Targeting Chorea in Huntingtons Disease: Emerging Therapeutic Strategies

Huntington's disease (HD) is a currently incurable neurodegenerative disorder caused by an autosomal dominant mutation in the HTT gene, leading to the production of mutant huntingtin protein (mHTT) with an expanded polyglutamine (polyQ) tract. This aberrant protein aggregation results in progressive neuronal dysfunction, particularly in the striatum and cortex, manifesting as involuntary choreiform movements (resembling dance-like behaviors), cognitive decline, and psychiatric disturbances. Despite advances in symptomatic managementsuch as antidepressants, dopamine-modulating agents, and physical therapyexisting treatments fail to halt disease progression or reverse neuronal damage.In recent years, novel therapeutic strategies have emerged, offering hope for disease modification rather than mere symptom alleviation. One promising approach involves mini-intrabodies, engineered antibody fragments designed to selectively bind and neutralize mHTT. These intrabodies facilitate the degradation of toxic protein aggregates via lysosomal pathways, effectively reducing neuronal toxicity. Other cutting-edge interventions include antisense oligonucleotides (ASOs) to suppress mHTT expression, CRISPR-based gene editing to correct the HTT mutation, and stem cell therapy to replace damaged neurons.This article evaluates these innovative strategies, with a focus on lysosome-targeted mini-intrabodies as a potential curative approach. By analyzing preclinical and clinical advancements, we aim to highlight future research directions that could transform HD treatment from palliative care to definitive therapy.