Identification and Cross-validation of Early Stage Phenotypes in Mouse Models of Huntington s disease

Lead Research Organisation: King's College London
Department Name: Genetics and Molecular Medicine

Abstract

Huntington?s disease (HD) is an inherited neurodegenerative disorder with an average age of onset of 40 years. Affected individuals lose their ability to control movement, develop psychiatric problems, an impaired mental capacity and lose weight. The disease progresses for 15-20 years until patients have almost no movement and cannot swallow or speak. There are effective treatments for some psychiatric problems (e.g. depression) but there is no way to halt or slow the mental decline or disease progression. The European Huntington?s Disease Network (EHDN) (funded by the CHDI Foundation) has been established to provide the infrastructure, tools and resources necessary to perform clinical trials for HD in Europe. Unlike Alzheimer?s and Parkinson?s disease, HD is always inherited and a genetic test can be used to diagnose individuals with early stage disease and before symptoms develop. This group of people will be particularly suited to receive disease-modifying treatments once they are developed. To develop the tests to monitor the emergence and progression of disease in this group, the CHDI Foundation has funded TRACK-HD, a three year initiative that commenced in 2007 to develop clinical, magnetic resonance imaging and blood tests and compare their utility.
The mechanisms that underlie HD are extremely complex and many potential therapeutic avenues have been proposed. However, because clinical trials will remain resource intensive and expensive, the number of drugs that can be tested in the clinic will inevitably be limited. Mice that have been genetically altered to carry the HD mutation are very good models of the human disease. Therefore, because drug trials can be performed relatively quickly in mice, the demonstration that a treatment has a beneficial effect in an HD mouse model is the factor most likely to be used to prioritise drugs for testing in clinical trials. Therefore, mouse trials must be rigorous, controlled and reproducible and ideally incorporate tests that are relevant to the human disease. In partnership with the CHDI Foundation, we shall conduct a detailed comparative evaluation of HD mouse models, with a particular focus on presymptomatic and early stage disease using tests chosen to complement the TRACK-HD clinical study. This project will inform the design of mouse trials using tests that emerge as being the most useful for clinical evaluation. This synergy will maximise the chance of translating successful therapeutic strategies for HD into the clinic using validated HD mouse models.

Technical Summary

Huntington?s disease (HD) is an autosomal dominant neurodegenerative disorder with a mean age of onset of 40 years. Symptoms include motor disorders, psychiatric disturbances, cognitive decline and weight loss, disease duration is approximately 15-20 years and death occurs from co-morbid events. Effective symptomatic therapy is available for some psychiatric symptoms, but treatment of the motor disorder is challenging and there are no therapies that halt or slow the cognitive decline or disease progression. The combination of a slowly progressive disease of variable presentation with a poor battery of assessment tools has meant that phase III clinical efficacy trials performed to date have been underpowered. To remedy this situation, the European Huntington?s Disease Network (EHDN) (funded by the CHDI Foundation) has been established to provide the infrastructure, tools and resources necessary to perform clinical trials for HD in Europe. Because HD is an autosomal dominant disease with a genetic diagnostic test, virtually all individuals in the ultimate HD target group, those with premanifest or early stage disease, can be determined with certainly. To develop the assessment tools to monitor the emergence and progression of disease in this group, the CHDI Foundation has funded TRACK-HD, a three year initiative that commenced in 2007 to identify and compare head-to-head clinical, imaging and wet biomarker assessment tools.
The molecular pathogenesis of HD is extremely complex and many potential therapeutic targets have been proposed. However, because clinical efficacy trials will remain resource intensive and expensive, the number of compounds that can be tested in the clinic will inevitably be limited. The demonstration that a therapeutic strategy has disease modifying effects when administered to HD mouse models is the factor most likely to influence the prioritisation of compounds entering the clinical. Therefore, preclinical efficacy trials must be as rigorous, controlled and reproducible as possible and ideally will incorporate clinically cross-validated outcome measures. In partnership with the CHDI Foundation, this proposal will conduct a detailed comparative evaluation of HD mouse models, with a particular focus on presymptomatic and early stage disease using outcome measures chosen to complement the TRACK-HD clinical study. It aims to inform the design of preclinical assessment trials and to match the choice of outcome measures to those that will emerge as being the most useful for clinical evaluation. This synergy will maximise the chance of translating successful therapeutic strategies for HD into the clinic using validated HD mouse models.

Publications

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Turner MR (2010) Advances in the application of MRI to amyotrophic lateral sclerosis. in Expert opinion on medical diagnostics

 
Description EU JPND research initiative
Geographic Reach Asia 
Policy Influence Type Membership of a guidance committee
Impact The Joint Programming Initiative in Neurodegeneration (JPND) has been established by 23 European countries to address the growing societal challenge presented by age-related neurodegeneration. This initiative spans the biomedical, healthcare and social science agendas, and seeks to improve the scientific understanding of neurodegenerative disorders, provide new approaches for their prevention, diagnosis and treatment, and ensure effective provision of health and social care and support, so that individuals can receive optimum care at all stages of their illness.
 
Description grant support
Amount £125,370 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start  
End 09/2012
 
Description HD KI models 
Organisation University of Alabama at Birmingham
Department Department of Biochemistry and Molecular Genetics
Country United States 
Sector Academic/University 
PI Contribution analysed mouse models in the publication below
Collaborator Contribution provided mouse models
Impact Sathasivam K*, Neueder A*, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RLM, Roos RAC, Howland D, Detloff PJ, Housman DE, Bates GP (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington's disease. Proc. Natl. Acad. Sci. 110, 2366-2370.
Start Year 2010
 
Description cardiac MRI for mice 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided the mouse models of HD for scanning as part of a much wider analysis of cardiac dysfunction
Collaborator Contribution Advice on and supervision for cardiac MRI analysis
Impact Mielcarek et al PLoS Genetics 10, e1004550 2014
Start Year 2011
 
Description tensor based morphometry of MRI 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided longitudinal in vivo and ex vivo MRI scans of a mouse model of HD
Collaborator Contribution Applied tensor based morphometric analysis that they had developed
Impact Rattray et al 2013 PLoS ONE 8: e84726 Rattray et al 2017 PLoS ONE 12: e0168556
Start Year 2012
 
Description Careers afternoon for graduate students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Facilitated a careers afternoon for postgraduate students funded by the Neuromodel EU Marie Curie training netwrok

Good feedback from the students about the presentations and the opportunity to discuss career options
Year(s) Of Engagement Activity 2012
 
Description Headmasters annual conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Headmasters experienced going back to school for a day. Gave a lesson to approx. 30 headmasters

good feedback and request for transcript of presentation
Year(s) Of Engagement Activity 2013
 
Description School visit (Brompton Oratory) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact talk to and discussion with 6th formers about the ethics and implications of genetic research

Very positive feedback, the school regretted not having made a video of the afternoon
Year(s) Of Engagement Activity 2011
 
Description School visit (Guildford) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Very engaged sixth formers invited speakers to discuss topics in which they were interested. the lecture continued as a careers discussion.
Year(s) Of Engagement Activity 2015
 
Description UK HD netwrok 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Approximately 100 health professional involved in the care of Huntinton's disease (physiotherapists, psychologists, social workers etc.) and lay group members

Have been asked to address a psychiatric conference
Year(s) Of Engagement Activity 2011
 
Description symposium at care home 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact talk given to ~ 80 GPs, carers, physiotherapists etc involved in the care of HD patients.

Request to visit the research lab
Year(s) Of Engagement Activity 2013
 
Description work experience for sixth formers 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Arrangement with Tiffin Girls School for sixth form students to visit for work experience during the summer. Students from other schools take part on an ad hoc basis
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019