Promising New Treatment For Patients With Duchenne Muscular Dystrophy (DMD)
This disease involves mutations in the dystrophin gene. Usually deletions are found in 65 percent of cases. They prevent the body from being able to create the protein dystrophin, which is important for muscle structure. DMD is a fatal progressive muscle-wasting disease affecting about 1 in 3,500 males. Symptoms start at about 3 years of age and death generally occurs by age 30 from heart and respiratory failure.
There have been promising results achieved with antisense oligonucleotides. But, there is currently no treatment available to modify disease progression. These antisense molecules can be used to skip over parts of the gene that block the effective creation of dystrophin. In 13 percent of people with DMD, mutations in the dystrophin gene affect parts of the gene immediately before or after the region known as exon 51. This means that production of dystrophin cannot develop further than the mutated region. The antisense oligonucleotide binds to exon 51 and prevents the affected regions from stopping production. In consequence, a version of the protein dystrophin can still be made. This effect could benefit patients with DMD.
Francesco Muntoni from University College London Institute of Child Health and his team conducted a dose escalation trial to test this theory. They assessed the safety and biochemical efficacy of AVI-4658. It is a type of antisense oligonucleotide called a phosphorodiamidate morpholino oligomer that is targeted to skip exon 51.
They tested a group of seven patients with DMD who had a mutation that could in theory be rescued by the skipping of exon 51. They 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. Between three and four weeks after injection, a biopsy of both EDB muscles was done.
In general, findings indicated that treatment with AVI-4658 resulted in the skipping of exon 51 and the production of dystrophin. It was not related with any systemic or local adverse events, or with any immune response against dystrophin.
The higher-dose of AVI-4658 particularly resulted in increased dystrophin expression in all treated EDB muscles. The authors explain: "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 write in conclusion: "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 associated comment, Annemieke Aartsma-Rus and Gert-Jan van Ommen from Leiden, Netherlands remark: "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 continue by indicating that the skipping of exon 51 is applicable to only 13 percent of DMD patients and will not benefit the other 87 percent. But they suggest that eventually the skipping of another ten exons may be beneficial for more than 70 percent of all patients with deletions in the dystrophin gene.
"Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study"
Maria Kinali, Virginia Arechavala-Gomeza, Lucy Feng, Sebahattin Cirak, David Hunt, Carl Adkin, Michela Guglieri, Emma Ashton, Stephen Abbs, Petros Nihoyannopoulos, Maria Elena Garralda, Mary Rutherford, Caroline Mcculley, Linda Popplewell, Ian R Graham, George Dickson, Matthew JA Wood, Dominic J Wells, Steve D Wilton, Ryszard Kole, Volker Straub, Kate Bushby, Caroline Sewry, Jennifer E Morgan, Francesco Muntoni
The Lancet Neurology
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