Using gene or cell therapies to treat Huntington's disease

Huntington's disease is caused by a CAG repeat expansion in the first exon of the HTT gene, leading to the production of gain-of-toxic-function mutant huntingtin protein species and consequent transcriptional dysregulation and disrupted cell metabolism. The brunt of the disease process is borne by the striatum from the earliest disease stages, with striatal atrophy beginning approximately a decade prior to the onset of neurologic signs. Although the expanded CAG repeat in the HTT gene is necessary and sufficient to cause HD, other genes can influence the age at onset of symptoms and how they progress. Many of these modifier genes have roles in DNA repair and are likely to modulate the stability of the CAG repeat in somatic cells. Currently, there are no disease-modifying treatments for HD that can be prescribed to patients and few symptomatic treatments, but there is a lot of interest in therapeutics that can target the pathogenic pathways at the DNA and RNA levels, some of which have reached the stage of human studies. In contrast, cell therapies aim to replace key neural cells lost to the disease process and/or to support the host vulnerable striatum by direct delivery of cells to the brain. Ultimately it may be possible to combine gene and cell therapies to both slow disease processes and provide some level of neural repair. In this chapter we consider the current status of these therapeutic strategies along with their prospects and challenges.