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Collaborative research between teams from the Department of Paediatrics and the Institut de Myologie shows how antisense oligonucleotides can penetrate muscles to treat myotonic dystrophy type 1, a rare muscle disease.

About 9,500 people in the UK suffer from a form of myotonic dystrophy – a rare genetic disease affecting the neuromuscular system. Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults, with an estimated prevalence of 1/8000. DM1 causes progressive muscle weakness and wasting, and a difficulty of muscles to relax after contraction; there is currently no cure for this debilitating and deadly neuromuscular disease.

Why is treating DM1 so challenging? On a molecular level, the disease is linked to a mutation in the DMPK gene. This genetic anomaly consists of an increase in the repeat number of a small three-nucleotide DNA sequence, which results in an accumulation of mutated DMPK RNA in the cell's nucleus. This in turn leads to a perturbation of the proper functioning of cells. Several rare genetic diseases may be treated using antisense oligonucleotides (synthesised RNA fragments) acting on the mutated RNA. However, in myotonic dystrophy type 1, unlike in other muscular dystrophies, the membrane barrier of muscle fibres is not weakened, which means that the antisense oligonucleotides cannot cross it easily. The reduced penetration leads to a reduced efficiency of the treatment.

However, promising advances have been made through collaborative effort from the teams of Professor Matthew J. A. Wood of the University of Oxford and Dr Denis Furling (Sorbonne Université – INSERM) of the Institut de Myologie research centre in Paris. To allow the antisense oligonucleotides to be efficiently distributed in the muscular fibre, the researchers coupled them with small pieces of protein – cell-penetrating peptides. Their work shows that the peptide allows the PMO antisense oligonucleotide to penetrate striated muscles of a myotonic dystrophy mouse model after a systemic administration. Additionally, low doses of treatment targeting pathological expansions of abnormal DMPK RNA, conjugated to peptides, are enough for the product to efficiently and durably correct disease symptoms in a mouse model.

Now, the teams continue to work together to develop this approach in the perspective of a clinical trial.

The research has been published in the Journal of Clinical Investigation.

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