Novel pathway specific β2-adrenergic receptor agonists as modulators of DUX4 in facioscapulohumeral muscular dystrophy

Investigators: Matthijs Vlasveld PhD, Silvère M van der Maarel PhD

Category: Research - Translational

Before 2000, the use of beta-2-adrenergic receptor agonists has been studied for the treatment of Facioscapulohumeral muscular dystrophy (FSHD). Although results of clinical trials involving albuterol were promising, treatment efficacy is limited by the development of treatment resistance and potential severe cardiac adverse outcomes (e.g. hypertrophic cardiomyopathy and heart failure). In the early 2000s, the DUX4 protein was identified as the causative protein for FSHD and in 2017, beta-2-adrenergic receptor agonists were found to reduce DUX4 expression in skeletal muscle cells in cell models. Recently, a new drug (ATR-258) that has a similar effect as traditional beta-2 agonists, but does not induce treatment resistance and has improved clinical safety compared to albuterol, has been identified. In a preliminary study, we have also found that this drug reduces the expression of DUX4. However, due to the nature of this new drug, we do not know how the stimulation of the beta-2 receptor promotes the repression of DUX4 in FSHD patient skeletal muscle cells. Therefore, we propose to conduct a study to better understand this mechanism. Using this information, follow-up studies (e.g., pre-clinical studies and clinical trials) involving this therapeutic candidate can be optimized for the treatment of FSHD.