New scleroderma therapy BLR-200 shows potential to prevent scarring
Findings in mice will guide treatment's transition to human patients
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BLR-200, a new therapy for scleroderma that’s being developed by a biotech startup in Chicago, may prevent activation of a group of cells involved in the disease’s characteristic scarring — possibly preventing patches of hardened skin from forming.
That’s according to new research conducted by the startup, BLR Bio, in a mouse model of scleroderma. The scientists believe their findings, presented at the British Society for Rheumatology Annual Conference last month, can be translated into treatments for people with the chronic condition, which is marked by scarring, or fibrosis.
“Our goal is to provide relief and healing to patients with this terrible disease,” Bruce Riser, PhD, CEO of BLR Bio, said in a press release from Rosalind Franklin University (RFU). The startup was launched through RFU’s Helix 51 Incubator program, which provides lab space and equipment to developing biotech companies.
“We are encouraged by BLR-200’s ability to interrupt key biological pathways that drive fibrosis, or tissue scarring, in scleroderma,” Riser said.
The study also suggested that levels of CCN3, a fibrosis-suppressing protein on which BLR-200 is based, vary among patients. This could help guide translation of the lab findings into human patients in future trials, the researchers noted.
Riser was the senior author of the study, presented in a poster titled “CCN3-derived peptide BLR-200 attenuates skin fibrosis by preventing activation of engrailed-1/COL8A1-expressing universal fibroblasts.” In addition to his position at BLR Bio, Riser is a professor of physiology and biophysics at RFU.
Scleroderma is an autoimmune disease in which cells called fibroblasts produce excessive amounts of collagen, a protein involved in scarring. High collagen levels can cause patches of thick and hardened skin, damage to internal organs, and other scleroderma symptoms.
Experiments involved both mice and humans
Scientists believe that reducing fibroblast activity could help treat scleroderma, but it isn’t clear how to achieve this goal. One possible approach is to boost the effects of CCN3, an antifibrotic protein that decreases scarring. CCN3 counteracts the profibrotic, or scar-promoting, activity of another protein in the same family, called CCN2.
“We have identified BLR-200 as a CCN3-derived peptide that retains CCN3’s antifibrotic properties,” the research team wrote in the study abstract. “However, if CCN3’s and BLR-200’s antifibrotic properties translate to scleroderma patients is unknown.”
The researchers designed two experiments to probe this open question. One assessed how BLR-200 works at the cellular level, while the other measured levels of CCN2 and CCN3 in people with scleroderma.
The first part of the study used a mouse model of scleroderma. The team gave the mice BLR-200 and isolated fibroblasts, then analyzed protein activity in these affected cells.
BLR-200 effectively prevented activation of fibroblasts with high activity from two profibrotic proteins, called engrailed-1 and COL8A1. Correspondingly, the treated mice didn’t develop skin thickening and scarring, while the untreated mice did, the scientists reported.
“It is exciting to learn that BLR-200’s downstream effect is prevention of activation of engrailed-1/COL8A1-expressing fibroblasts, a highly specific group of scar-forming cells,” Riser said. “Recent studies have shown that an equivalent skin fibroblast population is present in human scleroderma and is responsible for the overproduction of collagen that characterizes the disease.”
The second part of the study involved measuring blood CCN2 and CCN3 levels in healthy volunteers and people with scleroderma. Some of the scleroderma patients were in early stages of the disease, having received a diagnosis within the past two years. The remainder were in later stages, specifically at more than five years post-diagnosis.
The results surprised the researchers
The researchers hypothesized that CCN3 levels would be lower in patients than in controls. However, this was not the case. In early disease stages, average CCN2 and CCN3 levels were both significantly higher than in healthy controls.
“Given what is known about the relative activities of CCN2 and CCN3 in vivo, it is likely that [blood] levels of CCN3 rise in scleroderma patients in the body’s attempt to suppress CCN2-dependent fibrosis,” the researchers wrote.
We are hopeful that … BLR Bio’s innovative approach will lead to meaningful advances that improve both quality and length of life for [scleroderma] patients.
Later in the disease, CCN3 but not CCN2 levels were significantly elevated. There was also substantial variability in participants’ protein levels throughout the disease course.
“Why this dysregulation appears to be patient-specific is unclear and requires further investigation,” the team noted.
The scientists suggested that the antifibrotic mechanisms of BLR-200 may be more effective in individuals with lower CCN3 levels. Future studies could address this hypothesis.
“We are hopeful that Dr. Riser’s expertise and BLR Bio’s innovative approach will lead to meaningful advances that improve both quality and length of life for [scleroderma] patients,” said Janice Urban, PhD, RFU’s interim executive vice president for research.
