Researchers at University of Texas Southwestern (USA) have made an unexpected finding whilst testing genome editing in a mouse model of Duchenne muscular dystrophy (DMD). They have identified a way to improve the efficiency of the technology and boost dystrophin production.
The different exons in the dystrophin gene are like puzzle pieces that need to fit together. When certain exons are missing, the puzzle is incomplete and no dystrophin protein can be produced.
In previous work, Dr Eric Olson and his team had studied mouse and dog models of DMD that were missing exon 50 of the dystrophin gene. The researchers used genome editing to modify the surroundings of the missing exon 50, so that nearby exons could join up and complete the puzzle. This restored dystrophin production in the animals.
In this new study, the researchers wanted to see if a similar genome editing treatment would work in a new mouse model lacking exon 44. This approach could be relevant for 12% of patients with DMD. The researchers found that although the dystrophin gene was successfully corrected, only 10 percent of muscle fibres in the mice produced dystrophin. This was surprising given the success of their previous exon 50 studies.
Through trial and error, the researchers discovered that the amount of the two genome editing components had a significant impact on dystrophin production. They found that a 10-to-1 ratio was most optimal, leading to dystrophin restoration in about 90 percent of muscle fibres in the mice.
Dr Yi-Li Min, first author of the study, said:
This is surprising. We had always delivered the guide RNA and Cas9 using two viruses in equal amounts and hadn’t thought to look into changing the ratio.
This new knowledge is important because it will help scientists to maximise the amount of dystrophin produced from future genome editing treatments. This will hopefully lead to better clinical outcomes.
These findings also help to improve the efficiency of genome editing more generally. This is valuable for research into other genetic muscle-wasting conditions.
Although more research is needed, every new piece of information is a stepping stone to bringing this exciting technology to clinical trials.
Dr Olson said:
We have more to do before we can use this clinically, but it’s exciting to see how far we’ve come.
Find out more about genome editing.
Read UT Southwestern’s press release.
The study was published in the scientific journal Science Advances.