"We hope to develop novel therapeutic avenues for expanded CAG/CTG repeat disorders like Huntington's disease and myotonic dystrophy." Vincent Dion
UK DRI Group Leader

Prof Vincent Dion joins the UK DRI from the Center for Integrative Genomics at the University of Lausanne, Switzerland. Obtaining his PhD from Baylor College of Medicine, USA, in 2007, he completed postdoctoral training with Prof Susan M. Gasser at the Friedrich Miescher Institute, where he discovered a novel role for enzymes in DNA repair. He has been awarded several prizes, including a first place Sigma Xi Texas Medical Center Thesis Award in 2008, Researcher of the Month in December 2016 by the GenSuisse Foundation and a Professorship from the Academy of Medical Sciences in 2019. At the UK DRI at Cardiff he will lead an exciting program of research developing gene editing approaches to correct mutations in 14 different neurological and neurodegenerative diseases.

1. At a glance

Developing innovative new treatments for neurodegenerative diseases

Huntington’s disease is one of a group of inherited neurodegenerative diseases called ‘trinucleotide repeat disorders’ that also include myotonic dystrophy type 1 (DM1) and several spinocerebellar ataxias (SCAs). Although symptoms differ between diseases, they all involve the gradual loss of function and eventual death of neurons across different areas of the nervous system.

While the affected gene varies, these diseases share a similar type of fault – the abnormal expansion of a three-letter DNA sequence. For example, CAG is repeated 10 to 35 times within the normal Huntington’s gene – but the faulty version has up 120 repeats. Importantly, the number of repeats is linked with disease severity and age of onset in individuals affected – so finding ways to shorten this sequence could offer an effective treatment strategy.

Prof Vincent Dion is aiming to develop effective new treatments for trinucleotide repeat disorders. He is adapting the use of sophisticated gene-editing technologies to reduce the length of the repeat sequence and developing new techniques that can switch off the faulty gene in cells. His goal is to create effective new treatments that can stop, reverse or prevent the onset or progression of these devastating diseases that currently have no cure.

2. Scientific goals

Huntington’s disease (HD) is part of a family of 14 different neurological disorders caused by the expansion of CAG/CTG repeat, together with myotonic dystrophy type 1 (DM1) and several spinocerebellar ataxias (SCAs). They are dominant, generally late-onset, diseases caused by a gain-of-function mechanism that renders the mRNA and/or the protein toxic. Thus, there is a disruption of cognitive functions, including the development of dementia, loss of normal sleep patterns, and, invariably, death.

In the majority of people, the repeat tract at any one of the disease loci has between 5 and 30 triplets. Above 35 units, it becomes unstable and ultimately leads to the disease. Importantly, the size of the expanded repeat tract largely determines the severity of the disease. There is some evidence that HD, SCA1, and DM1 are reversible. This suggests that silencing the expanded allele or contracting the repeat tract would both be useful approaches to prevent and reverse the progression of these diseases.

CRISPR-Cas9 technologies have revolutionised the field of gene editing. Cas9 has been used to cut out the repeat tract or introduce mutations in HD and DM1. In the case of HD, it was also shown to work in vivo using an AAV-based delivery. These preliminary experiments show great promise, but the approach does have drawbacks including the editing of both normal and expanded alleles, the double-stranded break (DSB) leading to larger than expected rearrangements and the potential for deleterious off-target mutations in sequences flanking the repeat tract.

The team’s goal is to develop novel therapeutic approaches for expanded CAG/CTG repeat disorders. They have developed the first method that uses the Cas9 nickase to induce exclusively contractions of the repeat tract, without mutating the flanking sequences, in an allele-specific manner, and without detectable off-target mutations. They are also developing epigenome editing-based approaches to silence expanded CAG/CTG repeats.

Main objectives and research goals: 1. To determine whether the Cas9 nickase can induce contractions in non-dividing cells and in vivo.

2. To understand the mechanisms of nickase-induced contractions to improve its efficiency.

3. To determine the safety of nickase-induced contractions.

4. To develop novel tools for sequencing expanded CAG/CTG repeats for diagnosis, biomarker, and pre-clinical purposes.

5. To understand how somatic expansion, which promotes disease pathogenesis, occurs.

3. Team members

Dr Alys Aston (Postdoctoral Researcher)
Dr Alvaro Murillo Bartolome (Postdoctoral Researcher)
Dr Ruban Rex Peter Durairaj (Research Associate)
Emma Randall (Research Assistant)
Christopher Smith (Senior Technician)
Aeverie Heuchan (Senior Technician)
Soumyasree Bhattacharyya (Research Assistant)
Antoine Mangin (Technician & PhD Student)
Cerys Roberts (PhD Student)
Arshi Gyawall (PTY Student)

4. Collaborations

Within UK DRI:

Dr Gabriel Balmus, UK DRI at Cambridge
Prof Gill Bates, UK DRI at UCL
Dr Blanca Diaz-Castro, UK DRI at Edinburgh

Beyond UK DRI:

Prof Vanessa Wheeler, MGH
Dr Genevieve Gourdon, INSERM
Dr Stéphanie Tomé, INSERM
Prof Jack Puymirat, Laval University
Dr Francesca Cicchetti, Laval University
Dr Beverly Davidson, Children Hospital of Philadelphia
Prof Tuncay Baubec, University of Utrecht
Prof Ioannis Xenarios, University of Lausanne
Dr. Georgina Menzies, Cardiff University
Dr. Mariah Lelos, Cardiff University
Dr Thomas Massey, Cardiff University
Prof Darren Monckton, University of Glasgow
Dr Alice Davidson, UCL
Prof Bob Lahue, NUI Galway
LoQus23 Therapeutics
Prof William Gray, Cardiff University

5. Topics

Neurodegeneration, expanded CAG/CTG repeat disorders, gene editing, DNA repair.

6. Techniques

Cas9, AAV technologies, PinT, CRISPR screening, mouse models, iPSCs, siRNA screening, High throughput screening

7. Key publications

Taylor AS, Barros D, Gobet N, Schuepbach T, McAllister B, Aeschbach L, Randall EL, Trofimenko E, Heuchan ER, Barszcz P, Ciosi M, Morgan J, Hafford-Tear NJ, Davidson AE, Massey TH, Monckton DG, Jones L, REGISTRY Investigators of the EHDN, Xenarios I, Dion V. Repeat Detector: versatile sizing of expanded tandem repeats and identification of interrupted alleles from targeted DNA sequencing. BioRxiv 2022. doi: https://doi.org/10.1101/2022.03.08.483398

Yang B, Borgeaud AC, Buřičová M, Aeschbach L, Rodríguez-Lima O, Ruiz Buendía GA, Cinesi C, Taylor AS, Baubec T, Dion V. Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing.Hum Mol Genet. 2022 Feb 3;31(3):386-398.

Wheeler VC, Dion V. Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models. Journal of Huntingtons Dis. 2021;10(1):123-148.

Ruiz Buendía GA, Leleu M, Marzetta F, Vanzan L, Tan JY, Ythier V, Randall EL, Marques AC, Baubec T, Murr R, Xenarios I, Dion V. Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion. Science Advances. 2020 Jul 3;6(27):eaaz4012.

Cinesi, C., Aeschbach, L., Yang, B. and Dion, V., 2016. Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase. Nature communications, 7, 13272.