Meet the team

Sarah Tabrizi

"Our research programme aims to understand the mechanism by which genetic modifiers influence the age of onset and progression of Huntington’s disease. Harnessing these insights will enable us to develop new and targeted therapeutic interventions to slow disease progression." Sarah Tabrizi
UK DRI Group Leader

Prof Sarah Tabrizi is an award winning scientist who has published over 350 peer-reviewed publications, been elected a fellow of the Royal Society and the UK Academy of Medical Sciences, co-founded the UCL Huntington’s Disease Centre and helped set up the UK All-Party Parliamentary Group for Huntington's disease. She leads an internationally recognised basic bench science and translational research team focussed on finding disease modifying therapies for Huntington’s disease. She was PI on the first successful phase 1/2b trial of an antisense oligonucleotide, and currently serves on several SABs advising industry on the development of potential gene targeting and nucleic acid therapies for HD. Sarah’s research has been recognised by numerous major prizes including the 2019 Yahr Award, 2022 Osler Medal, 2022 HD Society of America Research Award, the 2022 MRC Millennium Medal, and the 2023 Arvid Carlsson Award.

1. At a glance

Huntington’s disease: Hunting for innovative new treatments

Huntington's disease is caused by an abnormal expansion of a sequence of three DNA building blocks (CAG) within the HTT gene. In healthy people, the CAG is repeated 10 to 35 times in a row, whereas people with the disease have 36-120+ repeats. This expanded sequence is inherently unstable and tends to get longer over time, causing the death of neurons – particularly within the brain tissues that are most vulnerable to the disease.

People with longer CAG expansions tend to develop symptoms at an earlier age – and their disease is likely to progress more quickly. However, this isn’t clear-cut and other genes elsewhere in a person’s genome can also influence age of disease onset. We are now starting to identify these so-called ‘modifying genes’ – and some are involved in repairing faults in our DNA.

Prof Sarah Tabrizi is aiming to build our understanding of how DNA repair mechanisms are involved in modifying the development of Huntington’s disease. She hopes to use this knowledge to develop novel therapeutic approaches that could stop, slow down or reverse the progression of the disease. She has already tested one potential new therapy in an early-stage clinical trial in people with dementia, with encouraging results.

2. Scientific goals

The DNA damage response (DDR) constitutes a series of overlapping pathways that sense and repair DNA damage occurring continually throughout our lives. Many repair defects result in neurodegeneration, such as ataxia telangiectasia, xeroderma pigmentosum, ataxia with oculomotor apraxia-1 (AOA1) and spinocerebellar ataxia with axonal neuropathy (SCAN1), suggesting the nervous system is especially sensitive to DNA damage.

Huntington’s disease (HD) is caused by an expanded CAG repeat in HTT exon 1. The repeat is inherently unstable, tending to increase in length in a time-dependent and tissue-specific manner, in a process known as somatic instability. There is prominent expansion in the striatum, the tissue most vulnerable to the disease, but relative stability in the cerebellum, which is neuropathologically unaffected. Expansion produces an increasingly toxic polyglutamine tract and is correlated with earlier age at onset and increasingly severe disease, suggesting it is a key mechanism underlying progressive, tissue-specific neurodegeneration in HD.

In HD patients, onset varies by several decades in people with the same CAG repeat length in blood, and around 50% of this variability is heritable, demonstrating the existence of genetic modifiers elsewhere in the genome. The DDR has been implicated as a modifier of CAG instability, with knockout or variation of DNA mismatch repair (MMR) components MutSβ (MSH2/MSH3), MutLα (MLH1/PMS2) or MutLγ (MLH1/MLH3) significantly reducing somatic expansion and improving disease phenotype in HD mice.

The GeM-HD GWAS identified the FANCD2/FANCI-associated nuclease-1 (FAN1), a DNA endo/exonuclease involved in DNA interstrand crosslink (ICL) repair and replication fork recovery as an HD disease modifier. The most significant FAN1 coding variant, p.R507H in the DNA binding domain, is predicted to be damaging in silico and was associated with a six-year earlier onset. The Track-HD GWAS identified a repeat variant in exon 1 of MSH3, which was associated with reduced expression of MSH3 in HD patient brain, reduced somatic CAG expansion in blood, delayed onset and slower disease progression. Importantly, the same variant was associated with reduced somatic CTG repeat expansion and delayed onset in myotonic dystrophy patients too, suggesting the same mechanism acts in different repeat expansion diseases.

Interventions harnessing these DNA repair mechanisms could have the potential to modify the disease course. One of the greatest challenges in the field is to understand how these DNA repair mechanisms maintain genomic stability, whilst also contributing to cell degeneration in HD.

Main objectives and research goals:

1. To assess the effect of antisense oligonucleotide (ASO)-mediated HTT knockdown on disease course.

2. To study the role of DNA repair proteins, including FAN1, MSH3 and their interactors, on CAG repeat instability.

3. To identify compounds that modulate DNA repair activity at CAG repeats and validate their therapeutic potential.

4. To study how temporal modulation and titration of DDR network proteins, including MMR components, influences somatic instability and disease phenotype in mouse models.

3. Team members

Rose Hopkins (Executive Assistant)
Dr Sangeeth Rajagopal (Clinical Researcher)
Dr Nicola Hobbs (Postdoctoral Researcher)
Dr Michael Flower (Senior Clinical Researcher)
Dr Robert Goold (Postdoctoral Researcher)
Dr Jasmine Donaldson (Postdoctoral Researcher)
Dr Ross Ferguson (Senior Postdoctoral Researcher)
Dr Michela Leocadi (Research Fellow)
Dr Rachael Scahill (Senior Researcher)
Marwa Elmasri (Senior Research Technician)
Florence Gidney (Senior Research Technician)
Freja Sadler (Senior Research Technician)
Róisín-Ana Ní Chárthaigh (Senior Research Technician)
James Behagg (Research Coordinator)
Kate Fayer (Research Coordinator)
Lucy Coupland (Research Assistant)
Jessica Olive (Research Assistant)
Claire Pimblett (Research Assistant)
Joe Hamilton (PhD Student)
Mitsuko Nakajima (Clinical Researcher and PhD Student)
Dr Mena Farag (Clinical Researcher and PhD Student)
Dr Michael Murphy (Clinical Researcher and PhD Student)
Olivia Thackeray (PhD Student)



4. Collaborations

Within UK DRI:

  • Dr Amanda Heslegrave, UK DRI at UCL
  • Prof Adrian Isaacs, UK DRI at UCL
  • Prof Henrik Zetterberg, UK DRI at UCL
  • Prof Mina Ryten, UK DRI at Cambridge Dr Gabriel Balmus, UK DRI at Cambridge
  • Prof David Rubinsztein, UK DRI at Cambridge
  • Dr Tom Massey, UK DRI at Cardiff

Beyond UK DRI:

  • Prof Gill Bates, UCL
  • Dr Natalia Gromak, University of Oxford
  • Prof Steve McCarroll, Harvard
  • Prof Alex Sartori, University of Zurich
  • Prof Darren Monckton, University of Glasgow
  • Dr Kostas Thalassinos, Institute of Structural and Molecular Biology, UCL

5. Topics

Huntington’s disease, repeat expansion disease, DNA repair, trinucleotide repeat instability, antisense oligonucleotides (ASO)

6. Techniques

Antisense oligonucleotides, mouse models, clinical trials, synthetic and patient-derived cell lines – including iPSCs and MSNs, GFP chromatin immunoprecipitation (ChIP) qPCR, chemical cross-linking mass spectrometry (CL-MS), TapeStation, Bioanalyser, Myc-Trap bead ChIP, Opera high content screening platform

7. Key publications

McColgan P, Thobhani A, Boak L, Schobel SA, Nicotra A, Palermo G, Trundell D, Zhou J, Schlegel V, Sanwald Ducray PS, Hawellek DJ, Dorn J, Simillion C, Lindemann M, Wheelock V, Durr A, Anderson KE, Long JD, Wild EJ, Landwehrmeyer GB, Leavitt BR, Tabrizi SJ*, and Doody R. Tominersen in Adults with Manifest Huntington's Disease. New England Journal of Medicine. 2023 Dec 7;389(23):2203-2205. *Corresponding author.

Tabrizi SJ, Schobel S, Gantman EC, Mansbach A, Borowsky B, Konstantinova P, Mestre TA, Panagoulias J, Ross CA, Zauderer M, Mullin AP, Romero K, Sivakumaran S, Turner EC, Long JD, Sampaio C; Huntington's Disease Regulatory Science Consortium (HD-RSC). A biological classification of Huntington's disease: the Integrated Staging System. Lancet Neurology. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X. PMID: 35716693

Goold R, Hamilton J, Menneteau T, Flower M, Bunting EL, Aldous SG, Porro A, Vicente JR, Allen ND, Wilkinson H, Bates GP, Sartori AA, Thalassinos K, Balmus G, Tabrizi SJ. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s Disease. Cell Reports. 2021 Aug 31;36(9):109649. doi: 10.1016/j.celrep.2021. PMID: 34469738. 16 citations. [Made Cell Reports’ special preview].

Flower MD, Tabrizi SJ. A small molecule kicks repeat expansion into reverse. Nature Genetics. 2020 Feb;52(2):136-137. doi: 10.1038/s41588-020-0577-6

Leavitt BR and Tabrizi SJ. Antisense oligonucleotides for neurodegeneration. Science. 2020 Mar 27;367(6485):1428-1429. doi: 10.1126/science.aba4624. Review.

Scahill RI, Zeun P, Osborne-Crowley K, Johnson EB, Gregory S, Parker C, Lowe J, Nair A, O’Callaghan C, Langley C, Papoutsi M, McColgan P, Estevez-Fraga C, Fayer K, Wellington H, Rodrigues FB, Byrne LM, Heselgrave A, Hyare H, Sampaio C, Zetterberg H, Zhang H, Wild EJ, Rees G, Robbins TW, Sahakian BJ, Langbehn D, Tabrizi SJ. Biological and Clinical Characteristics of Gene Carriers Far From Predicted Onset in the Huntington's Disease Young Adult Study (HD-YAS): A Cross-Sectional Analysis. Lancet Neurology. 2020 Jun;19(6):502-512

Goold, R, Flower M, Moss DH, Medway C, Wood-Kaczmar A, Andre R, Farshim P, Bates GP, Holmans P, Jones L, Tabrizi SJ. FAN1 modifies Huntington’s disease progression by stabilising the expanded HTT CAG repeat. Hum Mol Genet 2019; 28(4): 650-661.

Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron 2019; 101(5): 801-819.

Flower M, Lomeikaite V, Ciosi M, Cumming S, Morales F, Lo K, et al. MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain. 2019 Jun 19. pii: awz115. doi: 10.1093/brain/awz115

Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, Blair NF, Craufurd D, Priller J, Rickards H, Rosser A, Kordasiewicz HB, Czech C, Swayze EE, Norris DA, Baumann TF, Gerlach I, Schobel SA, Paz E, Smith AV, Bennett CF, Lane RM. Targeting Huntingtin Expression in Patients with Huntington’s Disease. The New England Journal of Medicine. 2019 May doi: 10.1056/NEJMoa1900907; included in the NEJM’s Notable Articles of 2019