Gene therapy for Huntington’s disease

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.