Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing

“…Currently, several therapeutic approaches (gene therapy, cell therapy, and exon skipping) have been investigated to restore the expression of dystrophin in DMD muscles. 35,36 Deletion/excision of intragenic DNA and removing the duplicated exon by CRISPR/Cas-9 are the new and promising approaches in correcting the DMD gene, which restores the expression of dystrophin protein. 37 Moreover, the latest researches show that the CRISPR/ Cas-mediated single-base editing and prime editing systems can directly install mutations in cellular DNA without the need for a donor template.…”

Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

“…Prednisone, prednisolone, and deflazacort, mostly through inhibition of NF-κB signaling, represent a gold standard for the treatment of DMD for their ability to exert long-term protective effects [175]. Importantly, to date, an increasing variety of therapeutic strategies aimed at restoring dystrophin production and to preserve muscle mass has been proposed, ranging from gene therapy to antisense oligonucleotide therapies [176,177]. Several studies propose therapeutic approaches for DMD aimed not only at restoring dystrophin function but also to mitigate secondary and downstream pathological mechanisms that contribute to the disease's progression, such as calcium dysregulation, oxidative stress, mitochondria dysfunction, fibrosis and muscle wasting.…”

Palliative Care in Pediatric Pulmonology

“…The past decade has seen substantial growth in the number of available novel therapies in treating specific neuromuscular disorders, especially Duchenne's Muscular Dystrophy, Spinal Muscular Atrophy, and Limb Girdle Muscular Dystrophy. In broad terms, these treatments utilize a variety of approaches to either target the dysfunctional mutation through pre-mRNA splicing, replace mutated genes using a viral vector, or by upregulating other physiologic products in the muscle with similar properties to the dysfunctional protein [47,48]. For many patients, these therapies provide significant improvement in physical functioning, disease-related biomarkers, and slowing the progression of illness.…”