Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s; recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

“…It will therefore be very important in the near future to determine whether treatment with metformin can improve dystrophic cardiomyopathy in the advanced stage of the pathology. To conclude, our data support the concept that metformin alone or in combination with other drugs might be a potential therapeutic strategy to ameliorate the dystrophinopathies (Casteels et al, 2010 ; Ljubicic and Jasmin, 2015 ; Hafner et al, 2016 , 2019 ; Mantuano et al, 2018 ; Vitiello et al, 2019 ).…”

“…Therefore, targeting mitochondrial function and/or metabolism in DMD has become a therapeutic issue over the last decade. Among the therapeutic candidates, the antidiabetic drug metformin has recently been evaluated in DMD both in preclinical studies and in clinical trials (Ljubicic and Jasmin, 2015 ; Hafner et al, 2016 , 2019 ; Mantuano et al, 2018 ; Vitiello et al, 2019 ). This N,N-dimethylbiguanide interferes with the activity of mitochondrial complex I and activates AMP-activated protein kinase (AMPK), a critical hub for metabolic-mediated signaling pathways (for a review, see Foretz et al, 2014 ).…”

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

“…Barton-Davis et al demonstrated the possibility of treating DMD nonsense mutation using gentamicin. The drug was administered by S.C. injection to mdx mice at different dosages to identify the optimal dose to restore the full-length dystrophin [ 87 , 89 ]. To determine the efficacy on the suppression of premature stop codon in mdx mice, evaluation of dystrophin protection against contraction-induced damage was examined.…”

“…Several DMD animal models have been developed by reproducing the deficient dystrophin expression. As previously reported, the mdx mouse (BL10- mdx ) is the most commonly used DMD animal model and is characterised by the presence of a stop codon located in exon 23 that leads to loss of full-length dystrophin whereas smaller isoforms are still expressed [ 89 , 255 ]. Recently, D2- mdx mouse models issued from a different genetic background (DBA2/J) have demonstrated a more pronounced phenotype closer to patients [ 256 ].…”

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

“…In fact, a clinical trial is presently recruiting DMD patients to study endomysial fibrosis, deregulated inflammatory responses and Ca 2+ influx dysfunction in order to better understand the relationship between each secondary pathology in dystrophin-deficient humans ( , trial NCT01823783). Other possible therapeutic strategies aimed at targeting signaling pathways to improve functional outcome of dystrophic muscles can be designed to target endogenous genes to restructure the DAPC, and tackle inflammation, calcium imbalance, fibrosis and oxidative stress [ 2 , 72 , 73 ].…”