ArticleEMBO molecular medicine2024
Lowering mutant huntingtin by small molecules relieves Huntington's disease symptoms and progression.
Article in EMBO molecular medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 4 citations in OpenAlex.
- CAG-targeting artificial miRNA with reduced off-target risk for efficient lowering of pathogenic polyglutamine proteins.NAR molecular medicine · 2026Article
- Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.Current neuropharmacology · 2026Review
- Berberine can be a Potential Therapeutic Agent in Treatment of Huntington's Disease: A Proposed Mechanistic Insight.Molecular neurobiology · 2025Review
- Accurate Quantification of Mutant and Wild-Type polyQ Proteins Using Simple Western Capillary Immunoassays.Molecular neurobiology · 2025Article
- Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications.Signal transduction and targeted therapy · 2024Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is an incurable inherited disorder caused by a repeated expansion of glutamines in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological symptoms. Selective downregulation of the mutant Htt gene expression is considered the most promising therapeutic approach for HD. We report the identification of small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression, and improved motor and anxiety-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier. Prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutant Htt levels by small molecules can be an effective therapeutic strategy for HD.
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Registered trials
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