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.
| Original language | English |
|---|---|
| Pages (from-to) | 523-546 |
| Number of pages | 24 |
| Journal | EMBO Molecular Medicine |
| Volume | 16 |
| Issue number | 3 |
| Early online date | 19 Feb 2024 |
| DOIs | |
| State | Published - 14 Mar 2024 |
Bibliographical note
Publisher Copyright:© The Author(s) 2024.
Funding
We would like to thank Dr. Efrat Ben-Zeev from the Medicinal Chemistry unit of the Nancy and Stephen of G-INCPM (Weizmann Institute of Science) for performing the SAR-by-catalog search; The Crown Genomics Institute of the Nancy and Stephen G-INCPM and the iGE3 Genomic Platform of the University of Geneva for RNA-Seq services; Dr. Eviatar Weizman from the Mantoux Institute for Bioinformatics of the Nancy and Stephen G-INCPM for the RNA-Seq data analysis; Dr. Shelly Zinamon for her help and guidance with animal care and treatment; Dr. Yuri Kuznetsov for his help with animal perfusion technique; Science in Action company for performing the PK experiment; Bienta department in Enamine for the formulations screen service. This work was supported by external grants from The Israel Innovation Authority Kamin and from the Hereditary Disease Foundation and by Weizmann Institute internal grants from Dr. Barry Sherman Institute for Medicinal Chemistry; David and Fela Shapell Family Center for Genetic Disorders Research; Weizmann - Center for Research on Neurodegeneration; the Estate of Manfred and Margaret Tannen and Joel and Mady Dukler Fund for Cancer Research and a fellowship from the Society of Swiss Friends of the Weizmann Institute of Science to BW. MT is the incumbent of the Carolito Stiftung Research Fellow Chair in Neurodegenerative Diseases; YK is incumbent of the Sarah and Rolando Uziel Research Associate Chair; RD is the incumbent of the Ruth and Leonard Simon Chair of Cancer Research.
| Funders |
|---|
| Center for Research on Neurodegeneration |
| Society of Swiss Friends of the Weizmann Institute of Science |
| Hereditary Disease Foundation |
| Israel Innovation Authority |
Keywords
- DSIF
- Huntington’s Disease
- RNA Pol II
- Spt5
- Spt5-Pol II inhibitor