A team of researchers led by Cardiff University has developed a promising new gene-editing approach that could transform the treatment of Huntington's disease in the future.
Huntington's disease is caused by repetitive "stutters" in DNA - specifically repeated CAG sequences - that expand abnormally over time, leading to toxic protein accumulation that contribute to the progression of the disease. There is currently no cure for this rare and fatal genetic disease.
Professor Vincent Dion of the UK Dementia Research Institute at Cardiff University, who led the research team, said: "The length of these repeated sequences accounts for most of the variation in how severe the disease is, so targeting and reducing these sequences is a potentially viable therapeutic avenue.
"Traditional gene-editing techniques often cut both strands of DNA to disable mutated genes, but this can trigger unpredictable rearrangements, off-target mutations, or damage to healthy copies of the gene. Some researchers are also trying to apply these traditional gene-editing techniques to treating Huntington's disease in pre-clinical work, but they have limitations."
We wanted to finesse this technique to explore whether there are more reliable potential genetic treatments for Huntington's disease.
In the new study, published in Science Translational Medicine, researchers used a more precise gene-editing enzyme called Cas9 nickase, which cuts only a single strand of DNA within the repeated CAG/CTG sequences in mouse models of Huntington's disease.
Professor Dion said: "When packaged into viral vectors and delivered directly to the striatum - the brain region primarily impacted by Huntington's disease - in a mouse model, the therapy shortened the DNA repeats in the majority of targeted neurons.
"This led to fewer toxic Huntington protein aggregates, restored healthier gene expression pathways in brain cells, and showed significant improvements in motor function during locomotion tests."
The team say no unwanted mutations were detected in brain cells in the mouse models with this approach, and it offers a potentially safer alternative to conventional gene-editing methods.
While much more research is needed - and our results only apply to mouse models of Huntington's - these are exciting findings because there is currently no treatment for Huntington's disease that changes the course of the disease. This could represent a novel therapeutic pathway through which we may be able to prevent the progression of - or effectively treat - Huntington's disease.
The research was based on the CRISPR gene editing method and has potential application beyond Huntington's disease in other genetic diseases caused by expanded repetitions in genetic codes.
Now, the team say more research is needed that involve optimising delivery methods to ensure stable, long-term expression of the editing tools without triggering immune responses, investigating whether treating animals at earlier stages can prevent neurodegenerative damage before symptoms ever appear, and conducting rigorous safety and efficiency testing in larger preclinical models to build the foundation for human clinical trials.
The research, Cas9 nickase–mediated contraction of CAG/CTG repeats is associated with phenotypic improvements in a Huntington's disease mouse model, was published in Science Translational Medicine.
