Current Pharmacological Strategies for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, X-linked neuromuscular disorder caused by the absence of dystrophin protein, which is essential for muscle fiber integrity. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. There is still no cure for DMD so far and the standard of care is principally limited to symptom relief through glucocorticoids treatments. Current therapeutic strategies could be divided into two lines. Dystrophin-targeted therapeutic strategies that aim at restoring the expression and/or function of dystrophin, including gene-based, cell-based and protein replacement therapies. The other line of therapeutic strategies aims to improve muscle function and quality by targeting the downstream pathological changes, including inflammation, fibrosis, and muscle atrophy. This review introduces the important developments in these two lines of strategies, especially those that have entered the clinical phase and/or have great potential for clinical translation. The rationale and efficacy of each agent in pre-clinical or clinical studies are presented. Furthermore, a meta-analysis of gene profiling in DMD patients has been performed to understand the molecular mechanisms of DMD.

Treating Duchenne Muscular Dystrophy: The Promise of Stem Cells, Artificial Intelligence, and Multi-Omics

“…This work showed that the anti-oxidant effects of these herbal compounds can be effective at reducing oxidative stress. In a recent review of DMD therapeutics, a meta-analysis of gene expression comparisons of other DMD samples showed that extracellular matrix (ECM) and cell-to-cell interaction molecules are prime targets for reversing late-stage DMD, which makes logical sense because to restore ambulation, the musculature would need to be strengthened ( 10 ). Stem cells give us the ability to generate and characterize the different cell types affected by DMD, as well as the ability to perform high-throughput drug screens, paving the way toward patient-specific treatment programs.…”

“…As more cellular processes are disrupted, more evidence of cellular dysfunction is exhibited that can be detected in the form of higher levels of serum biomarkers like creatine kinase and myoglobin as signs of muscle wasting, and TNF-α, IFN-γ, IL-5 and IL-6 as signs of chronic inflammation (6)(7)(8)(9). Therapeutic efforts for DMD are therefore divided between targeting (i) the underlying cause of DMD, loss of dystrophin, or (ii) targeting a secondary pathology (10).…”

Evaluation of the GSP Creatine Kinase-MM Assay and Assessment of CK-MM Stability in Newborn, Patient, and Contrived Dried Blood Spots for Newborn Screening for Duchenne Muscular Dystrophy

“…A majority of patients become nonambulatory by age 15 years, require ventilatory support by age 20, and up to 60% of patients die by age 30 from progressive cardiac and respiratory complications [ 9 ]. Genetic testing in the newborn (NB) period is typically not considered unless family history suggests risk of disease; however, recent and emerging treatments for DMD [ 10 ] underscore the need to evaluate the potential importance of presymptomatic identification and access to early treatment.…”

Development of Therapeutic RNA Manipulation for Muscular Dystrophy

“…As conventional drugs are not effective for the treatment of DMD, this strategy is becoming a more common alternative. This group comprises DNA-editing therapy (CRISPR-Cas9; usually exon manipulation) ( Long et al, 2014 ; Li et al, 2015 ; McTague et al, 2021 ), gene-addition therapy (microdystrophin with the AAV vector) ( Yoshimura et al, 2004 ; Duan, 2018 ), RNA-manipulation therapy (Eteplirsen, Golodirsen, Viltolarsen, Casimersen, ASO-cocktail therapy, and RNA-editing therapy), and cell therapy ( Motohashi et al, 2019 ; Yao et al, 2021 ). Since the lack of functional dystrophin causes DMD, restoring dystrophin is an apparent therapeutic strategy.…”