Lowering mutant huntingtin by small molecules relieves Huntington's disease symptoms and progression.
EMBO Mol Med
; 16(3): 523-546, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-38374466
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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MEDLINE
Assunto principal:
Doença de Huntington
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article