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PreprintCC BY-NC-NDbioRxiv

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

  • B. Röttgering
  • R. Weij
  • S. Bijl
  • R. Verheul
  • J. Testerink
  • L. Toonen
  • R. Bragg
  • J. B. Carroll
  • C. Beekman
  • N. Datson1
  1. 1VICO Therapeutics B.V., J.H. Oortweg 21, 2333CH Leiden, The Netherlands
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@misc{rottgering2026vo659,
  title = {{VO659, a CAG repeat-targeting antisense oligonucleotide, lowers multiple neurotoxic mutant huntingtin proteins in Huntington's disease}},
  author = {B. Röttgering and R. Weij and S. Bijl and R. Verheul and J. Testerink and L. Toonen and R. Bragg and J. B. Carroll and C. Beekman and N. Datson},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.16.758452},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - VO659, a CAG repeat-targeting antisense oligonucleotide, lowers multiple neurotoxic mutant huntingtin proteins in Huntington's disease
AU  - B. Röttgering
AU  - R. Weij
AU  - S. Bijl
AU  - R. Verheul
AU  - J. Testerink
AU  - L. Toonen
AU  - R. Bragg
AU  - J. B. Carroll
AU  - C. Beekman
AU  - N. Datson
PY  - 2026
DA  - 2026/10/16
PB  - bioRxiv
DO  - 10.64898/2026.10.16.758452
UR  - https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1
AB  - 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.
ER  -