Basic science research

Huntington’s disease (HD) is a devastating inherited neurodegenerative disorder that affects movement and cognition and is ultimately fatal. It is caused by the expansion of a CAG repeat within exon 1 of the huntingtin gene (HTT). The Bates lab is focused on understanding the molecular events that are triggered by the HD mutation and that initiate the pathogenic cascade.

Individuals with 40 CAGs or more, as measured in blood, will develop HD within a normal lifespan, whereas those with 35 CAGs or less will remain unaffected. The CAG repeat mutation expands further with age in certain brain regions and tissues and so the length of the CAG repeat in brain can be much longer than that in blood. Genome-wide association studies have found that several genetic modifiers are DNA mismatch repair genes that impact the rate of somatic CAG repeat expansion. This has led to the widely held hypothesis that somatic CAG expansion drives the age of onset and rate of progression of disease. Understanding the biology of somatic CAG expansion and how this impacts HD is a major focus of the Tabrizi lab, and the Bates lab works closely with them in the preclinical assessment of therapeutics targeting the DNA mismatch repair pathway.  

The Bates lab have found that, in the context of an expanded CAG repeat, the HTT pre-mRNA can be alternatively processed to generate the small HTT1a transcript that encodes the HTTexon1 protein. HTTexon1 is aggregation-prone and has been shown to be highly pathogenic in a wide range of model systems. The longer the CAG repeat the more HTTexon1 is produced, and therefore, this is a candidate for the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences. Research projects in the Bates lab are directed toward understanding the mechanism through which HTT1a is produced and determining the extent to which HTTexon1 contributes to disease pathogenesis. They are investigating whether the most successful HTT-lowering approach might be to target full length HTT, HTT1a, or both the HTT and HTT1a transcripts together. These data will directly inform the clinical development of HTT-lowering strategies.

Huntington’s disease
Huntington's disease is caused by an abnormal expansion of a sequence of three DNA bases, or 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.
The Tabrizi lab are aiming to build our understanding of how DNA repair mechanisms are involved in modifying the development of Huntington’s disease. We hope to use this knowledge to develop novel therapeutic approaches that could stop, slow down or reverse the progression of the disease. We have already tested one potential new therapy in an early-stage clinical trial in people with dementia, with encouraging results.

Scientific goals
The DNA damage response (DDR) is a series of overlapping pathways that sense and repair the DNA damage that occurs continually throughout our lives. Defects in components of this DDR system 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.
In Huntington’s disease (HD) the expanded CAG 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 unaffected. Expansion produces an increasingly toxic protein and is correlated with earlier age at onset and increasingly severe disease, suggesting it is a key mechanism underlying the tissue-specific neurodegeneration seen 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 DNA damage response 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. 
Genome-wide association studies (GWAS) studies have identified the DNA interstrand crosslink repair nuclease FAN1, the DNA mismatch detector complex MutSβ, nuclease complexes MutLα and MutLγ, and ligase LIG1, as modifiers of somatic instability, HD onset and progression.
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.
 

High Content Screening
This research focuses on using a high throughput screening platform to characterise and examine phenotypes in pluripotent stem cell derived neurons. High content imaging allows for unbiased experimental observation and rapid acquisition of large volumes of data. We are currently investigating the role of mutant huntingtin in nuclear cytoplasmic transport and whether defects observed can be alleviated using antisense oligonucleotides (ASOs) in collaboration with Takeda Pharmaceuticals.
 

Team Wild undertakes research using human volunteers, to make discoveries and therapeutic advances in Huntington’s disease. Our particular focus is biomarkers – substances that can be measured in body fluids like blood or cerebrospinal fluid, that can tell us something useful about how Huntington’s affects the brain and body. 

In 2015 we led the development and testing of the first technique to accurately measure the amount of mutant huntingtin in cerebrospinal fluid. Mutant huntingtin is the abnormal protein that causes Huntington’s, and cerebrospinal fluid is a clear liquid produced by the brain, that bathes and supports the nervous system. This measurement technique is now being used as a biomarker in multiple trials of new treatments to lower the production of the mutant huntingtin. It was used to show in 2017 that the huntingtin-lowering drug HTTRx/RG6042 successfully lowered huntingtin production for the first time in Huntington’s patients.

Professor Wild has been involved in huntingtin-lowering programs since 2014 and was a senior investigator on the first-in-human trial of HTTRx. He is the global chief investigator of the Roche Gen-PEAK trial, studying the pharmacokinetics and pharmacodynamics of RG6042.

Team Wild has pioneered the study of cerebrospinal fluid as a means of understanding Huntington’s disease in patients. Our HD-CSF study, funded by the Medical Research Council, was the first longitudinal study of cerebrospinal fluid with advanced magnetic resonance imaging.

We have led the development of neurofilament light protein as a biomarker in Huntington’s disease. In 2017 we showed that this protein, which is released from damaged neurons, could be detected at increased levels in the blood of Huntington’s disease mutation carriers many years before symptoms begin, and that the level predicts onset, progression and the rate of brain atrophy. In 2018 we measured neurofilament light and mutant huntingtin in parallel in cerebrospinal fluid and showed that neurofilament was the better predictor of disease severity. 

Professor Wild is the Global Chief Investigator of the HDClarity study, the first multi-national cerebrospinal fluid collection initiative in Huntington’s disease. HDClarity is funded by CHDI Foundation and samples and data are available for any researcher to study Huntington’s disease.

Our current focus is advanced studies in cerebrospinal fluid to understand the events leading to neurodegeneration in the brains of Huntington’s disease mutation carriers.

We collaborate widely with academic, industry and foundation researchers from across the globe to understand HD in patients and advance the development of new treatments.

Huntington’s disease (HD) is caused by having an expanded CAG repeat in the DNA of the huntingtin gene, larger inherited expansions are associated with younger disease onset. When the gene is passed from one generation to the next the size of the CAG repeat may or may not change.  When the repeat expands with each generation, causing younger onset in children than their parents, this is called genetic anticipation.  Genetic anticipation usually occurs down the paternal line, meaning that studying sperm of people with Huntington’s may give us valuable insights.  The Sperm-CAG study study aims to understand how variable the huntingtin expansion is in the sperm of men with Huntington’s disease, and the genetic and non-genetic factors that may influence this.

Beyond understanding the process of genetic anticipation, characterising the variability of CAG repeat sizes in sperm, and knowing whether this correlates with somatic instability elsewhere in the body may be valuable in providing a biological marker of repeat instability in people with HD.