Abstract
Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by progressive muscle weakness, is caused by the absence or a decreased amount of the muscle cytoskeletal protein dystrophin. Currently, several therapeutic approaches to cure DMD are being investigated, which can be categorized into two groups: therapies that aim to restore dystrophin expression, and those that aim to compensate for the lack of dystrophin. Therapies that restore dystrophin expression include read-through therapy, exon skipping, vector-mediated gene therapy, and cell therapy. Of these approaches, the most advanced are the read-through and exon skipping therapies. In 2014, ataluren, a drug that can promote ribosomal read-through of mRNA containing a premature stop codon, was conditionally approved in Europe. In 2016, eteplirsen, a morpholino-based chemical capable of skipping exon 51 in premature mRNA, received conditional approval in the USA. Clinical trials on vector-mediated gene therapy carrying micro- and mini- dystrophin are underway. More innovative therapeutic approaches include CRISPR/Cas9-based genome editing and stem cell-based cell therapies. Here we review the current status of therapeutic approaches for DMD, focusing on therapeutic approaches that can restore dystrophin.
Highlights
Duchenne muscular dystrophy (DMD) is a muscular disorder caused by the absence or reduction of the muscle cytoskeletal protein dystrophin
Several therapeutic approaches to treat DMD have been investigated that can be divided into two groups: therapies that aim to restore dystrophin expression, and those that aim to compensate for the lack of dystrophin [8]
Other promising antisense oligonucleotides (ASOs) include an antisense oligonucleotide consisting of ethylene-bridged nucleic acids, DS-5141b, (Daiichi-Sankyo Co., Ltd., Tokyo, Japan) to skip exon 45, which recently was announced to be safe and has shown mRNA exon 45 skipping in all treated patients in a phase 1/2 trial [37]
Summary
Duchenne muscular dystrophy (DMD) is a muscular disorder caused by the absence or reduction of the muscle cytoskeletal protein dystrophin. Several therapeutic approaches to treat DMD have been investigated that can be divided into two groups: therapies that aim to restore dystrophin expression, and those that aim to compensate for the lack of dystrophin [8] The former group includes read-through therapy, exon skipping therapy, vector-mediated gene therapy, and cell therapy. The latter group includes anti-inflammatory, anti-fibrotic, antioxidants, myostatin pathway inhibition, neuronal nitric oxide synthase pathway enhancement, and utrophin upregulation therapies. Of these approaches, read-through and exon skipping therapies have taken the development lead. PMO phosphorodiamidate morpholino oligomer, PPMO peptide-conjugated morpholino oligomer, ENA ethylene-bridged nucleic acids oligonucleotides, ASO antisense oligonucleotides
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