Evidence map›Paper›PMID 40667291›Full record

ArticlebioRxiv : the preprint server for biology2025

Blocking somatic repeat expansion and lowering huntingtin via RNA interference synergize to prevent Huntington's disease pathogenesis in mice.

Jillian Belgrad, Ashley Summers, Christian Landles, Jonathan R Greene, Samuel Hildebrand, Emily Knox, Ellen Sapp, Nozomi Yamada, Raymond Furgal, Rachael Miller and 16 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors.

Jillian BelgradUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.ORCID 0000-0002-2577-2336
Ashley SummersUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Christian LandlesDepartment of Neurodegenerative Disease and Huntington's Disease Centre, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.
Jonathan R GreeneRancho Biosciences, LLC, San Diego, CA, USA, 92127.
Samuel HildebrandUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Emily KnoxUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Ellen SappMassachusetts General Hospital, Mass General Institute for Neurodegenerative Disease (MIND), Charleston, MA, USA, 02129.
Nozomi YamadaUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Raymond FurgalUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Rachael MillerUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.ORCID 0000-0002-4594-0640
Georgina F OsborneDepartment of Neurodegenerative Disease and Huntington's Disease Centre, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.
Kathryn ChaseUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Eric LuuUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Jason FreedmanUMass Chan Medical School, Program in Molecular Medicine, Worcester, MA, USA, 01605.
Brianna BramatoUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Nicholas McHughUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Vicky BenoitUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Daniel O'ReillyUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Paul GreerUMass Chan Medical School, Program in Molecular Medicine, Worcester, MA, USA, 01605.
Gillian P BatesDepartment of Neurodegenerative Disease and Huntington's Disease Centre, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.
Thomas F VogtCHDI Foundation, Princeton, NJ, USA, 08540.
Ramee LeeCHDI Foundation, Princeton, NJ, USA, 08540.
David HowlandCHDI Foundation, Princeton, NJ, USA, 08540.
Marian DiFigliaMassachusetts General Hospital, Mass General Institute for Neurodegenerative Disease (MIND), Charleston, MA, USA, 02129.
Neil AroninUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.
Anastasia KhvorovaUMass Chan Medical School, RNA Therapeutics Institute, Worcester, MA, USA, 01605.

Funding

Expanding the Chemical Diversity of Therapeutic OligonucleotidesR01NS104022 · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2025 to 2025
$688k
Training in the Molecular Basis of Autoimmunity and AutoinflammationT32AI132152 · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2025 to 2025
$250k
Modulation of Somatic Repeat Expansion as a Therapeutic Approach to Huntington's DiseaseF31NS132424 · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2025 to 2025
$6k
NIAID NIH HHS T32 AI132152NIA NIH HHS R56 AG089801NIH HHS S10 OD020012NIH HHS S10 OD036329NINDS NIH HHS F31 NS132424NINDS NIH HHS R01 NS104022
6 · The paper itself

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Two major molecular drivers-somatic expansion of inherited CAG repeats and toxic mutant HTT (mHTT) variants-lead to neuronal dysfunction. Despite multiple trials, HTT-lowering strategies have not shown meaningful clinical benefit. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MSH3 (a key regulator of somatic expansion), HTT, or both. In Q111 HD mice (>110 CAGs), which exhibit robust expansion, mHTT inclusions, and transcriptional dysregulation by 12 months, long-term MSH3 silencing blocked expansion, reduced inclusions, and reversed gene expression changes. HTT silencing alone had limited effect, but combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based co-silencing of MSH3 and HTT as a disease-modifying strategy for HD.

Identifiers

PMID40667291
PMCPMC12262703

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.