CRISPR genome editing corrects a Duchenne muscular dystrophy deletion mutation in mice

Two genome editing approaches can correct a variety of mutations associated with Duchenne muscular dystrophy (DMD), researchers have shown.

DMD is a genetic disorder caused by mutations in the dystrophin gene, leading to a fatal decline in muscle integrity. For the first time, researchers have used two CRISPR-based genome editing techniques to correct multiple dystrophin mutations in mice. It is hoped this could pave the way for new genome editing therapies for DMD.

'Every cell in the human body has three billion letters of DNA sequence in its genome, and this method makes it possible to correct large deletions in the DMD gene by specifically swapping one of these letters,' said Professor Eric Olson, of the University of Texas Southwestern Medical Centre in Dallas, and senior author of the study. 'That level of specificity and efficiency is remarkable,' he added.

The study, published in Science Advances, investigated two methods of genome editing termed 'prime editing' and 'base editing'. The techniques are similar to the CRISPR/Cas9 approach, where specialised proteins are introduced into cells to make edits to genomic DNA, but they enable more precise changes to single DNA 'letters', called bases.

In a significant proportion of DMD patients, dystrophin mutations produce an errant 'stop' signal that halts production of functional protein. By changing single DNA bases, the researchers were able to bypass these mutations and restore 97 percent of functional dystrophin production in human heart muscle cells in vitro. When applied to a mouse model of DMD, functional dystrophin returned to over half of leg muscle fibres within three weeks.

'A lot more work needs to be done to develop the technology before it can be applied to patients – but this paper does represent a very promising step' said Professor Robin Lovell-Badge, from the Francis Crick Institute, London, not involved in the research. 'This study is therefore a pointer of which way to proceed in other situations where genome editing is being used to correct a defective gene.'

The findings have been hailed as an important proof-of-concept for base editing and prime editing, although the authors stressed that there is still a long way to go before these techniques can be translated to the clinic. For instance, in order to deliver the cargo of genome-editing proteins into cells, the team used a very high number of viral particles as vehicles – too high to safely trial in bigger animal models and humans.

Nevertheless, the research team are hopeful this method could one day be broadly applied to the treatment of DMD.

Professor Olson explained: 'The power of our method is that you don't need a new gene editing strategy for every patient with a new mutation; you can correct multiple different mutations with a consolidated approach.'