The dystrophin gene, which is central to the pathology of Duchenne Muscular Dystrophy (DMD) , comprises 79 exons, which are interspersed with non-coding introns. Deletions of 1 or more exons disrupts the synthesis of the dystrophin protein which plays a central role in linking the contractile apparatus of a muscle fiber to the cell membrane and surrounding extracellular matrix. An absence or a low level of dystrophin leads to progressive muscle fiber degeneration characteristic of DMD, with fatty and fibrous tissue replacement of muscle.
The extent and nature of the mutations are different in different sub-populations of DMD patients, but the key factor of the disease is a disruption in the coding of mRNA for dystrophin. This defective mRNA is said to be "out of the transcription reading frame" and results in a premature halt of the protein synthesis. Patients with DMD therefore have a truncated, non-functional dystrophin protein in their muscles.
Patients with Becker Muscular Dystrophy (BMD) show intermediate to milder phenotypes with mostly longer to normal life expectancies when compared with DMD patients. Here, the mutations in the DMD gene maintain the open reading frame and result in an internally truncated but semi-functional dystrophin. The specific skipping of 1 or more exons flanking the specific deletion in DMD patients allows restoration of the mutated open reading frame, introduction of novel, BMD-like dystrophin, and conversion of a severe DMD into a typically milder BMD phenotype.
Our aim through our exon-skipping technology is to restore the coding reading frame of mRNA so that it can be read to produce a shorter, but still functional dystrophin protein, such as in patients with BMD. This means that patients with DMD may be maintained or even improved.
See schematic representation of how exon-skipping works below:
Schematic representation of the exon-skipping strategy
This DMD patient exhibits a deletion of exon 50 resulting in an out-of-frame mRNA transcript and a prematurely aborted dystrophin synthesis.
Employing an antisense oligonucleotide (drisapersen) binding to exon 51 in the pre-mRNA, an in frame mRNA transcript is produced resulting in a shortened, but BMD-type dystrophin protein.
Although exon skipping is a mutation-specific treatment, representing personalized medicine, an important intrinsic advantage compared with conventional gene therapy is that it simultaneously corrects all dystrophin isoforms. It also maintains the original tissue-specific gene regulation. Moreover, the antisense compounds inducing exon skipping are small, synthetic, and highly sequence-specific.
For some frequently asked questions (FAQ) about the potential application of exon skipping, see the FAQ’s in the Patients & Family section .