---
title: "VO659 antisense oligonucleotide reduces multiple mutant huntingtin proteins in Huntington's disease"
id: "biorxiv-6-vo659-a-cag-repeat-targeting-antisense-oligonucleotide-lowers-multiple"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-6-vo659-a-cag-repeat-targeting-antisense-oligonucleotide-lowers-multiple"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1?rss=1"
published_at: "2026-10-22T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# VO659 antisense oligonucleotide reduces multiple mutant huntingtin proteins in Huntington's disease
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-6-vo659-a-cag-repeat-targeting-antisense-oligonucleotide-lowers-multiple
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1?rss=1)
- **Published At:** 2026-10-22T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The preprint reports that **VO659**, a CAG repeat‑targeting antisense oligonucleotide (ASO), lowers several neurotoxic mutant huntingtin (**mHTT**) protein species by blocking translation. - Investigators observed an allele‑preferential, CAG repeat length‑dependent reduction in mHTT species; wild‑type HTT was relatively spared. - VO659 reduced **HTT1a** mRNA in HD fibroblasts carrying an ultra‑long CAG repeat, according to the authors. - The study team showed that VO659 blocked translation of HTT exon 1 overexpression constructs, including HTT1a and polyalanine repeat‑associated non‑AUG (RAN) proteins. - Data indicated a long tissue half‑life for VO659 in mouse brain, supporting the possibility of infrequent dosing. - The authors note a first‑in‑human, open‑label phase 1/2a trial (NCT05822908) is currently ongoing in HD patients. - This article is a preprint and has not been peer reviewed; the source did not report detailed clinical dosing, safety outcomes, or quantitative efficacy measures from human subjects. - Competing interests: multiple authors are employees of VICO Therapeutics BV and hold stock options; listed consultants received fees from industry.
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Bas Röttgering 1 VICO Therapeutics B.V., J.H. Oortweg 21, 2333CH Leiden, The Netherlands; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Bas%2BR%C3%B6ttgering%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=R%C3%B6ttgering%20B&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ABas%2BR%25C3%25B6ttgering%2B) * [ORCID record for Bas Röttgering](http://orcid.org/0000-0001-5241-3948 "Open in new tab") Rudie Weij 1 VICO Therapeutics B.V., J.H. Oortweg 21, 2333CH Leiden, The Netherlands; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Rudie%2BWeij%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Weij%20R&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ARudie%2BWeij%2B) * [ORCID record for Rudie Weij](http://orcid.org/0009-0006-3153-0137 "Open in new tab") Suzanne Bijl 1 VICO Therapeutics B.V., J.H. 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Oortweg 21, 2333CH Leiden, The Netherlands; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Nicole%2BDatson%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Datson%20N&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ANicole%2BDatson%2B) * [ORCID record for Nicole Datson](http://orcid.org/0000-0003-2887-0238 "Open in new tab") * For correspondence: nicole.datson@vicotx.com * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5893778/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5893778/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5893778/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5893778/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5893778/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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](https://www.biorxiv.org/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05822908&atom=%2Fbiorxiv%2Fearly%2F2026%2F10%2F22%2F2026.10.16.758452.atom)) 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. ### Competing Interest Statement B.R., R.W., S.B., R.V., J.T., L.T., C.B., N.D., are employees of VICO Therapeutics BV and have stock options. J.B.C has been paid consulting fees and has performed sponsored research for Wave Life Sciences, Skyhawk Therapeutics, Cajal Neuroscience, Ionis Pharmaceuticals, Alnylam, and Guidepoint. R.M.B has been paid consulting fees by Takeda. ## Funder Information Declared VICO Therapeutics BV Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC-ND 4.0 International license](http://creativecommons.org/licenses/by-nc-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. [Donate to openRxiv ](https://www.zeffy.com/en-US/donation-form/donate-to-make-a-difference-10981) [ Back to top](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1?rss=1#page) [ Previous](https://www.biorxiv.org/content/10.64898/2026.10.16.759120v1 "A brain-behavior generative model links individual brain dynamics to perceptual decisions") Posted October 22, 2026. [ Download PDF](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/10/22/2026.10.16.758452.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [Supplementary Material ](https://www.biorxiv.org/content/10.64898/2026.10.16.758452v1.supplementary-material) [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) VO659, a CAG repeat-targeting antisense oligonucleotide, lowers multiple neurotoxic mutan
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