CRISPR base editing reduces DNA repeats that cause Huntington's and Friedreich's ataxia

Genome editing has been used to disrupt a type of repetitive DNA sequence that is found in certain genes and can cause severe neurological disease.

The work took place at the Broad Institute, Cambridge, Massachusetts, in the lab of Professor David Liu, who first developed base editing and prime editing (see BioNews 1285). Base editing is a variation of CRISPR that makes specific changes of one nucleotide base 'letter' to another without cutting the genome, enabling controlled 'rewriting' of DNA sequences.

'There's still a lot of work to be done, but we're hopeful that this approach could really accelerate therapeutic development for a lot of these diseases' said Dr Mandana Arbab, who worked as a researcher on the project and was second author of the paper published in Nature Genetics.

Many genes contain repetitive sections of three nucleotides that can continue for different lengths and can also expand during a person's lifespan, meaning that the genes' protein product varies in size between individuals. While this is useful in evolution because it allows flexibility, when these repeats are too long, they can produce a protein that is toxic to cells and causes neurological disorders, such as Huntington's disease.

The huntingtin gene encodes a protein that is crucial for neuronal function, and contains a series of C-A-G base pair repeats (CAG repeats). Huntington's disease arises when there are more than 40 CAG repeats, causing the huntingtin protein to have toxic effects. On the other hand, Friedrichs ataxia, another neurodegenerative disease, is caused when there are more than 22 repeats of the bases G-A-A (GAA repeats) in the frataxin gene, which encodes a protein thought to help assemble iron and sulphur, which are crucial for energy production.

Editing these repeats in patient DNA has been suggested as a potential therapy to treat both diseases, as well as other disorders with similar genetic causes. To test this, the researchers developed a base editing strategy that disrupts the CAG and GAA repeats associated with Huntington's disease and Friedrich's ataxia respectively, in a way that mimics mutations observed in patients.

Their base editing approach successfully reduced the repeat lengths, and halted the expansion of repeats, in connective tissue cells from patients and mouse models of both diseases. However, the researchers did not test whether the approach improved disease symptomsin mice, and it is expected that the approach will lead to repeats in other, unrelated genes being edited inadvertently. For these reasons, it is not yet known whether this strategy could have a therapeutic effect.

'A lot more studies would be needed before we can know if disrupting these repeats with a base editor could be a viable therapeutic strategy to treat patients' said Professor Liu. 'But being able to illuminate the biological consequences of interrupted repeats is a really useful and important milestone.'

BioNews has previously reported on many developments in base editing as a tool for therapy (see, for example, BioNews 1289 and 1282). BioNews has also reported on recent developments in the search for a cure for Huntington's, including another CRISPR-based approach to treating the disease (see BioNews 1277, 1274 and 1172).