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.

Figure 1

The dystrophin protein. (a) Schema representing the four main domains of dystrophin: the N-terminal part, central rod domain (containing 24 spectrin-like repeats and four hinge domains), cystein-rich region and the C-terminal part. The protein binding domains are also indicated. (b) Diagram of the dystrophin-associated glycoprotein complex (DGC). This complex includes dystrophin with its C-terminal (Ct), cysteine-rich (CR), and N-terminal (Nt) regions as well as proteins associated in this complex. DG, dystroglycan; nNOS, neuronal nitric oxide synthase; Sg, sarcoglycan; Syn, syntrophin. Modified from Odom et al.

Figure 2

Example of exon skipping in Duchenne muscular dystrophy (DMD) patient who has a deletion of exon 50. (a) The absence of exon 50 in the dystrophin gene leads to an out-of-frame mRNA creating a premature stop codon in exon 51, thus aborting dystrophin synthesis during translation. (b) Using an antisense oligonucleotides (AO) targeting exon 51, this exon is skipped during splicing. This restores the open reading frame of the transcript and allows the synthesis of an internally deleted dystrophin. Modified from Van Deutekom et al.

Figure 3

Dystrophin versions. The full-length dystrophin cDNA (11 kb) is represented at the top. The middle schema represents an example of a mini-dystrophin cDNA with an H2-R18 deletion; the approximate size of mini-dystrophins is about 6 kb. The bottom representation is a schema of a micro-dystrophin cDNA (around 4 kb) with an R3-R21 and C-terminal deletion.