“The possibility that you could treat someone with gene editing is incredibly exciting”: in conversation with Prof Vincent Dion

As we start to see treatments emerge for dementia, we expect the effects to be quite modest at first. It would typically take further years or decades of therapeutic development to bring larger benefits and something more resembling a 'cure'. However, with recent breakthroughs in genetic technology, a more permanent solution may not seem so far off for some neurodegenerative diseases. To learn more, we spoke to Prof Vincent Dion, Group Leader from UK DRI at Cardiff and DNA repair theme Lead, whose work into gene editing is at the cutting-edge of the search for therapeutics.

Huntington’s disease is a devastating neurodegenerative condition which often tragically impacts people in their forties, causing abnormal movements and the gradual inability to think and communicate before death around 15 years later. Unlike a more common disease associated with dementia such as Alzheimer’s, Huntington’s has a purely genetic origin, with an individual having a 50% chance of inheriting the condition if a parent is affected. 

The underlying biological cause of Huntington’s, and at least 14 other neurological and neuromuscular diseases, is an increased or expanded number of repetitive stretches of DNA, for example the sequence CAG/CTG (CAG repeats). The resulting Huntington’s protein is toxic and thought to have many harmful effects in the brain including interference with a neuron’s transport network and gene regulation, leading to the clinical symptoms observed. Additionally, the more CAG repeats that a person has, the more severe the manifestation of the disease.

Prof Vincent Dion, a Canadian researcher now based at the UK DRI at Cardiff, is an expert in DNA repair and has been studying expanded repeat diseases like Huntington’s for over a decade. A breakthrough in Prof Dion’s investigations came in the mid-2010s when he had just started his lab at the Center for Integrative Genomics at the University of Lausanne, Switzerland. He asked a simple question - “if expanded repeats lead to a more severe disease, what happens if we shrink these repeats and cause a contraction?” Fortunately, at that time, a recently developed and revolutionary gene editing technology would allow Prof Dion to try and answer that question – CRISPR-Cas9.

“An additional challenge posed by the repeats is genome instability, where abnormal DNA structures form and can be mistaken as damaged. The resulting repair process carried out by cellular machinery can compound issues including causing further expansion of these bad repeats. What we discovered though is that some forms of DNA damage, particularly that which only cut a single strand of the DNA, cause more beneficial contractions than expansions.”

The team set about exploiting CRISPR-Cas9 so that it cut a single strand in the DNA rather than the double-stranded break usually induced by the technology to edit the genome. They did this by introducing a mutation into the enzyme and creating a nickase enzyme. Like normal CRISPR-Cas9, the modified enzyme could be specifically targeted to anywhere in the genome such as the regions of expanded CAG repeats. Prof Dion was able to demonstrate in cellular systems that when these single strand breaks were induced and then repaired, the desired contractions were occurring. 

Prof Dion’s lab in the UK DRI at Cardiff is now at a stage of testing a therapeutic approach in animals. The treatment uses a viral system to deliver a molecular package to affected neurons in a mouse model of Huntington’s disease. The package contains instructions for the mutated CRISPR-Cas9 enzyme (nickase) and guide RNAs to specifically target the enzyme to the expanded CAG repeats. The theory is that the single strand DNA breaks made by the nickase will cause contractions when repaired, slowing progression of the disease.

Milestones are already being reached in human studies as well. In a recent landmark clinical trial, it was shown that CRISPR-Cas9 gene editing was safe and effective when delivered into the human body via the bloodstream. The novel treatment targeted the TTR gene which encodes a protein that can misfold and cause the rare, but fatal, condition transthyretin amyloidosis. On average trial participants who received the higher of the two doses, saw levels of the protein decline by a remarkable 87%.

“The possibility that you could treat someone with gene editing is incredibly exciting. I think that's been a big change we’ve seen in the last few years.”

It’s hard not to be enthused by the progress and opportunities opening in this new era of scientific advancement but Prof Dion is quick to recognise there are still significant technological, and even ethical, challenges to overcome.

“The main advantage of gene editing may also be viewed as its main weakness – a permanent change. So, although we may be able to treat the disease permanently, any mistakes made along the way are also there to stay. Editing the genome is not without risk and there may be off-target mutations which can cause cancers. Our job as scientists is to refine the technology, minimising this risk, but decisions will have to be made when you decide what risk you are willing to take to treat an incurable disease like Huntington’s.

From my point of view, you would want to administer this treatment relatively swiftly after the onset of mild symptoms and stop disease progression to have the biggest impact. Even then you are taking a risk of causing life-changing mutations in someone who is relatively healthy at the time. It also won’t be cheap to receive these types of treatments. We’re going to have to face these difficult questions more and more as we accelerate the possibilities in medicine.”

For Prof Dion and his growing team in Cardiff, their focus is on developing the technology and getting it to point where it can be translated for the clinic. To give himself the best chance of making that a reality, Prof Dion joined the UK DRI in 2019, surrounding himself with expertise in dementia research and the means to turn breakthroughs into much-needed treatments for neurodegenerative disease.

“You talk to people with expanded repeat diseases such as Huntington’s or muscular dystrophy, and one of the things that really drives them is the hope that we're going to find something. It's a big expectation but we will put all our efforts into trying to deliver that for them.”

Article published: 12 July 2021
CAG/CTG repeat image: rumruay/Shutterstock.com