Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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

References

  1. Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388:1545–602.

    Article  Google Scholar 

  2. Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F, et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res Ther. 2009;11:R7.

    PubMed  PubMed Central  Google Scholar 

  3. Haraoui B, Jovaisas A, Bensen WG, Faraawi R, Kelsall J, Dixit S, et al. Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population. RMD Open. 2015;1:e000078.

    Article  Google Scholar 

  4. Bijlsma JW, Jacobs JW. Glucocorticoid in the treatment of rheumatoid arthritis: still used after 65 years. Ann NY Acad Sci. 2014;1318:27–31.

    Article  CAS  Google Scholar 

  5. Keystone EC, Smolen J, Riel PV. Developing an effective treatment algorithm for rheumatoid arthritis. Rheumatology (Oxford). 2012;51:v48–54.

    Article  CAS  Google Scholar 

  6. Baschant U, Lane NE, Tuckerman J. The multiple facets of glucocorticoid action in rheumatoid arthritis. Nat Rev Rheumatol. 2012;8:645–55.

    Article  CAS  Google Scholar 

  7. Ethgen O, Esteves FDL, Bruyere O, Reginster JY. What do we know about the safety of corticosteroids in rheumatoid arthritis? Curr Med Res Opin. 2013;29:1147–60.

    Article  CAS  Google Scholar 

  8. Jacobs JW, Bijlsma JW, van Laar JM. Glucocorticoids in early rheumatoid arthritis: are the benefits of joint-sparing effects offset by the adverse effect of osteoporosis? the effects on bone in the Utrecht study and the CAMERA-II study. Neuroimmunomodulation. 2015;22:66–71.

    Article  CAS  Google Scholar 

  9. Rehman Q, Lane NE. Effect of glucocorticoids on bone density. Med Pediatr Oncol. 2003;41:212–6.

    Article  Google Scholar 

  10. Herrlich P. Cross-talk between glucocorticoid receptor and AP-1. Oncogene. 2001;20:2465–75.

    Article  CAS  Google Scholar 

  11. Coghlan MJ, Elmore SW, Kym PR, Kort ME. The pursuit of differentiated ligands for the glucocorticoid receptor. Curr Top Med Chem. 2003;14:1617–35.

    Article  Google Scholar 

  12. Hudson WH, Vera IMS, Nwachukwu JC, Weikum ER, Herbst AG, Yang Q, Bain DL, Nettles KW, Kojetin DJ, Ortlund EA. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. Nat Commun. 2018;9:1337.

    Article  Google Scholar 

  13. Reeves EK, Hoffman EP, Nagaraju K, Damsker JM, McCall JM. VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid. Bioorganic Med Chem. 2013;21:2241–9.

    Article  CAS  Google Scholar 

  14. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Sali A, et al. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. 2013;5:1569–85.

    Article  CAS  Google Scholar 

  15. Heier CR, Yu Q, Fiorillo AA, Tully CB, Tucker A, Mazala DA, Uaesoontrachoon K, et al. Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Sci Alliance. 2019;2(1):6.

    Article  Google Scholar 

  16. Damsker JM, Dillingham BC, Rose MC, Balsley MA, Heier CR, Watson AM, et al. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice. PLoS One. 2013;8:e63871.

    Article  CAS  Google Scholar 

  17. Dillingham BC, Knoblach SM, Many GM, Harmon BT, Mullen AM, Heier CR, et al. VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis. Cell Mol Neurobiol. 2015;3:377–87.

    Article  Google Scholar 

  18. Damsker JM, Conklin LS, Sadri S, Dillingham BC, Panchapakesan K, Heier CR, et al. VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis. Inflamm Res. 2016;65:737–43.

    Article  CAS  Google Scholar 

  19. Hoffman EP, Riddle V, Siegler MA, Dickerson D, Backonia M, Kramer WG, et al. Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes. Steroids. 2018;134:43–52.

    Article  CAS  Google Scholar 

  20. Conklin LS, Damsker JM, Hoffman EP, et al. Phase Iia trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Elsevier Pharma Res. 2018;136:140–50.

    CAS  Google Scholar 

  21. Baudy AR, Sali A, Jordan S, Kesari A, Johnston HK, Hoffman EP, Nagaraju K. Non-invasive optical imaging of muscle pathology in mdx mice using cathepsin caged near-infrared imaging. Mol Imaging Biol. 2011;13:462–70.

    Article  Google Scholar 

  22. Kachigian LM. Collagen antibody induced arthritis. Nat Protoc. 2006;1:2512–6.

    Article  Google Scholar 

  23. Tong B, Wan B, Wei Z, Wang T, Zhao P, Dou Y, et al. Role of cathepsin B in regulating migration and invasion of fibroblast-like synoviocytes into inflamed tissue from patients with rheumatoid arthritis. Clin Exp Immunol. 2014;177:586–97.

    Article  CAS  Google Scholar 

  24. Ohmura K, Nguyen LT, Locksley RM, Mathis D, Benoist C. Interleukin-4 can be a key positive regulator of inflammatory arthritis. Arthritis Rheum. 2005;52:1866–75.

    Article  CAS  Google Scholar 

  25. Firestein GS, Alvaro-Gracia JM, Maki R, Alvaro-Garcia JM. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol. 1990;144:3347–53.

    CAS  Google Scholar 

  26. van Leeuwen MA, Westra J, Limburg PC, van Riel PL, van Rijswijk MH. Interleukin-6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid. Ann Rheum Dis. 1995;54:33–8.

    Article  Google Scholar 

  27. Sreetama SC, Chandra G, Van der Meulen JH, Ahmad MM, Suzuki P, et al. Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit. Mol Ther. 2018;26:2231–42.

    Article  CAS  Google Scholar 

  28. Fujisawa K, Aono H, Hasunuma T, Yamamoto K, Mita S, Nishioka K. Activation of transcription factor nf-κb in human synovial cells in response to tumor necrosis factor α. Arthritis Rheum. 1996;39:197–203.

    Article  CAS  Google Scholar 

  29. Miyazawa K, Mori A, Yamamoto K, Okudaira H. Constitutive transcription of the human interleukin-6 gene by rheumatoid synoviocytes: spontaneous activation of NF-kappaB and CBF1. Am J Pathol. 1998;152:793–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wernecke C, Braun HJ, Dragoo JL. The effect of intra-articular corticosteroids on articular cartilage. Orthop J Sports Med. 2015;3:2325967115581163.

    Article  Google Scholar 

  31. Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, Baharpoor A, et al. Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum. 2012;64:3886–96.

    Article  CAS  Google Scholar 

  32. Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD, Tanasescu R. Extra-articular manifestations in rheumatoid arthritis. Maedica (Buchar). 2010;5:286–91.

    Google Scholar 

  33. Hansson AS, Lu S, Holmdahl R. Extra-articular cartilage affected in collagen-induced, but not pristane-induced, arthritis models. Clin Exp Immunol. 2002;127:37–42.

    Article  Google Scholar 

  34. Marinova-Mutafchieva L, Williams RO, Mason LJ, Mauri C, Feldmann M, Maini RN. Dynamics of proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis (CIA). Clin Exp Immunol. 1997;107:507–12.

    Article  CAS  Google Scholar 

  35. Rioja I, Bush KA, Buckton JB, Dickson MC, Life PF. Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response to prednisolone treatment. Clin Exp Immunol. 2004;137:65–73.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. ReveraGen BioPharma Inc., Rockville, MD, 20850, USA

    Jesse M. Damsker, Michaelyn R. Cornish, Priya Kanneboyina, Ila Kanneboyina, Rachel Lipson & Kanneboyina Nagaraju

  2. Research Center for Genetic Medicine, Children’s National Health System, Washington, DC, 20010, USA

    Qing Yu, Aditi Phadke, Susan M. Knoblach, Karuna Panchapakesan, Alyson A. Fiorillo, Terence Partridge & Kanneboyina Nagaraju

  3. School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA

    Melissa Morales & Kanneboyina Nagaraju

Authors
  1. Jesse M. Damsker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michaelyn R. Cornish
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Priya Kanneboyina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ila Kanneboyina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rachel Lipson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aditi Phadke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Susan M. Knoblach
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karuna Panchapakesan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Melissa Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alyson A. Fiorillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Terence Partridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kanneboyina Nagaraju
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jesse M. Damsker or Kanneboyina Nagaraju.

Ethics declarations

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.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-019-01279-z

Keywords

Search

Navigation