Blocking somatic repeat expansion and lowering huntingtin via RNA interference synergize to prevent Huntingtons disease pathogenesis in mice
Belgrad, J.; Summers, A.; Landles, C.; Greene, J. R.; Hildebrand, S.; Knox, E.; Sapp, E.; Yamada, N.; Furgal, R.; Miller, R.; Osborne, G. F.; Chase, K.; Luu, E.; Freedman, J.; Bramato, B.; McHugh, N.; Benoit, V.; OReilly, D.; Greer, P.; Bates, G. P.; Vogt, T. F.; Lee, R.; Howland, D.; DiFiglia, M.; Aronin, N.; Khvorova, A.
Show abstract
Huntingtons 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding 98%
- PMS1 as a target for splice modulation to prevent somatic CAG repeat expansion in Huntington's disease 97%
- Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins 96%
Similar papers in this journal
- Single cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging and disease 96%
- Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration 94%
- Abnormal hyperactivity of specific striatal ensembles encodes distinct dyskinetic behaviors revealed by high-resolution clustering 94%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.