Research Article: Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus

Date Published: April 2, 2018

Publisher: Public Library of Science

Author(s): Kristen R. Taylor Meadows, Marcos W. Steinberg, Bryan Clemons, Matthew E. Stokes, Gregory J. Opiteck, Robert Peach, Fiona L. Scott, Jose C. Crispin.

http://doi.org/10.1371/journal.pone.0193236

Abstract

Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compared with vehicle-treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination. Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy. Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys. Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen. Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus.

Partial Text

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the production of autoantibodies and immune complex deposition in a multitude of tissues including kidney, skin, joints, heart, lungs, and brain. Both B and T cells drive chronic inflammation, and cellular trafficking of lymphocytes to tissues and organs plays a major role in SLE [1–4].

The NZBWF1 mouse model has several characteristics of human SLE including immune-complex glomerulonephritis, loss of kidney function, and autoantibody production [26]. Ozanimod (RPC1063) and its metabolite RP-101075, both selective S1PR1 and S1PR5 modulators, demonstrated significant therapeutic benefit in this murine SLE model. Mice treated with ozanimod and RP-101075 showed a dose-dependent reduction in proteinuria and serum BUN, and improvements in multiple parameters of kidney pathology, including reduced interstitial infiltrates, tubular atrophy, and interstitial fibrosis. Furthermore, ozanimod demonstrated a reduction in multiple components of glomerular lesions, including reduced mesangial expansion, endocapillary proliferation and glomerular deposits. The reduction in immune cell infiltration into the kidney is of particular clinical significance as ectopic lymphoid structures are a hallmark of many autoimmune diseases, including SLE [27–30]. Together, this data demonstrates that ozanimod and RP-101075 reduce kidney inflammation and improve kidney function.

 

Source:

http://doi.org/10.1371/journal.pone.0193236

 

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