Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease affecting about one in every 3,500 boys. This X-linked pathology is due to the absence of dystrophin in muscle fibers. This lack of dystrophin leads to the progressive muscle degeneration that is often responsible for the death of the DMD patients during the third decade of their life. There are currently no curative treatments for this disease but different therapeutic approaches are being studied. Gene therapy consists of introducing a transgene coding for full-length or a truncated version of dystrophin complementary DNA (cDNA) in muscles, whereas pharmaceutical therapy includes the use of chemical/biochemical substances to restore dystrophin expression or alleviate the DMD phenotype. Over the past years, many potential drugs were explored. This led to several clinical trials for gentamicin and ataluren (PTC124) allowing stop codon read-through. An alternative approach is to induce the expression of an internally deleted, partially functional dystrophin protein through exon skipping. The vectors and the methods used in gene therapy have been continually improving in order to obtain greater encapsidation capacity and better transduction efficiency. The most promising experimental approaches using pharmaceutical and gene therapies are reviewed in this article.

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

“…12 Moreover, the phosphorylation of b-DG was involved in the adhesion in skeletal muscle fibers 27 and DGs were downregulated in the muscle fibers and brains of DMD patients and mdx mice. [77][78][79] In addition, altered a-DG glycosylation, and aberrant AQP4 and potassium channel Kir 4.1 location in perivascular domains have been reported in an animal model of dystroglycanopathies, 80 supporting the role of a correct link between the extracellular matrix and DAPs in the clustering of the channel proteins.…”

Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study

“…Approximately 7-9% of patients with dystrophin gene deletions disagree with the readingframe rule. 8 We suggest that this type of inaccurate judgment accounts for at least a part of the discordance between genotype and phenotype.…”

“…8 Gentamycin and ataluren (PTC24), allowing nonsense mutation reversion, have completed phase II clinical trials. 9,10 The antisense oligonucleotides, such as AVI-4658 and PRO051, which induce exon 51 skipping, have completed phase II clinical trials; PRO051 is currently undergoing a phase III clinical trial.…”

“…[8][9][10][11][12] Exon skipping, which rectifies the aberrant reading frame, aims to treat patients with large deletions; yet, to achieve this, the selection of appropriate patients with detailed genetic diagnosis is very important.…”

Avaliação de pacientes com distrofia muscular de Duchenne em laboratório computadorizado de marcha através do índice de alteração da marcha

“…Com a evolução da terapia gênica, novas modalidades terapêuticas surgem para auxiliar o manuseio desta patologia (6) . A mensuração dos resultados funcionais destes tratamentos pode ser realizada com a avaliação da marcha.…”