Therapy development in Huntington disease: From current strategies to emerging opportunities.

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration. Research into the mechanistic basis of HD has highlighted a role for bioenergetics abnormalities stemming from mitochondrial dysfunction, and for synaptic defects, including impaired neurotransmission and excitotoxicity. Interference with transcription regulation may underlie the mitochondrial dysfunction. Current therapies for HD are directed at treating symptoms, as there are no disease-modifying therapies. Commonly prescribed drugs for involuntary movement control include tetrabenazine, a potent and selective inhibitor of vesicular monoamine transporter 2 that depletes synaptic monoamines, and olanzapine, an atypical neuroleptic that blocks the dopamine D2 receptor. Various drugs are used to treat non-motor features. The HD therapeutic pipeline is robust, as numerous efforts are underway to identify disease-modifying treatments, with some small compounds and biological agents moving into clinical trials. Especially encouraging are dosage reduction strategies, including antisense oligonucleotides, and molecules directed at transcription dysregulation. Given the depth and breadth of current HD drug development efforts, there is reason to believe that disease-modifying therapies for HD will emerge, and this achievement will have profound implications for the entire neurotherapeutics field.