An Orally Bioavailable Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis

Authors:
  • GFGary S. Firestein
    Gary S. Firestein
  • DBDavid L. Boyle
    David L. Boyle
  • RPRaymond Pieters
    Raymond Pieters
  • JFJames M. Frincke
    James M. Frincke
  • AGArmando Garsd
    Armando Garsd
  • SWSteven K. White
    Steven K. White
  • CRChristopher L. Reading
    Christopher L. Reading
  • DADominick L. Auci
    Dominick L. Auci
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Abstract
Dehydroepiandrosterone (DHEA) treatment provides diverse anti-inflammatory benefits in rodent models of diseases, including rheumatoid arthritis (RA), but only limited benefits to patients. In rodents, DHEA is metabolized to (among others) androstene-3β,7β,17β-triol (AET), which retains potent anti-inflammatory activity. 17α-Ethynyl-5-androstene-3β,7β,17β-triol (HE3286) is a novel, metabolically stabilized, orally bioavailable derivative of AET. In the DBA mouse model of collagen-induced arthritis (CIA), once-daily oral treatments (gavage) with HE3286 (40 mg/kg), beginning at onset of disease, significantly decreased disease. Benefit was associated with reduction in joint inflammation, erosion, and synovial proliferation as measured by histological analysis and mRNA of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-23. Significant benefit was also observed in the CIA model even when treatments were delayed until 7 days after the onset of arthritis. Furthermore, dose-dependent benefit was observed in the DBA mouse model of collagen antibody-induced arthritis, as well as reductions in IL-6 and matrix metalloproteinase-3 mRNA levels in joints at the peak of disease and at the end of the study. HE3286, in contrast to dexamethasone, was not immune-suppressive in several classic animal models of immune function. Instead, HE3286 treatment was associated with reduced nuclear factor-κB activation and in our previous studies, with increased regulatory T cells. We hypothesize that HE3286 may represent a novel, perhaps first-in-class, anti-inflammatory agent and may more fully translate the benefits of DHEA, heretofore largely limited to rodents, into treatments for human diseases, including autoimmune disorders such as RA.

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