Determining of the level of dystrophin essential to restore a physiological condition needed to the contractile function of muscles in GRMD dogs


A team from the Institute of Myology, leaded by France Piétri-Rouxel (Sorbonne Universities, Pierre and Marie Curie University / Inserm / CNRS / Institute of Myology) enabled to define a threshold of muscular fibres containing the dystrophin needed to normalize the condition of proteins essential to the contractile function of muscles, but also to significantly improve the overall muscle’s physiological condition.

Duchenne muscular dystrophy (DMD) is a severe disease characterized by a progressive muscle weakness, leading to a loss of walking abilities and respiratory and heart insufficiencies. The disease is caused by a mutation of the dystrophin gene leading to a lack of proteins. Up to now, no cure exists.

At present, the most advanced clinical strategy to treat DMD is that of exon skipping. While clinical trials with antisense oligonucleotides are being processed for DMD, it was vital to determine a threshold of dystrophin restoration needed to estimate the improvement of muscular physiology at a molecular level, notably studying the condition of proteins important for muscle contraction.

This study followed a preclinical trial recently led on GRMD dogs, naturally affected by a form of muscular dystrophy and whose forelimbs were treated with injections of rAAV8-U7snRNA vectors leading to exon skipping to restore the expression of dystrophin.

The published study therefore enabled to determine that a threshold of 40% of muscular fibres expressing dystrophin is needed to normalize the condition of proteins essential for the contractile function of muscles, and that this threshold is correlated with a significant improvement of muscle resistance. Hence, these works reveal that it is essential to reach a level of expression of dystrophin not only for the direct action of this protein, but also for a significant improvement of the function and the physiology of the overall muscle.

These works published on June 8th, 2016 in Human Gene Therapy magazine were supported by AFM-Telethon and are available online.