New Treatment Shows Promising Results In Patients With Duchenne Muscular Dystrophy
DMD is a fatal progressive muscle-wasting disease affecting about 1 in 3500 males. In this disease, mutations in the dystrophin gene-typically deletions, which are found in 65% of cases-prevent the body from being able to create the protein dystrophin, which is important for muscle structure. Symptoms begin at about 3 years of age and death usually occurs by age 30 from heart and respiratory failure.
There is currently no treatment available to modify disease progression, although promising results have been achieved with antisense oligonucleotides. These antisense molecules can be used to skip over parts of the gene that block the effective creation of dystrophin. In 13% of people with DMD, mutations in the dystrophin gene affect parts of the gene immediately before or after the region known as exon 51, which means that production of dystrophin cannot progress beyond the mutated region. By binding to exon 51, the antisense oligonucleotide prevents the affected regions from stopping production and means that a version of the protein dystrophin can still be made, which could benefit patients with DMD.
To test this theory, Francesco Muntoni from University College London Institute of Child Health and colleagues conducted a dose escalation trial to assess the safety and biochemical efficacy of AVI-4658, a type of antisense oligonucleotide called a phosphorodiamidate morpholino oligomer that is targeted to skip exon 51.
In total, seven patients with DMD who had a mutation that could in theory be rescued by the skipping of exon 51 were given an intramuscular injection of AVI-4658 into the extensor digitorum brevis (EDB), a relatively non-functional muscle in the foot. Two patients were injected with 0.09 mg and five patients were injected with 0.9 mg of AVI-4658 in one EDB muscle, and the EDB muscle of the other foot was injected with 900 µL of saline. A biopsy of both EDB muscles was done between 3 and 4 weeks after injection.
Overall, findings showed that treatment with AVI-4658 resulted in the skipping of exon 51 and the production of dystrophin, and was not associated with any systemic or local adverse events, or with any immune response against dystrophin.
In particular, the higher-dose of AVI-4658 resulted in increased dystrophin expression in all treated EDB muscles. The authors report: "Exon 51 skipping and distinct bands of dystrophin protein were seen in the drug-treated muscles…of patients in the high-dose group. Exon 51 skipping was also seen in the two patients in the low-dose group, but this was less abundant."
They conclude: "Intramuscular AVI-4658 was safe and induced the expression of dystrophin locally within treated muscles…On the basis of these observations, we have initiated a dose-ranging study…to assess the safety and efficacy of repeated doses of systemic intravenous AVI-4658."
In an accompanying Reflection and Reaction, Annemieke Aartsma-Rus and Gert-Jan van Ommen from Leiden, Netherlands say: "Only systemic trials will reveal the true promise of this approach, and further trials are needed to validate the functional benefit, or at least the decline in disease progression."
They go on to point out that skipping of exon 51 is relevant to only 13% of DMD patients, and will not benefit the other 87%, but suggest that eventually the skipping of another 10 exons may benefit more than 70% of all patients with deletions in the dystrophin gene.
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The Lancet Neurology
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