Only a fortnight ago, a synthetic steroidal drug, vamorolone, was approved for clinical use in the US.
But already an independent analysis by researchers at UWA has revealed the promising potential for the drug to treat Duchenne muscular dystrophy.
While genetic studies on animals are well underway to find a suitable gene-replacement or transcription therapy for DMD, anti-inflammatory drugs, including glucocorticoid steroids, such as prednisone/prednisolone and deflazacort, were still the first line of defence.
Yet, their adverse effects, such as “restricted height, increased bone turnover, insulin resistance, and weight gain,” pose a major problem for patients, and significantly, the study found that each of these symptoms was less pronounced with vamorolone.
UWA’s Emeritus Professor Miranda Grounds, an Honorary Senior Research Fellow in UWA’s School of Human Sciences – with more than 40 years’ experience investigating muscular dystrophies – was invited to write the piece on vamorolone’s potential by The Journal of Neuromuscular Diseases.
Assisted by Dr Erin Lloyd, a postdoctoral researcher and lecturer from UWA’s School of Human Sciences, Professor Grounds said their analysis found that vamorolone showed promising potential for DMD, “with similar efficacy and some reduced adverse side effects in comparison with… prednisone and deflazacort.”
“Our findings showed some of the beneficial effects of vamorolone included reduced inflammation and improved muscle function, with less adverse effects on growth and bone quality, which are well-documented adverse effects of glucocorticoids,” she explained.
“However, some adverse effects, such as adrenal suppression, were still evident.”
Professor Grounds noted that a key cause of the severe dystropathology of DMD was the high incidence of intrinsic myonecrosis, characterised by complete breakdown of segments of myofibres – clustered in small groups, called focal necrosis – and the presence of many inflammatory cells within these necrotic myofibres.
“The onset of myonecrosis is linked with calcium dysregulation and rapid accumulation of neutrophils (that are transitory) followed by other inflammatory cells including macrophages, associated with elevated levels of the major pro-inflammatory cytokine tumour necrosis factor,” she said.
“When myonecrosis occurs, inflammatory cells are essential for phagocytosis of the necrotic muscle tissue, remodelling of ECM, and activation of myogenesis, all required for successful regeneration and formation of new muscle cells to repair the damaged myofibre segment.
“Such myonecrosis/regeneration requires high-energy and takes between 1–2 weeks to restore function of the affected myofibres.
“Thus, a primary objective of drugs that aim to reduce the severity of dystropathology in DMD, is to protect dystrophic myofibres from myonecrosis, by stabilising the sarcolemma and calcium dysregulation, with a particular focus on preventing excessive inflammation and oxidative stress.”
Studies using RNA analyses of human DMD and control muscles have found that specific inflammatory pathways – and a specific transcription factor (NF-κB), activated in B-cells – were pronounced during the early pre-symptomatic stages of DMD.
“Like other glucocorticoids, vamorolone binds to the glucocorticoid receptor and suppresses transcription of the NF-κB signalling pathway (transrepression),” Professor Grounds explained.
“But importantly, vamorolone appears to avoid much of the broad transcriptional activity (transactivation) associated with the many adverse side effects of other glucocorticoids, as well as functioning as an antagonist (instead of an agonist) of mineralocorticoid receptor activity.”
The full analysis is available below:
https://content.iospress.com/articles/journal-of-neuromuscular-diseases/jnd230161