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

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

  • Sci Transl Med. 2021 Oct 27;13(617):eabd5991. doi: 10.1126/scitranslmed.abd5991.
Jessica A Bush 1,  Haruo Aikawa 1,  Rita Fuerst 1,  Yue Li 1,  Andrei Ursu 1,  Samantha M Meyer 1,  Raphael I Benhamou 1,  Jonathan L Chen 1,  Tanya Khan 1,  Sarah Wagner-Griffin 1,  Montina J Van Meter 1,  Yuquan Tong 1,  Hailey Olafson 2,  Kendra K McKee 2,  Jessica L Childs-Disney 1,  Tania F Gendron 3,  Yongjie Zhang 3,  Alyssa N Coyne 4,  Eric T Wang 2,  Ilyas Yildirim 5,  Kye Won Wang 5,  Leonard Petrucelli 3,  Jeffrey D Rothstein 4,  Matthew D Disney 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
  • 2 Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
  • 3 Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
  • 4 Robert Packard Center for ALS Research, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
  • 5 Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL 33458, USA.
PMID: 34705518 DOI: 10.1126/scitranslmed.abd5991
Abstract

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.

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