MICA: HD-CSF: Studying cerebrospinal fluid to understand key CNS pathobiological targets in Huntington's disease

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

Abstract

Huntington's disease (HD) is a fatal, incurable inherited disease that causes brain degeneration and dementia. It is one of the commonest inherited causes of neurodegeneration and causes complex disability lasting around twenty years from onset to death. HD is always caused by a mutation that causes cells to produce a harmful protein called mutant huntingtin (mHTT).

The most promising experimental treatments being developed are drugs to reduce production of the mHTT protein that causes HD. This is called 'gene silencing' or 'huntingtin lowering'. Another promising approach is to develop drugs to restore the balance of protective and toxic chemicals produced by the brain's immune cells. These are known as kynurenine pathway or 'KP' metabolites and we know from animal models and post-mortem human brains that their balance is altered in HD in a way that seems to make the disease worse.

Cerebrospinal fluid (CSF) is a clear fluid, produced by the brain, which surrounds the brain and spinal cord, contains chemicals derived from the brain, and can be collected from living patients by a relatively straightforward procedure called lumbar puncture.

Developing huntingtin-lowering drugs would happen faster if we could measure how much mHTT is in the nervous system - then we would know if we have successfully lowered it. The same is true for KP metabolites and drugs to alter them. But nobody has ever measured CSF huntingtin levels, because the concentration is too low; and KP metabolites have never been accurately measured in HD patients.

We have developed an ultra-sensitive test to measure mutant huntingtin levels, using laser-activated counting of single huntingtin molecules labelled with newly-developed antibodies. Our pilot data show that this test can measure mHTT for the first time, in CSF from two different populations. What's more, the level of mHTT seems to increase as the disease progresses, meaning that it potentially serve as a 'biomarker' to predict progression or decide on the best time to treat patients with drugs in the future. We are working to develop tests that will mention the different chopped-up lengths of mHTT, to help figure out which are the most harmful ones.

We have also developed sensitive and reliable tests for KP metabolites, and we need good quality CSF to measure them in.

The 'HD-CSF' study will collect CSF and clinical data from 80 HD gene carriers and controls, twice each, two years apart, using methods designed to ensure the CSF is as pure and useful as possible. Poor quality CSF, and inconsistencies in handling and processing it, has been a problem with previous studies trying to use CSF to study HD.

Importantly, as well as CSF collection, HD-CSF participants will undergo detailed clinical and cognitive assessment, and MRI scanning to measure the rate of brain shrinkage. These assessments have been developed and proven to be of clinical relevance through our ground-breaking TRACK-HD study. The CSF and clinical and MRI data will be used to help us understand how mHTT levels and LP metabolites change as the disease progresses; and which chemical changes in CSF predict disease progression.

Measuring these chemicals in CSF using our ultra-sensitive tests will help understand how HD damages the brain, and provide new ways to measure its progression and, in future, whether a drug is having the desired effect, ultimately accelerating the development of treatments.

Technical Summary

Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disease causing motor and psychiatric symptoms and dementia. No disease-slowing treatment exists. HD is caused by an expanded CAG triplet repeat in HTT, resulting in mutant huntingtin protein (mHTT). Promising therapeutic candidates nearing human trials include nucleotide-based huntingtin-lowering drugs and kynurenine mono-oxygenase inhibitors.

Huntingtin has never been quantified in the living CNS, limiting our understanding of the role of wild-type and mutant HTT and their cleaved species in patients, and how these roles change over time; and preventing demonstration of target engagement by HTT-lowering drugs.

We have developed a novel, ultra-sensitive immunoassay which can quantify mHTT for the first time in patient CSF, completely distinguishing controls, premanifest mutation-carriers and patients. mHTT level correlates with neurofilament light chain, indicating likely neuronal origin.

Depending on the activity of KMO, the kynurenine pathway (KP) produces either neurotoxic or neuroprotective metabolites. It is deleteriously deranged in HD but has never been studied using accurate methods in patient CSF.

HD-CSF is the first comprehensive longitudinal study of CSF to elucidate key CNS pathobiological targets in HD. CSF, blood and robust phenotypic data including volumetric MRI will be collected from an 80-subject cohort at two timepoints. Samples will be analysed using our novel assays to quantify mHTT and KP metabolites and examine associations with disease progression. These core findings will be enriched through the targeted study of CNS-specific proteins in CSF.

Comprehensive longitudinal study of KP metabolites and huntingtin species in patient CSF, linked to robust clinical and MRI atrophy data, will enhance our understanding of HD neuropathobiology in the living patient CNS, and provide pharmacodynamic biomarkers to accelerate therapeutic development.

Planned Impact

Through presentation of the results of this work in peer-reviewed articles and conference presentations, the academic beneficiaries will gain an increased understanding of the pathobiology of HD in the living patient CNS. This will benefit not only the global HD research community but also the broader neurodegenerative disease field, since HD can serve as a model for the earliest events in neurodegeneration.

HD-CSF will generate meaningful CSF biomarkers and an understanding of how those biomarkers predict progression. This will enable the efficient conduct of clinical trials through pharmacodynamic biomarkers of CNS huntingtin-lowering and KMO inhibition. More broadly, CSF HTT and kynurenine pathway metabolites may prove useful for stratification to determine which patients should enter clinical trials and when. The immediate beneficiaries of this will be industry-academic collaborations essential to the conduct of large-scale trials of disease-modifying therapies for HD. Patients and those at risk of HD will ultimately benefit through the accelerated development of disease-slowing therapeutics. Again, the applicability of these techniques beyond HD (especially given the involvement of the kynurenine pathway in many brain diseases) will benefit academia, industry and patients across neurodegeneration. Bringing pharma-funded clinical trials to the UK and to UCL will be financially advantageous to the UK economy and the UK academic sector's international reputation.

The biobank of CSF, collected longitudinally and rich phenotypic data including MRI that HD-CSF will generate will provide many opportunities for further research, primarily into HD but also to explore differences and similarities between HD and other brain diseases. The beneficiaries of this will be the researchers (including myself and future team members) whose work will be stimulated by this collection; UCL and the UK research community through attracting collaborations and funding; and the patient communities affected, through the discoveries that will emerge from this valuable resource.

HD-CSF may generate intellectual property through the identification of novel CSF pharmacodynamic and clinical biomarkers for Huntington's disease. This will enable clinical trials by identifying drug efficacy and consequently will be a valuable commercial tool of high interest to pharma companies. IP may come not only from the assays themselves, developed and tested in these samples, but their application to Huntington's disease and to detect a meaningful biological response to treatment with KMO inhibitors or HTT-lowering drugs. They will likely be of value in other neurodegenerative diseases such as Alzheimer's and Parkinson's. UCL Business PLC (UCLB) is the technology transfer company of UCL responsible for the management of UCL's intellectual property. Any IP that develops under the funded work at UCL will be appraised by UCLB for IP protection and, if appropriate, a patent application will be filed. UCLB will pay for the filing and the prosecution of the patent and will work with the MRC, GSK, CHDI Foundation and IRBM Promidis to identify appropriate routes to market.

The main motivation behind HD-CSF is to benefit the global community of HD patients and family members through accelerating the development of therapies for HD. Given the decades-long burden of complex physical, cognitive and behavioural disability that HD causes in every sufferer, and the psychological trauma to those at risk, the potential for benefits to the health of the nation are significant.

Publications

10 25 50
 
Title 'Tree' - collaboration with Highly Sprung Performance Company 
Description A physical performance piece aimed at introducing genetics and science to young (primary school) children. I was a scientific advisor. 
Type Of Art Performance (Music, Dance, Drama, etc) 
Year Produced 2017 
Impact Coverage in news media 
URL http://www.highlysprungperformance.co.uk/tree
 
Description CHDI Foundation Clinical Fellowship
Amount £56,858 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2015 
End 02/2016
 
Description CHDI Foundation Inc 5-year personal Fellowship
Amount £825,842 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 05/2019 
End 04/2024
 
Description CHDI Foundation: HDClarity Central Coordination
Amount £600,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 05/2015 
End 04/2019
 
Description Origin-HD startup grant
Amount £18,116 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 03/2017 
End 04/2018
 
Description Roche research grant
Amount £280,046 (GBP)
Funding ID 803543 
Organisation F. Hoffmann-La Roche AG 
Sector Private
Country Global
Start 01/2018 
End 07/2019
 
Description Wellcome Trust Multi-User Equipment Award
Amount £119,531 (GBP)
Funding ID 108457/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
 
Title Optimised methodology for the collection and processing of cerebrospinal fluid in Huntington's disease 
Description Optimised protocol for the collection and processing of cerebrospinal fluid in Huntington's disease and other neurodegenerative disorders 
Type Of Material Biological samples 
Year Produced 2016 
Provided To Others? Yes  
Impact Multi-site HDClarity study - I am the global CI 
URL http://hdclarity.net/study-information/
 
Title Quantification of mutant huntingtin using single-molecule counting 
Description Novel single molecule counting immunoassay to quantify mutant huntingtin protein in cerebrospinal fluid. 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact Publication in JCI 2015 (Wild et al) Huntington Study Group "Insight of the Year" award 2015 Use of assay in Ionis clinical trial of huntingtin-lowering therapeutic 
URL https://www.jci.org/articles/view/80743
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation CHDI Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation Centre For Movement Disorders
Country Canada 
Sector Hospitals 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation Johns Hopkins University
Department Department of Chemical and Biomolecular Engineering
Country United States 
Sector Academic/University 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation Leverndale Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation Ulm University Medical Center
Country Germany 
Sector Hospitals 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation University of British Columbia
Country Canada 
Sector Academic/University 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: global CI of HDClarity study 
Organisation University of Cambridge
Department Faculty of Education
Country United Kingdom 
Sector Academic/University 
PI Contribution On the basis of my research to date in CSF biomarkers for Huntington's disease I was selected as the global CI of a new multi-site study, HDClarity. This aims to enrol up to 30 sites globally and produce the largest collection of CSF to date. It is highly complimentary to the work of my MRC Fellowship but places me at the centre of CSF research in HD globally. Sample collection is now underway at 2 sites beyond UCL (Vancouver and Glasgow).
Collaborator Contribution CHDI is the funder (3 staff members at UCL - Trial manager, Research Administrator and Clinical Fellow) and provides infrastructural support and direct funding to clinical sites (total value estimated at £3m). Other sites listed are clinical sites either active or under enrolment.
Impact Oral presentation at the European Huntington's Disease Network Plenary Meeting, September 2016. Oral presentation at the Hereditary Disease Foundation biennial meeting, August 2016.
Start Year 2015
 
Description CHDI Foundation: study of kynurenine pathway 
Organisation CHDI Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution Supply of expertise and samples for studying the kynurenine pathway in HD
Collaborator Contribution Analysis of KP metabolites (ongoing)
Impact Oral presentation at CHDI Foundation Annual Therapeutics conference in 2015. Oral presentation at Hereditary Disease Foundation Biennial meeting in 2016.
Start Year 2015
 
Description Collaboration with Dr Ali Khoshnan (Caltech) 
Organisation California Institute of Technology
Department Division of Biology and Biological Engineering (BBE)
Country United States 
Sector Academic/University 
PI Contribution Supply of samples to study oligomerisation in Huntington's disease CSF.
Collaborator Contribution Analysis and data on oligomers in CSF
Impact No outputs yet
Start Year 2018
 
Description Collaboration with Dr Vanessa Wheeler at MGH 
Organisation Massachusetts General Hospital
Department Center for Genomic Medicine
Country United States 
Sector Hospitals 
PI Contribution We supplied CSF and clinical data for a study of huntingtin mRNA in CSF
Collaborator Contribution They are doing the RNA analysis and we will publish collaboratively
Impact None yet
Start Year 2017
 
Description Collaboration with Prof Leslie Thompson (UC Irvine) 
Organisation University of California, Irvine
Department School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Supply of samples to study exosomes in CSF
Collaborator Contribution Data and analysis of exosomes
Impact No outputs yet
Start Year 2016
 
Description Collaboration with University of Gothenberg (Zetterberg) 
Organisation University of Gothenburg
Department Department of Pathology and Genetics
Country Sweden 
Sector Academic/University 
PI Contribution Samples, data, analysis of results. Collaboration to quantify CSF biomarkers for Huntington's disease
Collaborator Contribution Expertise and resources in assaying CSF biomarkers
Impact 3 publications so far: Wild et al JCI 2015 Rodrigues et al PLoS One 2016 Rodrigues et al J Neurochem 2016
Start Year 2015
 
Description Collaboration with William Yang UCLA 
Organisation University of California, Los Angeles (UCLA)
Department UCLA Cardiac Arrhythmia Center
Country United States 
Sector Academic/University 
PI Contribution CSF samples supplied to study huntingtin seeding in CSF
Collaborator Contribution Assaying of CSF seeding (in progress)
Impact No outputs yet
Start Year 2016
 
Description Consultancy with Roche 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution Consultancy on design of future gene-silencing trials in Huntington's disease
Collaborator Contribution Roche intends to run the next trial
Impact Collaboration likely to secure my role in design and conduct of groundbreaking trials
Start Year 2015
 
Description Consultancy with Sangamo / Shire 
Organisation Sangamo Biosciences, Inc
Country United States 
Sector Private 
PI Contribution I am a consultant on the design of clinical trials of a zinc-finger transcriptional repressor drug for Huntington's disease
Collaborator Contribution Shire and Sangamo are intending to run the trial
Impact No outputs yet
Start Year 2015
 
Description Consultancy with Sangamo / Shire 
Organisation Shire Pharmaceuticals
Country Ireland 
Sector Private 
PI Contribution I am a consultant on the design of clinical trials of a zinc-finger transcriptional repressor drug for Huntington's disease
Collaborator Contribution Shire and Sangamo are intending to run the trial
Impact No outputs yet
Start Year 2015
 
Description Digital-HD project 
Organisation F. Hoffmann-La Roche AG
Department Roche Diagnostics
Country Global 
Sector Private 
PI Contribution Funded academic study of digital biomarkers in HD. We designed the protocol and are running the study
Collaborator Contribution They designed the hardware and app, and are processing the digital biomarker data
Impact To be presented at Movement Disorders Congress 2019.
Start Year 2017
 
Description GSK Kynurenine pathway 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Conception and design of clinical translational study, collection and provision of CSF samples and clinical data, and analysis of data
Collaborator Contribution Expertise, finance, KMO pathway assays and laboratory work
Impact Partnership agreed but no outputs yet
Start Year 2013
 
Description GSK: Advisory Board 
Organisation GlaxoSmithKline (GSK)
Department Neuroscience (GSK)
Country United Kingdom 
Sector Private 
PI Contribution I am a member of an advisory board for GSK on a novel target in neurodegeneration (details confidential)
Collaborator Contribution GSK is developing the target
Impact No outputs yet
Start Year 2016
 
Description Gen-PEAK study of PK/PD of RG6042 in Huntington's disease (global CI) 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution I have led the development of this study from concept to ethics submission. It is expected to bring significant revenue and innovation but the details are not yet final.
Collaborator Contribution Roche are the study sponsor
Impact No outputs yet
Start Year 2017
 
Description Huntingtin quantification: CHDI / IRBM / BioFocus 
Organisation Biofocus
Country United States 
Sector Private 
PI Contribution I have defined protocols and collected biosamples (blood and CSF) and phenotypic data to refine several generations of assays for mutant and total huntingtin protein and used them to study the pathobiology of Huntington's disease.
Collaborator Contribution Our partners have supplied funding, assay development technology and reagents but the projects have been clinically led from UCL.
Impact Paper in JCI 2012 (PMID 22996692). Prize-winning poster presentation at international HD Therapeutics meeting 2013.
Start Year 2009
 
Description Huntingtin quantification: CHDI / IRBM / BioFocus 
Organisation CHDI Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution I have defined protocols and collected biosamples (blood and CSF) and phenotypic data to refine several generations of assays for mutant and total huntingtin protein and used them to study the pathobiology of Huntington's disease.
Collaborator Contribution Our partners have supplied funding, assay development technology and reagents but the projects have been clinically led from UCL.
Impact Paper in JCI 2012 (PMID 22996692). Prize-winning poster presentation at international HD Therapeutics meeting 2013.
Start Year 2009
 
Description Huntingtin quantification: CHDI / IRBM / BioFocus 
Organisation IRBM Promidis
Country Italy 
Sector Private 
PI Contribution I have defined protocols and collected biosamples (blood and CSF) and phenotypic data to refine several generations of assays for mutant and total huntingtin protein and used them to study the pathobiology of Huntington's disease.
Collaborator Contribution Our partners have supplied funding, assay development technology and reagents but the projects have been clinically led from UCL.
Impact Paper in JCI 2012 (PMID 22996692). Prize-winning poster presentation at international HD Therapeutics meeting 2013.
Start Year 2009
 
Description Isis Pharmaceuticals 
Organisation Isis Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Partnership (formal consultancy) in developing trial protocol for antisense oligonucleotide huntingtin-lowering trial for Huntington's disease
Collaborator Contribution Partnership in developing trial protocol for antisense oligonucleotide huntington-lowering trial for Huntington's disease
Impact No outputs yet
Start Year 2014
 
Description RAND Corporation (causal modelling in HD) 
Organisation RAND Boston
Country United States 
Sector Charity/Non Profit 
PI Contribution Design of protocol, application for funding to CHDI Foundation; ongoing intellectual input. Study using causal modelling to identify factors influencing the onset of Huntington's disease.
Collaborator Contribution Conduct of statistical analysis.
Impact Funding from CHDI Foundation to RAND corporation.
Start Year 2016
 
Description Scientific Advisory Board, Ionis Pharmaceuticals huntingtin-lowering trial 
Organisation Ionis Pharmaceuticals
PI Contribution Senior advisor, member of Scientific Advisory Board and senior investigator on first ever huntingtin-lowering trial in human HD patients. Trial active since September 2015.
Collaborator Contribution Ionis (formerly ISIS) developed the compound and is the trial sponsor.
Impact News articles: Telegraph http://www.telegraph.co.uk/science/2016/03/12/first-drug-to-reverse-huntingtons-disease-begins-human-trials/ BBC http://www.bbc.co.uk/news/health-34552041 New Scientist https://www.newscientist.com/article/mg23230943-300-children-with-fatal-muscle-disease-walk-after-drug-breakthrough/
Start Year 2014
 
Description University of Lisbon (Prof Joaquim Ferreira) 
Organisation University of Lisbon
Department Institute for Molecular Medicine
Country Portugal 
Sector Academic/University 
PI Contribution Under my supervision, my Clinical Fellow Filipe Rodrigues established this partnership and we have worked together on multiple meta-analysis projects in Huntington's disease.
Collaborator Contribution Expertise (Prof Ferreira and his partners are members of the Cochrane Collaboration)
Impact In-press publication in Movement Disorders Clinical Practice (Rodrigues et al 2017)
Start Year 2015
 
Description Wave Life Sciences: consultancy 
Organisation Wave Life Sciences
Country Unknown 
Sector Private 
PI Contribution I am a member of the Clinical Advisory Board to Wave Life Sciences, who are developing novel antisense therapies for Huntington's disease
Collaborator Contribution Wave is the pharmaceutical company that is developing the assets and establishing the trial
Impact No outputs yet
Start Year 2016
 
Title Quantification of mutant huntingtin in CSF 
Description Single-molecule immunoassay for quantifying mutant huntingtin. The concentration of mutant huntingtin in CSF is an independent predictor of clinical phenotype in HD (Wild et al JCI 2015). The method is undergoing validation to FDA / EMA standards for clinical trial use (manuscript in draft). 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact Method is being used in a clinical trial 
URL http://dx.doi.org/10.1172/JCI80743
 
Description 'Pint of Science' festival 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public lecture on my research to the Pint of Science festival, widely attended and open to the public
Year(s) Of Engagement Activity 2015
URL http://pintofscience.com
 
Description Audience with Pope Francis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I was invited to meet Pope Francis at an audience at the Vatican to raise awareness of Huntington's disease. The event attracted considerable media attention.
Year(s) Of Engagement Activity 2017
URL http://www.ucl.ac.uk/news/slms/slms-news/slms/ed-wild-to-meet-pope-francis
 
Description BBC / Telegraph / Times - news coverage of Huntington's disease trial 
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 Extensive news media coverage of the start of our clinical trial (sponsored by Ionis pharmaceuticals) of the first Huntington's disease gene silencing treatment.
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/news/health-34552041
 
Description BBC Radio 4 - Women's Hour 
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 Interview with Jenni Murray about Huntington's disease, broadcast on BBC Radio 4 Woman's Hour on 15th July 2016
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b07jqr4j
 
Description HDBuzz 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact HDBuzz, a registered charity, is an online source of reliable, impartial, easy-to-understand information about Huntington's Disease research. I have assembled a team of 17 scientists to serve as writers, and 99 volunteers to translate content into 12 languages. HDBuzz is now the world's foremost HD research news source, receiving ~100,000 unique visitors per month and supplying HD research news to all the world's main HD websites.

HDBuzz has dramatically raised my profile among the global HD community of affected family members as well as scientists. As a result I am regularly invited to give keynote lectures at national and international patient meetings. It has also raised my personal profile among scientist colleagues through networking and recognition. We now support and award the 'HDBuzz Prize for Scientific Writing' annually.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
URL http://hdbuzz.net
 
Description Hereditary Disease Foundation Gala 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Invited keynote lecture to a Fundraising Gala for the Hereditary Disease Foundation at the Metropolitan Club, New York City. The event raised $2m for Huntington's disease research.
Year(s) Of Engagement Activity 2016
URL http://www.newyorksocialdiary.com/party-pictures/2016/celebrating-the-neighborhood
 
Description Huntington Society of Canada - keynote lecture at annual convention 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Invited keynote lecture to the Annual Convention of the Huntington Society of Canada Biennial Convention - Halifax, 2016
Year(s) Of Engagement Activity 2016
URL http://huntingtonsociety.ca
 
Description Huntington's Disease Society of America - keynote lecture at annual convention 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Invited keynote lecture to the Huntington's Disease Society of America annual convention, Baltimore, June 2016
Year(s) Of Engagement Activity 2016
URL http://hdsa.org
 
Description Media activity around Lancet Neurology NfL paper 2017 
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 Media (as a channel to the public)
Results and Impact Press release for 2017 Lancet Neurology First+Senior author paper (Byrne et al) attracted media coverage from BBC, Daily Mail, Telegraph, The Biomedical Scientist.
Year(s) Of Engagement Activity 2017
URL http://edwild.com/category/news/
 
Description New Scientist 
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 Interview about Huntington's disease "gene silencing" trial in New Scientist, published 6th October 2016
Year(s) Of Engagement Activity 2016
URL https://www.newscientist.com/article/mg23230943-300-children-with-fatal-muscle-disease-walk-after-dr...
 
Description Press release and media relating to JCI 2015 paper 
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 Media (as a channel to the public)
Results and Impact Press release about my JCI 2015 paper which was picked up by several news outlets including Nature Reviews Neurology as a Research Highlight

Many people were made aware of my research
Year(s) Of Engagement Activity 2015
URL http://www.nature.com/nrneurol/journal/v11/n5/full/nrneurol.2015.63.html
 
Description Substantial coverage of huntingtin-lowering trial, December 2017 
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 Media (as a channel to the public)
Results and Impact Top line results from the phase 1/2 clinical trial of IONIS-HTTRx, on which I was a senior investigator and advisor, was announced in a press release in December 2017. I appeared on the BBC News at 6 and 10 and was interviewed by The Guardian, CNN, Times, RTE television, Al Arabiya TV, Irish Times, Deutscher Welle and others. Full list in URL
Year(s) Of Engagement Activity 2017
URL http://edwild.com/category/news/
 
Description Third-party article about my HDBuzz project in Journal of Huntington's Disease 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Huntington's Disease Society of America wrote an article for the Journal of Huntington's Disease in which my HDBuzz outreach project was described and praised.
Year(s) Of Engagement Activity 2017
URL http://dx.doi.org/10.3233/JHD-160230
 
Description WIRED 
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 Interview with WIRED magazine about CRISPR/Cas9
Year(s) Of Engagement Activity 2017
URL http://www.wired.co.uk/article/crispr-cas9-technique-explained