From diagnosis to therapy in Duchenne muscular dystrophy

Abstract

Genetic approaches for the diagnosis and treatment of inherited muscle diseases have advanced rapidly in recent years. Many of the advances have occurred in the treatment of Duchenne muscular dystrophy (DMD), a muscle wasting disease where affected boys are typically wheelchair bound by age 12 years and generally die in their twenties from respiratory failure or cardiomyopathy. Dystrophin is a 421 kD protein which links F-actin to the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the muscle membrane. In the absence of dystrophin, the DAPC is lost, making the muscle membrane more susceptible to contraction-induced injury. The identification of the gene causing DMD in 1986 resulted in improved diagnosis of the disease and the identification of hotspots for mutation. There is currently no effective treatment. However, there are several promising genetic therapeutic approaches at the preclinical stage or in clinical trials including read-through of stop codons, exon skipping, delivery of dystrophin minigenes and the modulation of expression of the dystrophin related protein, utrophin. In spite of significant progress, the problem of targeting all muscles, including diaphragm and heart at sufficiently high levels, remains a challenge. Any therapy also needs to consider the immune response and some treatments are mutation specific and therefore limited to a subgroup of patients. This short review provides a summary of the current status of DMD therapy with a particular focus on those genetic strategies that have been taken to the clinic.

Matrilineal analysis of mutations in the DMD gene in a multigenerational South Indian cohort using DMD gene panel sequencing

“…Recently several novel therapies targeting specific DMD mutations (including stop-codon read-through agents, exonskipping antisense oligonucleotides (AONs) etc.) that target and restore Dystrophin function (Aartsma-Rus et al, 2009;Babbs et al, 2020;Haas et al, 2015;Laing et al, 2011;Ousterout et al, 2015;Reinig et al, 2017) have been developed. An early and accurate molecular diagnosis is critical for most of these therapies (Aartsma-rus et al, 2016).…”

Molecular Insights into Determinants of Translational Readthrough and Implications for Nonsense Suppression Approaches

“…Since the first attempt by Howard and colleagues in 1996 [ 64 ], several relevant diseases have been challenged with this correction strategy, including Duchenne/Becker dystrophy [ 68 , 114 , 115 , 116 , 117 , 118 ], cystic fibrosis [ 119 , 120 , 121 , 122 , 123 , 124 ], and spinal muscular atrophy [ 84 , 125 , 126 ]. Broad information on the efficacy of drug-induced readthrough for these disease models, as well as a detailed discussion on readthrough -inducing compounds, have been recently reviewed [ 87 , 127 , 128 , 129 ]. In addition, further details on approaches related to stop codon suppression or other strategies for the correction of molecular defects in genetic disorders have also been described [ 130 , 131 , 132 ].…”

Nutraceutical Screening in a Zebrafish Model of Muscular Dystrophy: Gingerol as a Possible Food Aid

“…More recently, research has focused on possible gene-based strategies, and a few of these are now reaching the phase II/III clinical trial stage. They include, among others, upregulation of utrophin, enhancement of muscle regeneration, and virus-mediated minidystrophin gene therapy (www.clinicaltrials.gov; NCT03362502-accessed on 1 February 2021) [2]. Moreover, recently, the use of a group of cells called muscle side population (SP) cells to deliver genes, such as the human microdystrophin, showed that these SP cells are capable of recapitulating the myogenic lineage.…”