A blood–brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome

Jessica A. Bush, Samantha M. Meyer, Rita Fuerst, Yuquan Tong, Yue Li, Raphael I. Benhamou, Haruo Aikawa, Patrick R.A. Zanon, Quentin M.R. Gibaut, Alicia J. Angelbello, Tania F. Gendron, Yong Jie Zhang, Leonard Petrucelli, Torben Heick Jensen, Jessica L. Childs-Disney, Matthew D. Disney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/ FTD. The RNA transcribed from the expansion, r(G4C2)exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G4C2)exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G4C2)exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

Original languageAmerican English
Article numbere2210532119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number48
DOIs
StatePublished - 29 Nov 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.

Keywords

  • RNA
  • RNA-targeted degradation
  • drug design
  • induced proximity
  • repeat expansion disorders

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