Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(G4C2) repeat expansion in vitro and in vivo ALS models

Jessica A. Bush, Haruo Aikawa, Rita Fuerst, Yue Li, Andrei Ursu, Samantha M. Meyer, Raphael I. Benhamou, Jonathan L. Chen, Tanya Khan, Sarah Wagner-Griffin, Montina J. van Meter, Yuquan Tong, Hailey Olafson, Kendra K. McKee, Jessica L. Childs-Disney, Tania F. Gendron, Yongjie Zhang, Alyssa N. Coyne, Eric T. Wang, Ilyas YildirimKye Won Wang, Leonard Petrucelli, Jeffrey D. Rothstein, Matthew D. Disney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded G4C2 RNA repeat [r(G4C2)exp] in chromosome 9 open reading frame 72 (C9orf72), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(G4C2)exp. The compound was able to selectively bind r(G4C2)exp’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms. In c9ALS patient–derived spinal neurons, the compound selectively degraded the mutant C9orf72 allele with limited off-targets and reduced quantities of toxic dipeptide repeat proteins (DPRs) translated from r(G4C2)exp. In vivo work in a rodent model showed that abundance of both the mutant allele harboring the repeat expansion and DPRs were selectively reduced by this compound. These results demonstrate that targeted small-molecule degradation of r(G4C2)exp is a strategy for mitigating c9ALS/FTD-associated pathologies and studying disease-associated pathways in preclinical models.

Original languageAmerican English
Article numbereabd5991
JournalScience Translational Medicine
Issue number617
StatePublished - 27 Oct 2021
Externally publishedYes

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