Huntington disease: somatic expansion, pathobiology and therapeutics

Expansion of simple DNA repeats causes over 45 human, predominantly neurodegenerative, inherited disorders. Huntington disease is a fatal, inherited, neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene (HTT), resulting in a toxic polyglutamine tract in the huntingtin protein. The disease leads to progressive motor, cognitive and psychiatric decline, primarily resulting from loss of medium spiny neurons in the striatum. Although Huntington disease has long been viewed as a consequence of age-dependent toxicity from mutant huntingtin, genome-wide association studies have identified genetic modifiers, mostly DNA repair genes, that significantly influence disease onset and progression. These findings point to somatic CAG repeat expansions in affected tissues as a key pathological mechanism. This emerging paradigm suggests that disease progression is not solely protein-driven but also shaped at the DNA level, a mechanism that is shared among other repeat expansion disorders. Therapeutically, this discovery opens new opportunities: interventions to limit somatic repeat expansion might be effective across multiple repeat expansion diseases and, when combined with disease-specific approaches, such as huntingtin lowering in Huntington disease, might offer more effective and longer-lasting clinical benefits than either strategy in isolation. This approach also poses challenges, determining the optimal point for therapeutic intervention and how best to establish phenotypic improvement in clinical trials when the target tissue is the brain.