Working with colleagues from the University of Lyon, researchers from the center for pathobiochemistry and genetics at the Medical University of Vienna have discovered common mutations in the genes that regulate the metabolic sensor mTOR in patients with familial sarcoidosis.1 Correspondingly, researchers in the department of dermatology at the Medical University of Vienna are beginning a clinical trial to test the efficacy of mTOR inhibitors for the treatment of sarcoidosis.
Sarcoidosis is a disease in which nodules of immune cells form, primarily in the lungs but also in the skin or in the heart. While the lung symptoms are similar to those of tuberculosis, the etiology of the disease is unknown. It is currently assumed that causation is multifactorial, whereby certain environmental factors and bacterial pathogens trigger sarcoidosis in genetically predisposed individuals.
Working with their clinical colleagues from the University of Lyon—Alain Calender, MD, professor of medicine, and Yves Pacheco, MD, professor of medicine—a Medical University of Vienna research team led by Thomas Weichhart, PhD, professor of medical genetics, and doctoral candidate Clarice Lim identified the genetic component that is involved in development of the disease. By conducting a genomic analysis of families in which there are clusters of sarcoidosis, the study found that the metabolic sensor mTOR plays a central role in the pathogenesis of sarcoidosis.
“The unique thing about the study design was that it allowed us to analyze patients and their unaffected siblings over three generations in some families,” says Weichhart. “In this way we were able to identify mutations that were passed on exclusively to patients but not to their healthy relatives.”
Following detailed bioinformatic analysis, it was found that many mutations relate to genes that normally deactivate the metabolic sensor mTOR. “The mutations then result in mTOR being more active, so that these nodules, so-called granulomas, are more readily able to form,” explains Lim.
Weichhart’s working group had already demonstrated in an animal model that the activation of mTOR in immune cells is sufficient to cause sarcoid granulomas to form. The new data now show that, on a genetic level as well, mTOR contributes to the development of sarcoidosis in patients.
Georg Stary, MD, associate professor of dermatology at the Medical University of Vienna, has initiated a clinical trial to test a therapeutic application of the relationship between mTOR and sarcoidosis. Funded by the Vienna Science and Technology Fund, the study is investigating the efficacy of the mTOR inhibitor sirolimus in sarcoidosis patients with skin and pulmonary involvement.
For further information, visit the Medical University of Vienna.
- Calender A, Lim CX, Weichhart T, et al. Exome sequencing and pathogenicity-network analysis of 5 French families implicate mTOR signaling and autophagy in familial sarcoidosis. Eur Respir J. Epub ahead of print, April 25, 2019; doi: 10.1183/13993003.00430-2019.
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