Bragg, R. | bioRxiv Science

bioRxiv2026

VO659, a CAG repeat-targeting antisense oligonucleotide, lowers multiple neurotoxic mutant huntingtin proteins in Huntington's disease

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene, encoding an elongated polyglutamine stretch in the corresponding mutant HTT (mHTT) protein. HD pathogenesis is driven by multiple neurotoxic mHTT protein species, including HTT1a and repeat-associated non-AUG translation (RAN) proteins, which increase in expression as mutant CAG repeats lengthen due to somatic expansion. VO659 is an investigational CAG repeat-targeting antisense oligonucleotide (ASO) that lowers mHTT protein levels by blocking translation. Here, we show that VO659 allele-preferentially lowers levels of multiple neurotoxic mHTT protein species in a CAG repeat length-dependent manner, relatively sparing wild-type HTT, while becoming more efficacious as somatic expansion occurs. VO659 reduced HTT1a mRNA levels in HD fibroblasts with an ultra-long CAG repeat, blocked the translation of HTT1a and polyalanine-containing RAN proteins derived from HTT exon 1 overexpression constructs, and displayed a long tissue half-life in mouse brain, supporting an infrequent dosing regimen. A first-in-human, open-label phase 1/2a clinical trial (NCT05822908) is currently ongoing in HD patients. VO659's unique CAG repeat-dependent and allele-preferential mechanism of action holds promise for its therapeutic effect in HD patients by targeting multiple core neurotoxic proteins derived from (somatically) expanded mHTT CAG repeats, while sparing wild-type HTT expression.

neuroscience↗

bioRxiv2016

Genome-scale transcriptional regulatory network models for the mouse and human striatum predict roles for SMAD3 and other transcription factors in Huntington’s disease

Transcriptional changes occur presymptomatically and throughout Huntingtons Disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome-scale model for the target genes of 718 TFs in the mouse striatum by integrating a model of the genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and Htt allele-dependent gene expression changes in the mouse striatum, and replicated many of these associations in independent transcriptomic and proteomic datasets. Strikingly, many of these predicted target genes were also differentially expressed in striatal tissue from human disease. We experimentally validated a key model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found Htt allele-dependent changes in the genomic occupancy of SMAD3 and confirmed our models prediction that many SMAD3 target genes are down-regulated early in HD. Importantly, our study provides a mouse and human striatal-specific TRN and prioritizes a hierarchy of transcription factor drivers in HD.

systems biology↗