A novel therapy for muscular dystrophy
DMD is an incurable degenerative muscle disease caused by mutations in the dystrophin gene, one of the largest human genes. Under normal circumstances, the 79 protein-coding parts of the dystrophin gene assemble to provide the functional protein. In contrast to DMD, where mutations in some of these exons lead to a non-functional protein, Becker muscular dystrophy (BMD) allows for a shorter but functional protein to be produced. This allows patients to walk and have a normal lifespan. Therapeutic strategies that genetically aim to create a milder BMD form of the disease are an attractive possibility for DMD patients. Towards this goal, scientists have developed a method known as exon skipping, which essentially encourages the cellular machinery to skip the mutated exon. Efforts thus far had concentrated on skipping exon 51 of DMD pre-mRNA, as its removal achieved restoration of the open reading frame in nearly 13 % of DMD boys. Scientists on the EU-funded SKIP-NMD (A phase I/IIa clinical trial in Duchenne muscular dystrophy using systemically delivered morpholino antisense oligomer to skip exon 53) project proposed to use antisense oligonucleotides for exon 53 as a molecular patch to produce the shorter version of the dystrophin protein. Different oligonucleotides were tested initially in vitro on immortalised myoblasts from DMD patients with different exon 53 mutations. The safety and clinical efficacy of the most efficient antisense oligonucleotide was tested in a randomised control clinical trial in UK, France and Italy. Scientists used muscle magnetic resonance imaging and magnetic resonance spectroscopy to validate the treatment outcome of 25 children, who received daily infusions of the oligonucleotide. The ongoing assessment of physiotherapy, biological and biochemical measures will determine the overall efficacy of the approach. Long term, the idea is to personalise this RNA therapy approach using antisense oligonucleotides to skip the mutated exon encountered in each case and produce a shorter yet functional dystrophin protein. This is expected to slow down disease progression and improve patient quality of life.
Keywords
Duchenne muscular dystrophy, dystrophin, exon skipping, SKIP-NMD, clinical trial
