University’s School of Medicine in Durham, North Carolina. “The mechanism is unclear in terms of what E4 does to fibroblasts [cells found in connective tissue]. However, the study showed a dramatic clinical effect.”

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E4 is a synthetic version of a peptide building block obtained from the natural protein endostatin, which prevents angiogenesis. In the past, studies have linked high endostatin levels in patients with ailments such as lung fibrosis. Yukie Yamaguchi, a post-doc at University of Pittsburgh’s School of Medicine in Pennsylvania, wanted to replicate in her lab how endostatin could possibly cause fibrosis. But the protein did not cause scarring as expected—instead it prevented the overproduction of collagen. Yamaguchi conveyed her findings to her mentor, Carol Feghali-Bostwick, who helped isolate a peptide portion of endostatin called E3. Since E3 easily degrades, researchers chemically modified it to create a more stable and effective peptide called E4.

The results, published online 30 May in Science Translational Medicine, show that E4, when injected under the skin of mice and in cultured human skin, can reduce fibrosis and even prevent it from forming. E4 appears to inhibit the transforming growth factor-β (TGF-β) responsible for ramping up the overproduction of collagen in human skin. It also reduced levels of an enzyme known as lysyl oxidase (LOX) that cross-links collagen and lowered levels of a transcription factor called early growth response gene-1 (Egr-1). The TGF-β–induced thickening of the cultured human skin samples and mouse skin decreased by 30% and 24%, respectively*.

Noble says continuing recent developments in fibrosis research have put the field at a tipping point for a drug therapy available on the market. But even if E4 goes into a clinical trial it would solve only a component of fibrosis. “There are three hallmarks of systemic sclerosis [a connective tissue disease]: immune system abnormalities, vascular changes and fibrosis. A peptide might benefit the fibrosis part of the disease but not other aspects of the disease,” says Feghali-Bostwick. However, she’s optimistic that her research could help a subset of patients: “Some diseases may be mostly fibrotic and the peptide may be more effective in those.”

Previous research has focused on the fibrotic aspects of connective tissue diseases. Massachusetts-based Biogen Idec, is currently recruiting patients for a phase 2 trial to test the efficacy of an antibody therapy called STX-100, says spokeswoman Amanda Galgay. STX-100 appears to interrupt the production of TGF-β. See our 2011 news feature, ‘Scarred by disease‘, to learn more.

*CORRECTION: An earlier version of this post inaccurately stated that cultured human skin samples and mouse skin decreased 75% in thickness after treatment.