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Gene mutations could point to new treatments for scleroderma

A study from the University of Alberta has identified genetic mutations in scleroderma patients, a finding that may lead to new treatments for the skin and connective tissue disease.

Previous investigations have suggested that while mutated cancer proteins, such as RNA polymerase III, are autoantigens that lead to an inflammatory response in systemic sclerosis, this study looked at non-neoplastic systemic sclerosis tissue to see if mutations may play a role in disease pathogenesis. The study was published in the Journal of Autoimmunity.

“Of all rheumatic diseases, scleroderma has the worst outcomes,” lead investigator Dr. Mohamed Osman said in a press release. He is a rheumatologist and assistant professor in the Faculty of Medicine & Dentistry at the University of Alberta.

“By uncovering some of the mechanisms linking abnormal DNA damage responses with fibrosis and inflammation, we hope to uncover novel mechanisms which we can use to better treat patients in the clinic.”

In the study, skin biopsies were obtained from eight sequential patients with a progressive form of early-stage systemic sclerosis (with severe skin and/or lung involvement). Areas of dermal fibrosis were microdissected and analyzed using whole exome sequencing. Gene mutation patterns were compared to autologous buccal mucosal cells that served as a control.

Nearly 2,000 mutated genes were identified, including the clock-like mutations that drive premature aging and cancer, and 25 oncogenes with cancer-causing potential, the authors said. The most common mutated genes found were important in the regulation of epigenetic histone modifications, DNA repair, and genome integrity. Some of the mutations typically present in cancer were not observed in the scleroderma cells, the researchers noted.

Based on these new findings, the investigators think cancer driver gene mutations may potentially play a fundamental role in the pathogenesis of systemic sclerosis, and that immunotherapy treatments such as those utilized for some cancers may turn out to be effective for the treatment of systemic sclerosis.

“Our study shows that there is a parallel between the mutations driving cancer and the mutations driving the development of scleroderma,” co-investigator Dr. Robert Gniadecki, professor and director of the Division of Dermatology at the University of Alberta, said in the press release.

“The endpoint in cancer is aggressive tumour growth, and in scleroderma it is fibrosis. The immune response is at the core of both processes.”


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