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Published on: July 18, 2019
Mouse models of Huntington's disease and methodological considerations for therapeutic trials
1Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, Massachusetts 01730, USA. rjferr@bu.edu
Insights
Huntington's disease (HD) mouse models are crucial for understanding disease mechanisms and testing treatments. This review guides the assessment of these models and their translation to human therapies.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a genetic mutation.
- The precise pathway from gene mutation to neuronal death in HD remains unclear.
- Murine models offer valuable systems for studying HD pathogenesis and therapeutic strategies.
Purpose of the Study:
- To review the current state of Huntington's disease mouse models.
- To discuss their successes in elucidating disease mechanisms.
- To provide guidance on translating findings from mouse models to human clinical trials.
Main Methods:
- Review of existing literature on Huntington's disease mouse models.
- Analysis of how these models replicate HD clinical, neuropathological, and molecular features.
- Discussion of challenges and considerations for interspecies translation.
Main Results:
- HD mouse models have significantly advanced the understanding of disease pathogenesis.
- These models provide experimentally accessible platforms for therapeutic development.
- Key issues in translating mouse model data to human applications are identified.
Conclusions:
- Huntington's disease mouse models are indispensable tools for research.
- Further refinement and careful application of these models are needed for effective therapeutic development.
- Successful translation requires addressing specific challenges in interspecies extrapolation.
Abstract:
Huntington's disease (HD) is an autosomal dominant, progressive, and fatal neurodegenerative disorder caused by an expanded polyglutamine cytosine-adenine-guanine repeat in the gene coding for the protein huntingtin. Despite great progress, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. One important advance in understanding the pathogenic mechanisms of this disease has been the development of multiple murine models that replicate many of the clinical, neuropathological, and molecular events in HD patients. These models have played an important role in providing accurate and experimentally accessible systems to study multiple aspects of disease pathogenesis and to test potential therapeutic treatment strategies. Understanding how disease processes interrelate has become important in identifying a pharmacotherapy in HD and in the design of clinical trials. A review of the current state of HD mouse models and their successes in elucidating disease pathogenesis are discussed. There is no clinically proven treatment for HD that can halt or ameliorate the inexorable disease progression. As such, a guide to assessing studies in mouse models and salient issues related to translation from mice to humans are included.
