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.
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.
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.
