Decoding Presymptomatic white matter changes in Huntington Disease (WIN-HD)

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Huntington disease (HD) is an inherited neurodegenerative disease caused by a single mutation in the huntingtin gene. Onset occurs in adults, with slow progression and a combination of motor signs and cognitive changes, including dementia, as a result of underlying neurodegeneration of brain tissue. The mutation is an expansion of a CAG sequence within the gene and the length of the expansion has a strong effect on disease onset and course.

Early postmortem and imaging studies in HD have focused on grey matter changes in the subcortical brain structures such as the caudate and putamen. However, there is increasing recognition that white matter changes also play a role in the disease from the very early stages, many years before any clinical signs are evident. The exact nature of these white matter changes are not fully understood. Most imaging techniques used to date do not have the power to determine the specific mechanisms underlying white matter degeneration. For example, loss of white matter integrity may be due to degeneration of the axonal section of the neurone, or a reduction in the amount of myelin surrounding it. Myelin is produced by oligodendrocytes and it is thought that dysfunction within these cells may play an important role in the underlying neuropathology in HD.

We aim to improve our understanding of the role of oligodendrocytes in the white matter degeneration which typifies HD by:
a) examining white matter changes in individuals who carry the HD mutation but are not yet affected by the symptoms using advanced neuroimaging techniques
b) using mouse models of HD to examine disease-related changes in living animals (using imaging) and in postmortem brain tissue
c) examining postmortem human brain tissue to understand the nature of white matter changes in terms of characteristics such as axonal loss, demyelination and numbers of oligodendrocytes
d) determining whether other genes which cause dysfunction in oligodendrocytes have an impact on the disease course in HD mouse models

Technical Summary

Our working hypothesis is that oligodendrocyte alterations underlie and exacerbate neurodegeneration in HD. Using new techniques of imaging, neuropathology, cell biology, and genetics, WIN-HD will investigate prodromal white-matter changes in HD patients (22 available human brain tissues and 30 premanifest carriers and 30 gene negative controls for imaging studies) and in mice model. We will use an HD knock-in rodent model and models expressing oligodendrocytes modifiers.

We will test the hypothesis that white-matter changes exacerbate the pathogenic cascade in Huntington Disease (HD) characterized by motor and cognitive signs. These changes may include (1) perturbed axon-glia interactions, (2) loss of oligodendroglial functions, and (3) demyelination. The proposal originates from surprising findings: (1) white-matter atrophy occurs far earlier than clinical onset in HD; and (2) extensive white-matter changes are present in mouse models; and (3) expression of the HD-causing protein in oligodendrocytes may contribute to disease progression in mice. For this project, we have assembled experts in the human disorder, in HD rodent models, in human and animal brain imaging and in the molecular and cellular biology of myelination. Together, we will examine white-matter changes well before the onset of disease signs and look for parallel changes in human and rodent models. We will use diffusion-weighted spectroscopy combined with diffusion tensor imaging to distinguish between axonal and glial contribution to white matter changes. Using genetic tools in mice, we will determine the effects of altered oligodendrocyte function on disease progression. Our two-year program will allow us to infer whether neuroprotective therapies should focus on molecular targets that primarily function in oligodendrocytes.

Planned Impact

Huntington's disease (HD) patients and families, scientists and clinicians working on HD will all be beneficiaries of this research, as well as biotechnology and pharmaceutical companies with research and development and/or commercial interests in these areas. Improving our understanding of the disease-related degeneration of white matter in HD could be an important step forward in developing disease modifying treatments. A number of pharmaceutical and biotechnology companies have existing interests in Huntington's disease, not least because of its genetic and fully penetrant nature make it highly useful in understanding more common neurodegenerative disorders with which its shares many features, such as Alzheimer's disease and Parkinson's disease. Understanding the underlying cellular mechanisms of pathogenesis and seeking to identify new therapeutic targets can only help those endeavours.
The economic and societal burden of neurodegenerative disease is considerable and is certain to increase. Huntington's disease itself affects entire families, with the loss of health in affected individuals having life-changing implications for them, their families and carers. Children in HD families, who themselves may be carrying the disease-causing genetic mutation, may be particularly affected. Furthering our understanding of the pathogenesis of HD will eventually lead to useful disease-modifying treatments. Significant advances in research bring hope to family members and encourage participation in clinical trials.


To maximise the potential gain from our research findings, we will encourage data sharing prior to publication through academic collaboration. Conferences and meetings will help to foster new academic collaborations in addition to those that already exist or have been newly formed as part of this proposal. We plan to hold collaborative review meetings on a regular basis to monitor project progress and identify common themes in neurodegenerative disease research. Our groups benefit from close links with other researchers in their host departments and institutions, and by encouraging greater synergy between groups working on different disorders we hope to identify common mechanisms and means of targeting inflammation in neurodegeneration.

Publications

10 25 50
 
Description WIN-HD collaboration with Paris 
Organisation Pitié-Salpêtrière Hospital
Country France 
Sector Hospitals 
PI Contribution Participant recruitment, analysis and scientific input on study results and dissemination
Collaborator Contribution Leadership of the project, participant recruitment, analysis and scientific input on study results and dissemination
Impact No output as yet as we are still in data collection phase
Start Year 2016
 
Description 2018 UCL Neuroscience Symposium, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact 2018 UCL Neuroscience Symposium, London, UK (June). Presented talk 'Antisense oligonucleotide therapy for Huntington's disease - results from the first HTT lowering clinical trial'. Generated questions and interest in HD trials
Year(s) Of Engagement Activity 2018
 
Description Cotzias Prize Lecture - LXX Annual Meeting of the Spanish Society of Neurology (SEN 2018), Gran Sevilla Events Center, Seville, Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on to Spanish Neurological Society: 'Huntington's disease: natural history, biomarkers and novel therapeutic horizons'
Year(s) Of Engagement Activity 2018
 
Description Distinguished Lecture Series, University of Leuven, Belgium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Distinguished Lecture Series, University of Leuven, Belgium. Talk titled: Meeting the therapeutic challenge of Huntington's disease. Generated questions and further interest in research
Year(s) Of Engagement Activity 2019
 
Description FIL Brain Meeting, UCL, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact FIL Brain Meeting, The Wellcome Centre for Human Neuroimaging, UCL London, UK. Presented talk 'meeting therapetic challenge of Huntignton's disease'. Talk generated discussion and lively debate.
Year(s) Of Engagement Activity 2018
 
Description Genetic Therapies in Neurodegeneration: Cohorts, Targets and Approaches Symposium, UCL London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Genetic Therapies in Neurodegeneration: Cohorts, Targets and Approaches Symposium, UCL, London, UK (May). Talk titled' Huntington's disease, results from the IONIS HTT Rx CS1 study - the first HTT lowering clinical trial'. Generated questions and interest in HD trials.
Year(s) Of Engagement Activity 2018
 
Description Great Ormond Street Hospital Neurosciences Meeting, London, UK (October) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Great Ormond Street Hospital Neurosciences Meeting, London, UK. Talk titled: Meeting Therapuetic Challenge of Huntington's Disease. Sparked questions and interest in involvement in clinical trials
Year(s) Of Engagement Activity 2018
 
Description Interview/profile in Lancet Neurology 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Professor Sarah Tabrizi completed a profile interview in the Lancet Neurology. Helps raise the profile of her research and the UCL HD Centre.
Year(s) Of Engagement Activity 2017
URL http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30303-4/abstract
 
Description Medicine at the Crick Inaugural Event - Gene and Genome Editing Therapy: A new challenge and opportunity in Clinical Medicine, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Medicine at the Crick Inaugural Event - Gene and Genome Editing Therapy: A new challenge and opportunity in Clinical Medicine, London, UK. Talk titled: 'Huntington's disease: RNA targetting therapy and prospects of gene therapy'. Talk generated questions and widened interest in HD research
Year(s) Of Engagement Activity 2018
 
Description Observer news article on Huntington diseae trials 03/03/2019 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article on Huntington's disease therapies at current clinical trail. https://www.theguardian.com/science/2019/mar/03/huntingtons-disease-new-drug--families. Increased awareness of HD and generated interest in trial.
Year(s) Of Engagement Activity 2019
URL https://www.theguardian.com/science/2019/mar/03/huntingtons-disease-new-drug--families
 
Description Plenary Lecture at 15th Annual Update Conference on Clinical Neurology and Neurophysiology, Tel Aviv, Israel (February) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary Lecture at 15th Annual Update Conference on Clinical Neurology and Neurophysiology, Tel Aviv, Israel. Talk title: Meeting the therapeutic challenge of Huntington's Disease. Form genetic modifiers to the first trial of antisense therapy. Talk presented by Prof Lanwehermeyer due Prof Tabrizi illness. Additional talk presented to patient and family groups. Generate questions and further interest in HD research trials.
Year(s) Of Engagement Activity 2019
 
Description Plenary Lecture at British Society for Genetic Medicine Annual Conference - UK Clinical Genomics 2018, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Plenary Lecture at British Society for Genetic Medicine Annual Conference - UK Clinical Genomics 2018, London. Talk entitled: `Meeting the therapeutic challenge of Huntington's disease'. Generated questions and interest in research and trials
Year(s) Of Engagement Activity 2018
 
Description Plenary Lecture at the 10th EHDN Plenary Meeting, Vienna, Austria 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary Lecture at the 10th EHDN Plenary Meeting, Vienna, Austria. Presented results of ongoing HTT lowering trials to scientists, patients, industy. Generated questions and interest in developing/participating the clinical trial
Year(s) Of Engagement Activity 2018
 
Description Plenary Lecture at the ABN 2018 Annual Meeting, Birmingham, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Plenary Lecture at the ABN 2018 Annual Meeting, Birmingham, UK. Talk titled: 'Antisense oligonucleotide therapy for Huntington's disease - results from the first HTT lowering clinical trial'. Generated questions and interest in HD trials
Year(s) Of Engagement Activity 2018
 
Description Plenary Lecture at the Alzheimer's Society Annual Conference, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Plenary Lecture at the Alzheimer's Society Annual Conference, London, UK. Presented talk entitled: Meeting the therapeutic challenge in Huntington's disease and other forms of dementia'
Year(s) Of Engagement Activity 2018
 
Description Plenary Lecture at the UK-Japan Neuroscience Symposium, Royal Society, London, UK (March) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary Lecture at the UK-Japan Neuroscience Symposium, Royal Society, London, UK; Presented talk titled: 'Meeting the therapeutic challenge in Huntington's disease'
Year(s) Of Engagement Activity 2018
 
Description Press conference at American Academy of Neurology Conference, Los Angeles following presentation of HTT lowering phase 1/2a clinical trial results. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Press conference at American Academy of Neurology Conference following presentation of HTT lowering phase 1/2a clinical trial results. Conference generated questions from media an a plethora of subsequent scientific news articles
Year(s) Of Engagement Activity 2018
 
Description Prof Raymund Roos Farewell Symposium - From bed to bench and back to the future: Huntington's disease, Leiden, The Netherlands 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Raymund Roos Farewell Symposium - From bed to bench and back to the future: Huntington's disease, Leiden, The Netherlands. Presented talk entitled 'The future clinics of Huntington's disease'. Generated questions and sparked debate,
Year(s) Of Engagement Activity 2018
 
Description Royal Society and Academy of Medical Sciences Conference `Delivering Novel Therapies in the 21st Century', London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Royal Society and Academy of Medical Sciences Conference `Delivering Novel Therapies in the 21st Century', London, UK. Presented talk entitled 'ASO Therapies for Huntington's Disease. Results from the first HTT lowering trial'. Talk generated discussion and further interest in clinical trial
Year(s) Of Engagement Activity 2018
 
Description Royal Society of Medicine 17th Medical Innovations Summit, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Royal Society of Medicine 17th Medical Innovations Summit, London, UK. Presented talk entiteld 'Meeting the therapeutic challenge of Huntington's disease'. Generated questions and interest in Huntington's disease reserach and trials
Year(s) Of Engagement Activity 2018
 
Description UCL Medical Society, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact UCL Medical Society, London, UK. Presented talk entitled 'meeting therapeutic challenge of Huntington's disease'. Sparked lively debate and widen knowldege and interest in clinical trial
Year(s) Of Engagement Activity 2018
 
Description Wellcome Researcher Meeting: Neuroscience and Mental Health, Coventry, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Wellcome Researcher Meeting: Neuroscience and Mental Health, Coventry, UK. Talk titled: 'Antisense oligonucleotide therapy for Huntington's disease - results from the first HTT lowering clinical trial'.. Generated questions re HD research trials
Year(s) Of Engagement Activity 2018
 
Description Women in Science Seminar Series, University of Sussex Falmer, Brighton, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Women in Science Seminar Series, University of Science, Falmer, Brighton, UK. Presented talk titled 'meeting therapeutic challenge of Huntignton's disease'. Talk generated questions and interest in HD research
Year(s) Of Engagement Activity 2018
 
Description • DZNE Lecture Series 2018, Bonn, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact DZNE Lecture Series 2018, Bonn, Germany (June). Presented talk titled: Meeting the therapeutic challenge in Huntington's disease'. Generated interest in HD trials and questions about further collaboration
Year(s) Of Engagement Activity 2018