An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 03 2022
03 03 2022
Historique:
received:
21
10
2021
accepted:
27
01
2022
entrez:
4
3
2022
pubmed:
5
3
2022
medline:
14
4
2022
Statut:
epublish
Résumé
Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam's utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.
Identifiants
pubmed: 35241644
doi: 10.1038/s41467-022-28653-6
pii: 10.1038/s41467-022-28653-6
pmc: PMC8894458
doi:
Substances chimiques
Huntingtin Protein
0
Oligonucleotides, Antisense
0
Banques de données
ClinicalTrials.gov
['NCT02268552']
Types de publication
Clinical Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1150Informations de copyright
© 2022. The Author(s).
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