Experimental Medicine

Details of our experimental medicine studies

A team of researchers from UCL and the University of Cambridge led by Professor Sarah Tabrizi, Director of the Huntington’s Disease Centre, UCL Institute of Neurology, have been granted a prestigious Wellcome Trust Collaborative Award in one of the largest investments in Huntington’s Disease (HD) ever given by a public funding body in the UK.

The 5-year, £3.4 million investment will support research to help our understanding of disease mechanisms in HD and, importantly, their response to treatment. This valuable work will, in turn, provide insights into other more common neurodegenerative diseases.

Huntington’s disease is a devastating inherited neurodegenerative condition for which there is currently no effective treatment to slow down the disease process. It is caused by a single faulty gene resulting in the build-up of a toxic protein – mutant huntingtin – which damages brain cells, leading to abnormal involuntary movements, psychiatric symptoms and dementia.

In September 2015, a ground-breaking ‘gene silencing’ trial started, with Professor Tabrizi as the Global Chief Clinical Investigator working in partnership with Ionis Pharmaceuticals. The drug is an antisense oligonucleotide (ASO) and is designed to instruct neurons to make less huntingtin protein.

The Wellcome Trust Collaborative Award builds on key collaborations with co-applicants Professor Geraint Rees at the Wellcome Trust Centre for Neuroimaging, Dr Gary Zhang (UCL Department of Computer Science and Centre for Medical Image Computing) and Professor Henrik Zetterberg (UCL and University of Gothenburg). ‘This is an exciting opportunity to link cutting-edge neuroscience with the novel development of therapies in HD to better understand mechanisms of neural recovery in humans’ said Professor Rees.

The Wellcome Trust Award has three key aims, each working in parallel:

Aim 1

To understand the way in which brain cells recover and respond to ‘gene silencing’ treatment in Huntington’s disease.

The Award provides a unique opportunity to link with this first human ASO trial in HD to understand neurodegeneration, and in particular, how it is modified by treatment.

Aim 2

To develop a new generation of ASO treatments.

Co-applicant and co-director of the UCL HD Centre – Professor Gillian Bates – will explore alternative ASO treatments to provide the next generation of therapies for HD patients. She will use mouse models of HD to develop and test novel compounds targeting the most toxic forms of the protein. These approaches could potentially slow down the disease process.

Aim 3

To determine when such therapies should be given to patients through the Huntington’s Disease Young Adult Study (HD-YAS).

We will examine young adult gene carriers, decades before expected disease onset, in order to identify the best time to intervene with therapy. The collaborative team will use brain imaging and novel cognitive tests (CANTAB and EMOTICOM), developed by co-applicants Professors Trevor Robbins and Barbara Sahakian at the University of Cambridge, to determine when the first signs of the disease can be detected. See Current Studies HD-YAS for more information.

‘For the first time, we have a realistic chance of finding treatments which actually slow down the disease process. Ideally, we aim to administer the most successful therapies to gene carriers years before widespread damage has occurred, with the hope that we can prevent or at least significantly delay disease onset,’ said Prof Tabrizi.

This ambitious project will be one of the first to be conducted in the newly-established Huntington’s Disease Centre, led by Professor Tabrizi and Professor Bates. This facility is well-placed at the UCL Institute of Neurology to benefit from links within UCL to the Leonard Wolfson Experimental Neurology Centre, the Wellcome Trust Centre for Neuroimaging, the Centre for Medical Imaging Computing and the FARR Institute of Health Informatics Research, collaborations with the Universities of Cambridge and Iowa and support from industrial partners Ionis Pharmaceuticals, Evotec, Cambridge Cognition and IXICO plc as well as the charitable organisation, CHDI Foundation Inc.

HD CSF

About the study

HD-CSF is a 2-year longitudinal observational study with the main purpose of collecting and studying biofluid biomarkers in Huntington’s disease, such as blood and cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord. Our aim is to help better understand what happens in the brains of people with HD, and to do so we are studying biomarkers in a large group of people as well as measuring how things change over time and in relation to other disease markers (i.e. clinical assessments and brain imaging).

This study is approaching the end of the final phase (2-year follow up visit), and is expected to be completed by the end of the year. The first phase (baseline visit) finished at the end of 2017 with the enrolment of 80 volunteers. The data collected have been the basis for a big step forward in our knowledge about HD. Indeed, several major scientific papers have been published thanks to the HD-CSF samples and data. This dataset will continue to be used to further advance our understanding about HD.

Links to these papers can be found below:

http://stm.sciencemag.org/content/10/458/eaat7108?rss=1

https://www.nature.com/articles/s41598-018-21788-x

The CSF will be analysed using new techniques to detect levels of the mutant huntingtin protein that causes HD, and also measure the balance of protective and harmful chemicals produced by the brain’s immune cells. Being able to measure levels of these substances in the CSF will be really important for assessing whether treatments are effective. For instance, it may help us decide in clinical trials of new treatments including ‘gene silencing‘ and KMO inhibition, whether the treatment is affecting levels of the protein in the brain.

Data and samples will be shared with HDClarity, a global multi-site cerebrospinal fluid collection initiative of which Dr Ed Wild will also be the chief investigator.

What is involved?

CSF will be collected at baseline and then at the follow-up two years later. There will be a screening visit up to 30 days before the baseline and follow-up CSF collection visits. At this visit participants will undergo all the core assessments from the Enroll-HD study. Participants will also provide blood samples for analysis and have optional MRI scans. Study visits may be half a day long. A hotel can be provided for the night before the CSF collection visit along with reimbursement of travel costs.

How do we collect the CSF?

CSF is collected by lumbar puncture, also known as a ‘spinal tap’, a minor procedure where a needle is used to withdraw about 4 teaspoonfuls of fluid from the base of the spine. It takes about 15-30 minutes and is done under local anaesthetic which numbs the area. You will stay in the Leonard Wolfson Experimental Neurology Centre (LWENC), a new clinical research facility at the NHNN, for half a day from 8:30am until midday when you are able to go home.

*No longer recruiting*

Clarity

Studying CSF to identify and validate biomarkers for HD clinical development.

HDClarity aims to collect a large amount of high quality cerebrospinal fluid (CSF) and blood samples from participants who carry the HD gene and matched controls. The samples will be used to further research into identifying biomarkers which will help in the development of new treatments for HD.

UCL HD Centre is coordinating HDClarity but not recruiting participants directly. Participants will attend other sites to complete the two study visits; screening visit then a sampling visit. The CSF is collected via a lumbar puncture during the sampling visit.

If you would like more information, please visit http://hdclarity.net/

Enroll-HD

About the study

Enroll-HD is a worldwide observational study which has now taken over from the REGISTRY study. A map of all Enroll-HD sites.

Enroll-HD is a study which aims to accelerate the development of therapies for HD by collecting more uniform clinical data and biological samples to better understand the natural history of HD. The study will build a comprehensive and extremely valuable database of information which will be available for use by HD researchers worldwide.

For more information about the differences between Enroll-HD and REGISTRY this article on HDBuzz provides a more detailed overview.

What is involved

Study visits are conducted annually and usually take between 1-2 hours depending on what information is needed.

Visits are conducted in the National Hospital for Neurology and Neurosurgery and can be conducted alongside your clinic appointment or if you would prefer to come in on a different day we can arrange a separate study visit at a time to suit you.

During each study visit, you will undergo a series of movement and behavioural tests. Functional tests will be given to determine how well you perform various tasks on your own. You will also answer questions to help the study team evaluate your emotional state and quality of life.

All participants are required to give a blood sample at their first appointment, this is compulsory at the first visit but does not need to be repeated at follow up visits if you are not keen on giving blood samples. Additionally, if you wish, you can choose to donate a small volume of blood at each follow up visit to help the study team understand why and when certain symptoms appear and to identify possible ways to develop new, effective drugs.

Enroll-HD and Clinical Trials

Enroll-HD is not a clinical trial, and potential therapies are not being tested. However, you can learn about upcoming clinical research studies that you might be interested in and the Enroll-HD study’s database is often consulted to select eligible patients for other studies and clinical trials in patients with Huntington’s disease.

Who can take part?

Any member of a family affected by HD can take part. This includes:

Individuals who know they carry the expanded gene, whether or not they show signs and symptoms of the disease Individuals who are at risk of developing the disease (but have not undergone genetic testing) Individuals who have a family history of HD but know they do not carry the expanded gene Spouses/partners (not blood-related) of family members with H

We are not currently recruiting any community controls, that is people from the general population who are not affected by HD (people who are not from an HD family). People with some medical conditions, or taking certain medications that may interfere with the tests, may not be able to take part. We will be able to assess this with you before your appointment.

How can I get involved?

To join ENROLL-HD at UCL please obtain a referral from your GP to Prof. Tabrizi’s clinic at the National Hospital for Neurology and Neurosurgery. Please contact us on the details below if you have any questions or require further information.

Children under the age of 18 with clinically diagnosed juvenile HD may be included in this study with the consent of a parent or legal guardian.

Who cannot take part?

How can I get involved?

WIN-HD

What’s the study about?

The WIN-HD is an MRC funded collaborative project between the Huntington’s Disease Research Centre at UCL and ICM, Pitié-Salpêtrière University Hospital in Paris. The project aims to understand the white matter changes that occur in HD in the years prior to the onset of visible clinical signs, known as the pre-manifest stage.

What is white matter?

White matter is made up of bundles of nerve fibres (axons) which are extensions of nerve cells (neurons). Many of these nerve fibers are surrounded by a type of sheath, or covering, called myelin. This myelin is white, which gives white matter its colour. These myelinated fibres are like the motorways between brain regions, speeding up transmission of electrical nerve signals and protecting nerve fibers from injury. Degeneration of this white matter may play a big role in the clinical symptoms we see in HD.

How do we measure ‘white matter’ with MRI?

Whereas previous magnetic resonance imaging (MRI) studies have detected volumetric changes in the brain, it is not known whether white matter changes are directly due to neuron loss or other processes that occur before this neurodegeneration. Using MRI we are using novel methods called Diffusion-Weighted NMR spectroscopy (DW-MRS) and diffusion MRI analysed using Neurite Orientation Dispersion and Density Imaging (NODDI) in people carrying the HD gene as well as non-carriers. DW-MRS offers the unique opportunity measure the movement of metabolites inside the neurons non-invasively, which will allow us to better distinguish between the different pathological processes that lead to the changes observed in pre-manifest HD. NODDI is a way of analysing diffusion imaging data that allows us to estimate the complexity of neurites in white matter, by estimating their density and spatial configuration in the brain.

What’s the bigger picture?

WIN-HD is part of a larger project (taking place at the ICM, Pitié-Salpêtrière University Hospital in Paris) that will combine clinical research, preclinical modelling, mouse biology, brain imaging in human pre-manifest HD gene carriers, post-mortem brain samples, and rodent models to investigate early white-matter changes in Huntington’s Disease. Imaging in humans will hopefully help us to untangle the relationship between the clinical and MRI measures seen in the human brain, with the cellular and molecular changes seen in post-mortem brain tissue. Due to the certainty of disease onset in pre-manifest HD gene-mutation carriers this will allow us to investigate the early interactions of cell sub-types long before clinical diagnosis.

*No longer recruiting*

HD-YAS

About this study

The HD Young Adult Study (HD-YAS) is an important and exciting study that has been designed to find the earliest time point at which any HD-related changes can be found in young-adult gene carriers, and therefore, the earliest time at which therapeutic intervention could be given to prevent HD-related changes and decline.

To do this we will recruit both young adult gene-carriers who are completely well, and control participants. A control is someone who does not carry the faulty gene.

What is involved?

The study requires a one-off visit to the National Hospital of Neurology and Neurosurgery in central London. We can provide hotel accommodation nearby if needed.

To study whether or not any changes can be identified, we will carry out a number of assessments. We will look at images of the brain using a safe technique called Magnetic Resonance Imaging (MRI). We will examine your cognitive and emotional function through a series of questionnaires and simple computer based tasks to examine the way you process, store and apply information, including about other people and social situations (cognitive and emotional tasks). We will also collect biological samples, such as blood and DNA (the genetic material in your blood) to look for potential biomarkers – a biomarker is something we can measure to help us better understand a disease.

We also want to collect cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord that can be used to provide information about the brain and the nervous system that is impossible to obtain in any other way.

Results

In May 2020, the publication of results from the Wellcome Trust funded HD-Young Adult Study in the Lancet Neurology (Scahill 2020) demonstrated that the earliest brain changes due to Huntington’s disease can be detected 24 years before clinical symptoms show. The study found that while early biological alterations in the cerebral spinal fluid and brains of gene carriers were detected, there were no differences in the cognitive and psychiatric symptoms of gene carriers, who were an average of 24 years from clinical onset, compared with the control group. This suggests a therapeutic window exists where intact clinical function is coupled with a detectable measure of subtle early biological that could guide monitoring of disease progression and treatment response in future therapeutic trials of pre-manifest HD gene carriers. The results were covered in national and regional news outlets including: i News, Telegraph, ITV News, BBC Science Focus, AOL News, Yahoo! News, Sky.

*No longer recruiting*

hd-yas_protocol_v6.0_sep18_signed.pdf

CLEAR-HD

At a glance
Active and recruiting
Observational study
Involves Magnetic Resonance Imaging
Involves Magnetoencephalography

About the study
The CLEAR HD study is an observational study using ultra-high resolution (or 7-Tesla) MRI and Magnetoencephalography (MEG). Both are safe and non-invasive techniques. We aim to characterize how the structure and function of specific layers of the brain are affected in HD and how these changes relate to abnormalities of deep brain structures.

What is involved?
Following a screening phone-call, eligible participants will be invited to a one-off visit, with the MEG scan in the morning, followed by clinical assessments and blood test, and MRI scan in the afternoon.

Who can take part?
We are recruiting patients with pre-manifest HD, as well as healthy controls (i.e. those without the HD gene, or those who are not from a HD family) between 18 and 65 years of age.

Link to the participant information sheets
Gene Carrier Information Sheet:

clear-hd_icf_gene_carrier_v6.0_13.07.21.pdf

Control Information Sheet:

clear-hd_icf_control_v6.0_13.07.21.pdf

Get in touch
Chief Investigator: Dr Peter McColgan
Co-Investigator: Dr Mitsuko Nakajima
Email: mitsuko.nakajima@ucl.ac.uk
Phone: +44 (0) 203 108 7204