Abstract
ABSTRACTDuchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutation of the dystrophin gene. Pharmacological therapies that function independently of dystrophin and complement strategies aimed at dystrophin restoration could significantly improve patient outcomes. Previous observations have suggested that serotonin pathway modulation ameliorates dystrophic pathology, and re-application of serotonin modulators already used clinically would potentially hasten availability to DMD patients. In our study, we used dystrophin-deficient sapje and sapje-like zebrafish models of DMD for rapid and easy screening of several classes of serotonin pathway modulators as potential therapeutics. None of the candidate drugs tested significantly decreased the percentage of zebrafish exhibiting the dystrophic muscle phenotype in the short-term birefringence assay or lengthened the lifespan in the long-term survival assay. Although we did not identify an effective drug, we believe our data is of value to the DMD research community for future studies, and there is evidence that suggests serotonin modulation may still be a viable treatment strategy with further investigation. Given the widespread clinical use of selective serotonin reuptake inhibitors, tricyclic antidepressants and reversible inhibitors of monoamine oxidase, their reapplication to DMD is an attractive strategy in the field's pursuit to identify pharmacological therapies to complement dystrophin restoration strategies.
Highlights
Duchenne muscular dystrophy (DMD) is a progressive X-linked muscle-wasting disease that affects approximately 1 in 4,000 male births (Emery et al, 2015) in which mutations in the dystrophin gene result in production of a truncated, nonfunctional dystrophin protein (Hoffman et al, 1987; Monaco et al, 1986)
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutation of the dystrophin gene
Pharmacological therapies that function independently of dystrophin and complement strategies aimed at dystrophin restoration could significantly improve patient outcomes
Summary
Duchenne muscular dystrophy (DMD) is a progressive X-linked muscle-wasting disease that affects approximately 1 in 4,000 male births (Emery et al, 2015) in which mutations in the dystrophin gene result in production of a truncated, nonfunctional dystrophin protein (Hoffman et al, 1987; Monaco et al, 1986). Eteplirsen and Golodirsen, two drugs that act to promote dystrophin production by restoring the translational reading frame of dystrophin, have recently been approved by the FDA (Aartsma-Rus and Corey, 2020; Frank et al, 2020; Mendell et al, 2013). These therapies are not expected to cure DMD given that they result in production of a low abundance of truncated, partially functional forms of dystrophin protein, and a dramatic change in the course of the disease will likely require a combinatorial treatment approach (Verhaart and Aartsma-Rus, 2019). Identification of therapies that improve pathology independent of dystrophin and work complementarily with genetic-based approaches would be of significant value to patients
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