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Gene Therapy for Huntington’s Disease

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Gene Delivery and Therapy for Neurological Disorders

Part of the book series: Neuromethods ((NM,volume 98))

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Abstract

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease characterized by loss of motor control, cognitive decline, and psychiatric manifestations. The underlying genetic cause of HD is a mutation in the huntingtin gene resulting in an expanded polyglutamine tract in huntingtin protein that confers a toxic gain of function. Abnormal intranuclear protein inclusions and the progressive degeneration of medium spiny neurons in the striatum as well as other brain areas at later stages are key neuropathological features of the disease. Gene therapy is an attractive therapeutic option for HD. Therapeutic strategies have primarily centered on neuroprotective and/or neuroregenerative approaches to prevent or ameliorate the extent of striatal neuron loss through the overexpression of neurotrophic factors which boost the resilience of neurons to the toxic effects of mutant huntingtin. More recently, attention has turned to gene silencing or intrabody approaches, powerful approaches that aim to mitigate the pathogenic effects of mutant huntingtin. Promising results have been shown in the evaluation of several of these strategies in rodent and non-human primate models of HD, and gene delivery technology has advanced to the stage where opportunities for long-term therapeutic intervention can be realized. In this chapter, we review the main gene therapy strategies for HD followed by a description of the methods used in our laboratory for the packaging of adeno-associated viral (AAV) vectors for therapeutic gene delivery, methods for AAV vector delivery into the rodent brain, and behavioral tests used for the assessment of functional deficits/recovery in rat models of HD.

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Authors and Affiliations

  1. Department of Pharmacology & Clinical Pharmacology and Centre for Brain Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand

    Angela Wu & Dahna M. Fong

  2. Department of Pharmacology & Clinical Pharmacology and Centre for Brain Research, Faculty of Medical & Health Sciences, University of Auckland, Private Bag 92019, M&HS Building 502, Level 5, Room 502-501C, 85 Park Road, Grafton, Auckland, 1023, New Zealand

    Deborah Young

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  1. Angela Wu
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  2. Dahna M. Fong
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  3. Deborah Young
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Correspondence to Deborah Young .

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Editors and Affiliations

  1. Queen Mary University of London, London, United Kingdom

    Xuenong Bo

  2. Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

    Joost Verhaagen

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Wu, A., Fong, D.M., Young, D. (2015). Gene Therapy for Huntington’s Disease. In: Bo, X., Verhaagen, J. (eds) Gene Delivery and Therapy for Neurological Disorders. Neuromethods, vol 98. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2306-9_5

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  • DOI: https://doi.org/10.1007/978-1-4939-2306-9_5

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