Reprogramming transcription factor networks with a HOX inhibitor to address Huntington′s disease biology beyond mutant huntingtin

Huntington′s disease (HD) is an inherited neurodegenerative disorder caused by CAG-repeat expansion in the huntingtin ( HTT ) gene. Although inherited CAG-repeat length and the underlying somatic instability are key determinants of age at onset, they explain only part of onset variability, suggesting additional disease mechanisms. We applied the Core Coefficient (CC), a transcription-factor (TF) network-decoding technology that quantifies TF functional dominance, to >100 post-mortem neuronal transcriptomes from HD and control brain datasets. Among human TF families, the HOX family is the only family that uniformly exhibits quiescence in controls versus large and significant functional dominance in vulnerable neurons of each HD donor brain we investigated. HOX TFs are already dominant at Vonsattel grade 0 and at inherited CAG-repeat length. The magnitude of HOX CC values correlates with age at onset and increases with disease grade and CAG-Age Product. HOX TFs form a self-sustained pathological unit targeting >4,000 genes implicated in neuronal patterning, identity, stress, signaling, structure, and senescence. In zQ175 mice, abrogation of mutant huntingtin (mHTT) protein production only transiently attenuates HOX dominance and does not durably eliminate it. COR-H800, a HOX inhibitor, restored TF-network hierarchy toward wild type, normalizing the functional dominance of transcription factors involved in neuronal differentiation, cell-fate determination, and developmental patterning, and improved disease-relevant phenotypes in R6/2 mice. These findings support the direct selective inhibition of HOX TFs to address the aberrant transcriptional state that can persist despite mHTT lowering or somatic instability-targeted therapeutic interventions.