Vamorolone shows efficacy and increases dystrophin protein in novel Becker muscular dystrophy mice


Translational Research

Poster Number: 301


Nikki McCormack, PhD, Children's National Research Institute, Nhu Nguyen, PhD, Center for Genetic Medicine Research, Children’s National Research Institute, USA, Christopher Tully, Children's National Hospital, Trinitee Oliver, Howard University, Alyson Fiorillo, PhD, Children's National Medical Center (Washington, DC), Chris Heier, PhD, Children's National Medical Center

The current standard of care for Duchenne muscular dystrophy (DMD) is chronic administration of glucocorticoids, such as prednisone and deflazacort, which aim to slow disease progression by suppressing inflammatory signaling pathways. Traditional glucocorticoids are not used for Becker muscular dystrophy (BMD) due to the adverse side effects of their chronic administration. We previously showed that the first-in-class dissociative corticosteroid vamorolone improves disease outcomes in mdx mice while bypassing several key adverse side effects caused by traditional glucocorticoids. Additionally, we showed that vamorolone reduces expression of dystrophin-targeting microRNAs (DTMs). These data suggest that vamorolone may be beneficial for BMD by reducing inflammatory signaling in skeletal muscle and by a novel mechanism through which it can potentially increase dystrophin protein levels by suppressing expression of DTMs.

Recently, our lab generated a novel mouse model of BMD (bmx) with a deletion of dystrophin exons 45-47. Bmx mice have skeletal muscle pathology, impaired motor function, increased expression of DTMs and reduced dystrophin protein expression. In the present study, we administered daily oral vehicle, prednisolone, or vamorolone to novel bmx mice from 6 weeks through 16 weeks of age and examined skeletal muscle pathology, motor function, DTMs and expression of dystrophin. We find vamorolone improves histopathology, improves strength phenotypes (grip strength, wire hang), and avoids prednisolone’s side effects to behavior (elevated plus maze) and growth. Intriguingly, we also find that vamorolone increases dystrophin protein expression in skeletal muscle. This data indicates vamorolone, which is nearing approval for DMD after its initial development in mdx mice, also shows efficacy in a mouse model of BMD and therefore warrants clinical investigation in BMD patients.