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New research into protein behaviour may help treatment of Muscular Dystrophy

Researchers in the Randall Division of Cell & Molecular Biophysics studying how to improve therapy for Duchenne Muscular Dystrophy (DMD), have had their findings published in the journal eLife.

Duchenne Muscular Dystrophy (DMD) is a disease that affects around one in 3,500 boys and which has no cure. The disorder is caused by a mutation of the gene that makes Dystrophin – an important component within muscle tissue – so muscles are unable to make it. This lack of Dystrophin leads to muscle fibre damage and a gradual weakening of the muscles.

Currently early-stage gene therapy trials, involving short versions of the protein Dystrophin being reintroduced into boys with DMD, have produced encouraging results, insofar as short Dystrophins were found in the boy’s muscles, but have not cured the disease. One of the possible explanations for this is that the short proteins are less stable than the long normal version. 

With backing from a number of organisations and charities (including the International Collaborative Effort for Duchenne Muscular Dystrophy (ICE for DMD) – a parent-led charity in Monaco), the MRC, and EU Marie Curie Programme, this study set out to understand the fundamental biology of the Dystrophin protein in living muscle tissue and improve gene therapy of the disease.

Up until now, there has been no available method to analyse human Dystrophin dynamics in the living animal. By developing a novel analysis method for an old method called Fluorescence Recovery After Photobleaching (FRAP) the research team aimed to overcome challenges of imaging in the living animal. Using muscle cells in zebrafish embryos to express a fluorescent version of human Dystrophin, the research team measured human Dystrophin diffusion and binding in real muscle fibres for the first time.

Their analysis showed that Dystrophin exists in several previously unknown forms in muscle cells and may also play other roles within them. These findings highlight a need to determine the nature of short versions of Dystrophin, as identifying which of these has similar properties to longer versions of the protein, could help optimise gene therapy for DMD. The novel methodology used in this study could also be used in other research into how muscle – and possibly other tissues – are built and repaired.

Dr Fernanda Bajanca, one of the research team working on the study said ‘The dynamics of Dystrophin have not previously been studied in live cells, let alone in contractile muscle fibres. Our result opens up a new window on Dystrophin biochemistry in vivo that may be important for re-introduced short Dystrophin molecules.’

Read the full eLife journal article In vivo dynamics of skeletal muscle Dystrophin in zebrafish embryos revealed by improved FRAP analysis.