Combined therapy of prednisone and mTOR inhibitor sirolimus for treating retroperitoneal fibrosis

Abstract Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum, whose development could encase surrounding organs and lead to severe conditions. Its current treatments involve long-term uptake of glucocorticoids (e.g., prednisone) for controlling inflammation; however, side effects are common, triggering search for replacement therapies. Here, we surveyed gene-disease databases and discovered that mTOR displayed significant changes in RPF, which we confirmed by immunohistological staining. Next, we inferred from drug-gene databases that mTOR inhibitor compound sirolimus could affect most biological pathways in RPF. We then designed a combined therapy in which a gradual reduction of prednisone was prescribed with a long-term, stable dosage of sirolimus. We implemented a single-arm clinical trial in RPF patients and assessed the treatment effects at three timepoints (0, 12 weeks and 48 weeks of treatment). By assessing fibrous tissue mass by computed tomography, inflammation markers and kidney functions by lab tests, immune cell types and abundances by flow cytometry, and plasma inflammation-related proteins by Olink proteomics, we revealed that our combined therapy resulted in significant fibrosis remission and an overall regression of the immune system towards healthy states. In addition, no obvious side effects were observed. We concluded that this new therapy had the potential to replace long-term steroid monotherapy for treating RPF.