Molecular and imaging biomarker responses to brain mutant HTT lowering in a mouse model of Huntington disease.

Therapies targeting mutant huntingtin (mHTT) reduction in the brain hold promise as disease-modifying treatments for Huntington disease (HD), necessitating biomarkers that accurately reflect treatment response. We evaluated candidate molecular and imaging biomarkers after mHTT reduction in YAC128 HD mice, with equal numbers of males and females per group. At 6 months of age, YAC128 mice received unilateral intracerebroventricular injections of saline or mHTT-lowering antisense oligonucleotide (HTT ASO). Plasma neurofilament light chain (NEFL) and glial fibrillary acidic protein (GFAP) were measured longitudinally from 6 to 12 months. Structural MRI was performed at 6, 9, and 12 months. At study endpoint, we quantified mHTT target engagement in the brain and performed striatal RNA sequencing. Treatment with HTT ASO produced a sustained reduction of mHTT levels throughout the brain for up to 6 months, significantly slowed plasma NEFL increases, and moderately attenuated GFAP elevation. Although mHTT levels inversely correlated with gray and white matter volumes, treatment did not significantly stabilize regional brain atrophy, highlighting an association between mHTT load and neuroanatomical integrity. HTT ASO also partially reversed striatal transcriptome dysregulation and restored oligodendrocyte-specific gene expression. Plasma NEFL, but not brain imaging, emerges as a sensitive and dynamic response biomarker for mHTT-lowering therapies.