Novel approaches to corticosteroid treatment in Duchenne muscular dystrophy

Abstract

Although prednisone has never been formally approved for use in Duchenne muscular dystrophy (DMD) by regulatory agencies, its efficacy has been confirmed in trials dating from the 1980s. There is a strong need for optimization of both specific type of glucocorticoid (eg, prednisone, vs deflazacort or others) and the dosing regimen. Ideally an optimized regimen would maximize efficacy while minimizing side-effect profiles. A new trial, FOR-DMD, aims to address this gap in knowledge. In parallel, there has been progress in the area of "dissociative steroids," drugs that are able to better separate efficacy and side effects, providing a broader therapeutic window.

Fig. 1

Chemical structures of glucocorticoids and dissociative steroids. The arrow indicates the position of the key 9,11 alterations distinguishing classic glucocorticoids (prednisone, dexamethasone) from dissociative steroids (Δ-9,11 analogues).

Fig. 2

Molecular action of glucocorticoids and dissociative steroids. Classic pharmacologic glucocorticoids have anti-inflammatory, membrane fluidity, and glucocorticoid response element (GRE)-mediated transcriptional activities. Dissociative steroids retain membrane and anti-inflammatory subactivities associated with efficacy, but do not retain the GRE-mediated transcriptional activities associated with side-effect profiles. GR, glucocorticoid receptor.