"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 300 peer-reviewed publications, been elected a fellow of 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. Her complementary research strategies - basic science focusing on cellular mechanisms of neurodegeneration, and a programme to translate those findings into treatments and cures - have led to exciting Phase I results from a novel ‘gene silencing’ treatment in Huntington's disease.
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
Dr Michael Flower (Postdoctoral Researcher)
Dr Robert Good (Postdoctoral Researcher)
Dr Alison Wood-Kaczmar (Postdoctoral Researcher)
Dr Heather Ging (Research Assistant)
Joe Hamilton (Research Assistant/ PhD Student)
Emma Bunting (PhD Student)
Within UK DRI:
- Prof Gill Bates, UK DRI at UCL
- Prof Nick Fox, UK DRI at UCL
- Dr Gabriel Balmus, UK DRI at Cambridge
- Prof Lesley Jones, UK DRI at Cardiff
Beyond UK DRI:
- Prof Darren Monckton, University of Glasgow
- Dr Kostas Thalassinos, Institute of Structural and Molecular Biology, UCL
- Prof Chris Pearson, Toronto, Canada
Huntington’s disease, repeat expansion disease, DNA repair, trinucleotide repeat instability, antisense oligonucleotides (ASO)
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
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 T, Gerlach I, Schobel SA, Paz E, Smith AV, Bennett CF, Lane RM. Targeting Huntingtin Expression in Patients with Huntington's Disease. N Engl J Med 2019; May 6. doi: 10.1056/NEJMoa1900907. [Epub ahead of print]
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.
Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron 2019; 101(5): 801-819.
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.