A novel therapy for muscular dystrophy

DMD is a progressive muscle degenerative condition that stems from a lack of the protein dystrophin. Loss of dystrophin leads to inflammation and replacement of muscle with fibrous tissue.

Despite prenatal diagnosis, the incidence of DMD is 1 in 5 000 births due to novel mutations that arise in the dystrophin gene. The dystrophin gene is one of the largest known, with 79 different protein-coding regions referred to as exons. Mutations in one of these exons interfere with the rest of the gene being put together and producing a functional protein.

In Becker muscular dystrophy (BMD), DMD mutations still produce a shortened but functional dystrophin protein, and most patients are able to walk and have a normal lifespan. This occurs because although some exons are missing, the remaining can join together.

Based on this observation, scientists have developed a method known as exon skipping, which essentially encourages the cellular machinery to skip the mutated exon. For this purpose, they are using oligonucleotides as molecular patches to produce the shorter version of the dystrophin protein.

Prior work by the members of the EU-funded SKIP-NMD consortium successfully demonstrated the therapeutic outcome of skipping exon 51 in clinical trials with boys with DMD. The scope of SKIP-NMD is to extend this work in other children with DMD and perform skipping of exon 53.

After finalising the optimal antisense oligonucleotide sequence, researchers have performed toxicology and pharmacology studies to prepare for the clinical trial. Good manufacturing practices- antisense oligonucleotide molecules have been produced and a clinical trial protocol has been submitted for authorisation. The study will also validate novel outcome measures and assess the role of muscle magnetic resonance imaging and spectroscopy and serum biomarkers levels as a means of monitoring therapeutic intervention.

Although antisense oligonucleotide therapy is not a cure, and for therapy to be effective it should be administered at regular intervals throughout life, it is expected that this novel therapeutic intervention will result in reduction of muscle damage and slow down disease progression. The SKIP-NMD clinical trial is expected to provide novel information on the efficacy of this novel RNA therapeutics compound and establish the role for non-invasive monitoring of disease progression.