Major Signaling Pathway in Scleroderma May Enable Effective Treatments, Cures
As any scleroderma patient knows, the disease has no cure and no effective treatments exist. The main goal of current treatments is reducing inflammation which, often times, is not enough to provide relief to patients, especially those who have developed pulmonary hypertension as a result of thickened pulmonary arteries.
Researchers at Michigan State University, led by chairperson of the Department of Pharmacology and Toxicology Dr. Richard Neubig, may have found a way to treat the trigger of scleroderma. Dr. Neubig and colleagues published findings in the Journal of Pharmacology and Experimental Therapeutics that describe the use of a small-molecule inhibitor to target the Myocardin-Related Transcription Factor/Serum Response Factor (MRTF/SRF) gene transcription pathway.
The research team targeted the MRTF/SRF gene transcription pathway in a murine model of skin injury. In humans, scleroderma is characterized by thick scar tissue composed of collagen and can occur on the skin (localized) or within the organs (systemic), making the research most relevant to localized scleroderma. While inducing skin fibrosis by administering bleomycin every day for two weeks to the backs of mice, the researchers simultaneously treated some mice with the small-molecule inhibitor CCG-203971 two times a day. After the two-week period, mice receiving CCG-203971 had less skin thickening than untreated, bleomycin-receiving mice. Collagen deposition was less severe, as evidence by histological analysis.
Choosing to use CCG-203971 resulted from cell studies using dermal fibroblasts taken from scleroderma patients. These cells over-expressed genes that are drivers of dermal fibrosis and are turned on via the MRTF/SRF pathway. They also proliferate more than dermal fibroblasts taken from healthy individuals. Treating the scleroderma cells with CCG-203971 inhibited their proliferation to a level similar to that of normal cells.
Although drugs exist that block one or two signaling pathways in scleroderma, Dr. Neubig’s group may have found the core pathway. CCG-203971 completely blocked the myofibroblast transition of normal fibroblasts and reversed the change in scleroderma fibroblasts.
“By validating this core switch as a viable drug target, we can now continue our work to improve the chemical compounds so they will work with doses that are appropriate for people,” said Dr. Neubig in a news report. “It’s definitely promising.” Translating Dr. Neubig’s work into the clinic would benefit the estimated 300,000 Americans with scleroderma, including the family of Jon and Lisa Rye, who contributed funding for the study, along with the Scerloderma Cure Fund set up by the family.