Duchenne Muscular Dystrophy: From Diagnosis to Therapy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options. OPEN ACCESS

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…Due to the deleterious role of inflammation in dystrophic muscles, anti-inflammatory steroids still represent the gold standard for the treatment of DMD, being able to improve the patients' quality of life [10,11]. Prednisone and deflazacort delay the loss of muscle strength and functionality, the loss of ambulation, the onset of scoliosis, and respiratory and cardiac failure.…”

“…Antisense oligonucleotides (AONs) are the molecules used to obtain exon skipping. These AONs are composed of 20-30 nucleotides, specifically designed to match the pre-mRNA sequence to skip the DMD exon with the mutation, thus leading to truncated transcripts that are translated into functional proteins [11]. Phosphorothioate oligonucleotides (PS, Drisapersen) and morpholino phosphorodiamidate oligomers (PMO, Eteplirsen) are useful for patients carrying the mutation in exon 51; they can be injected locally or delivered systemically [33].…”

“…Because of the several disadvantages of aminoglycosides (i.e., high dosages and the renal and oto-toxicity), other molecules have been developed with the same activity but fewer side effects [11]. One of these molecules is Ataluren (Translarna, former PTC124), a nonaminoglycoside without antibacterial activity [11]. The expression of dystrophin is upregulated in skeletal muscles (including diaphragm) and hearth of mdx mice treated with Ataluren [56,57].…”

“…Consequently, over the past years many studies have aimed at finding alternative therapeutic approaches to treat or cure DMD pathology [11].…”

Application of Multiplex PCR for Detection of Duchunne Muscular Dystrophy: A Childhood Neuromuscular Disorder

“…Therefore, most of the DMD mutations create premature stop codons, which presumably results in the expression of truncated proteins that lack the dystrophin C-terminus [46].…”