Vamorolone, a dissociative steroidal compound, reduces collagen antibody-induced joint damage and inflammation when administered after disease onset

Abstract

Objective and design

The objective of this study was to assess the effect of vamorolone, a first-in-class dissociative steroidal compound, to inhibit inflammation when administered after disease onset in the murine collagen antibody-induced arthritis model of arthritis.

Animals

84 DBA1/J mice were used in this study (n = 12 per treatment group).

Treatment

Vamorolone or prednisolone was administered orally after disease onset for a duration of 7 days.

Methods

Disease score and bone erosion were assessed using previously described scoring systems. Cytokines were measured in joints via immunoassay, and joint cathepsin B activity (marker of inflammation) was assessed using optical imaging of joints on live mice.

Results

We found that vamorolone treatment led to a reduction of several disease parameters including disease score, joint inflammation, and the presence of pro-inflammatory mediators to a degree similar of that observed with prednisolone treatment. More importantly, histopathological analysis of affected joints showed that vamorolone treatment significantly reduced the degree of bone erosion while this bone-sparing property was not observed with prednisolone treatment at any of the tested doses.

Conclusions

While many intervention regimens in other studies are administered prior to disease onset in animal models, the current study involves delivery of the potential therapeutic after disease onset. Based on the findings, vamorolone may offer an efficacious, yet safer alternative to conventional steroidal compounds in the treatment of rheumatoid arthritis and other inflammatory diseases.

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Abbreviations

CAIA:

Collagen antibody-induced arthritis

RA:

Rheumatoid arthritis

GCs:

Glucocorticoids

DMARDs:

Disease-modifying anti-rheumatic drugs

GREs:

Glucocorticoid response elements

MR:

Mineralocorticoid receptor

i.p.:

Intraperitoneal

LPS:

Lipopolysaccharide

Vam.:

Vamorolone

Pred.:

Prednisolone

Pisi:

Pisiform

NL:

Navicular lunate

Tri:

Triangular

mc:

Metacarpal

cb:

Cortical bone

ep:

Epiphysis

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Funding

Supported by a small business technology transfer (STTR) Grant from the National Institutes of Health (1R41AR068816-01). This award supported all experiments described in this manuscript.

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Correspondence to Jesse M. Damsker or Kanneboyina Nagaraju.

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Conflict of interest

:JMD, MRC, RL, and KN are employed by ReveraGen BioPharma Inc. JMD has ReveraGen BioPharma Inc. stock options, and KN has ReveraGen BioPharma Inc. founder shares. AAF has a consulting agreement with ReveraGen BioPharma Inc.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee at Children’s National Health System.

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Damsker, J.M., Cornish, M.R., Kanneboyina, P. et al. Vamorolone, a dissociative steroidal compound, reduces collagen antibody-induced joint damage and inflammation when administered after disease onset. Inflamm. Res. 68, 969–980 (2019). https://doi.org/10.1007/s00011-019-01279-z

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Keywords

  • Rheumatoid arthritis
  • Glucocorticoids
  • Inflammation
  • Autoimmunity