Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?

Abstract

Background: Pharmacological corticosteroid therapy is the standard of care in Duchenne Muscular Dystrophy (DMD) that aims to control symptoms and slow disease progression through potent anti-inflammatory action. However, a major concern is the significant adverse effects associated with long term-use. MAIN: This review discusses the pros and cons of standard of care treatment for DMD and compares it to novel data generated with the new-wave dissociative corticosteroid, vamorolone. The current status of experimental anti-inflammatory pharmaceuticals is also reviewed, with insights regarding alternative drugs that could provide therapeutic advantage.

Conclusions: Although novel dissociative steroids may be superior substitutes to corticosteroids, other potential therapeutics should be explored. Repurposing or developing novel pharmacological therapies capable of addressing the many pathogenic features of DMD in addition to anti-inflammation could elicit greater therapeutic advantages.

Keywords: Anti-inflammation; Anti-inflammatory drugs; Corticosteroids; Duchenne muscular dystrophy; Standard of care.

Fig. 1

Comparing the mechanisms of action of standard of care (S.O.C) glucocorticoids (i.e., prednisone and deflazacort) with novel dissociative steroid vamorolone and fumaric acid esters (FAE). a Glucocorticoids like prednisone (PRED), diffuse through the cell membrane, bind to the cytoplasmic nuclear hormone receptor (glucocorticoid receptor (GR)) to form a receptor-ligand complex, which translocates to the nucleus. This complex indirectly binds to the glucocorticoid response element (GRE), activating target genes that are associated with broad spectrum anti-inflammation (trans-activation), as well as the nuclear factor kappa B (NF-κB) binding element to supress transcription of master inflammatory regulator, NF-κB (trans-repression). These mechanisms elicit the beneficial effects of glucocorticoids in DMD. In contrast, adverse effects are mediated through direct binding of the GR-ligand complex to negative GRE on other target genes, which represses their transcription (cis-repression). b Similarly, vamorolone binds to the GR and retains the anti-inflammatory effects characteristic of standard of care glucocorticoids, inducing transrepression with hardly any transactivation or cis-repression to elicit fewer adverse effects. c Therapeutic efficacy of FAEs is mediated through the dual activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway and hydroxycarboxylic acid receptor 2 (HCAR2). Nrf2 regulates the essential cellular defence system when electrophiles/FAE bind and disrupt the interaction between Nrf2 and its negative repressor (Kelch-like ECH-associated protein 1 (Keap1)). This disruption allows Nrf2 to translocate to the nucleus, bind to the antioxidant response element (ARE) resulting in cytoprotection. Nrf2 and HCAR2 both strongly inhibit NF-κB signalling within the cellular inflammatory response. Created with BioRender.com