Hope or hype: novel disease-modifying treatments for Huntington disease.

Abstract

Huntington disease research is living a gilded age for experimental disease-modifying therapies (DMTs), unique in the field of neurodegenerative movement disorders. Several studies are evaluating huntingtin-lowering approaches, using a multitude of molecules from antisense oligonucleotides, RNA interference therapies, and small molecule splicing modifiers. In parallel, somatic instability occurring during the life of gene carriers is increasingly recognized as a pathogenic mechanism driving clinical onset and progression, alongside with the established role of the length of a germinal CAG repeat. Recent trials document a consistent reduction of cerebral huntingtin and provide unique hope to researchers, clinicians, and patients of a first disease-modifying therapies in HD. However, a meaningful clinical impact on disease progression remains to be confirmed in phase III studies to support the translation of a first DMT into clinical practice. Dual targeting of both huntingtin and somatic instability is a novel emerging therapeutic concept that provides additional hope for an effective disease modification in Huntington disease in the future.