Recent Advances in Pharmacological Interventions for Huntington's Disease: Evidence from Clinical Translation

Huntington's Disease (HD) is a rare autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, psychiatric disturbances, and cognitive decline. An expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene causes it to repeat, leading to the production of mutant Huntingtin Protein (mHTT), which drives selective neuronal degeneration, particularly in the striatum and cortex. Despite the identification of its genetic basis over three decades ago, HD remains incurable, with current therapies largely limited to symptomatic management. This review provides a comprehensive overview of emerging pharmacological strategies targeting the underlying molecular and cellular mechanisms of HD, with emphasis on translational insights from recent and ongoing clinical trials. Key pathogenic processes, including protein aggregation, transcriptional dysregulation, impaired proteostasis, mitochondrial dysfunction, synaptic deficits, and chronic neuroinflammation, are discussed to contextualize therapeutic approaches. Genetargeting strategies, including Antisense Oligonucleotides (ASOs), RNA interference (RNAi), and small-molecule splicing modulators, have demonstrated effective suppression of mutant huntingtin expression and favorable biomarker responses. However, despite robust target engagement, these molecular effects have not consistently translated into sustained clinical benefit, highlighting the complexity of achieving disease modification in Huntington's disease. Similarly, therapies targeting neuroinflammation, autophagy, mitochondrial dysfunction, and synaptic signaling have shown encouraging preclinical efficacy but only limited clinical success. The review highlights the critical role of biomarkers, including cerebrospinal fluid mHTT, neurofilament light chain, and imaging markers, in evaluating therapeutic efficacy, while underscoring the uncertainty in their correlation with long-term clinical outcomes. Persistent challenges in clinical translation emphasize the need for precision-based, stage-specific therapeutic strategies to achieve meaningful disease modification. Unlike previous reviews, this article critically integrates recent clinical trial outcomes with translational challenges, biomarker validation, regulatory perspectives, and future precision-medicine strategies, providing a comprehensive overview of the evolving therapeutic landscape for Huntington's disease.