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The cutting-edge of gene editing

Innovative, Trust-funded research shows exciting results for fixing one type of rare CFTR mutations and opens the door for tackling all CF genotypes.

Dr Patrick Harrison, who is working on the Cystic Fibrosis Trust’s gene editing Strategic Research Centre (SRC), led by Professor Stephen Hart at the UCL Great Ormond Street Institute of Child Health, has shown that a new method of gene repair could fix even more cells than in previous studies in one type of rare CFTR mutations called ‘deep intronic’ mutations.

Correcting gene mistakes

Gene editing techniques work by making a precise cut in the DNA where the gene mistake is located. The gene mistake is then corrected (by removing a part of the DNA or inserting a new piece of DNA) and the cut in the DNA is repaired. There are two methods of sealing up or ‘repairing’ the cut in the DNA afterwards – these methods are known as ‘HDR’ and ‘NHEJ’. Neither of these is a perfect method, and deciding which of these systems to use is part of Dr Harrison’s research.

The HDR method can edit very precisely and correct mutations, but is very inefficient and corrects few mutations. In comparison, the NHEJ method repairs the DNA cut very efficiently, but can make additional errors at the cut sites and even fail to correct the mutation.

In 2012, Dr Harrison and his team used gene editing to repair the F508del gene mutation using the HDR method, but efficiency was very low. With funding from the Trust, they managed to increase the HDR repair to correct two or three cells in every 100, but this was still too low for potential clinical development.

With the knowledge that the NHEJ method was very efficient but could cause errors, they wondered if the method could be used to correct mutations where these errors wouldn’t matter.

Switching repair methods

The researchers designed experiments to see if they could cut out rare, so-called ‘deep intronic’ mutations in the CF gene. To repair these mutations, which are found in approximately 1.5% of people with CF, no new bit of DNA needs to be added.

Dr Harrison has shown that gene editing using the NHEJ method on these rare mutations works successfully in human cells in the lab. Most importantly, the number of cells repaired has been much greater than in previous methods, with one in four cells being corrected as opposed to two or three in every 100 in the original technique. The next step will be to show that correcting the gene results in the creation of a fully functioning CFTR protein.

One size fits all

At present, this method only works with these specific, rare ‘deep intronic’ mutations, as they are found in a specific place in the CF gene that isn’t affected by the errors that the NHEJ method can cause. Dr Harrison has been awarded a Venture and Innovation Award by the Trust in collaboration with the Cystic Fibrosis Foundation in the USA, so that his group can continue to refine their new gene editing method. This time they’ll be adding a correcting section of DNA (as opposed to cutting out the mistake).

Rather than mending just one mutation, they’ll be testing out whether they can add a much longer section of DNA to correct all of the mutations in the CFTR gene in one go, making this a ‘one size fits all’ repair. This method is called ‘HITI-super-exon repair’, and could eventually provide an efficient gene editing method for all CF-causing mutations, rather than different methods being required for each specific CF gene mutation. If successful, further lab-based studies would be needed before it is ready to try in patients.

Interested in our gene editing research? Find out more about the work taking place behind the scenes at our Gene Editing Strategic Research Centre.

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