 Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical modelsYuanjing Liu,
Jean-Cosme Dodart,
Helene Tran,
Shaunna Berkovitch,
Maurine Braun,
Michael Byrne,
Ann F. Durbin,
Xiao Shelley Hu,
Naoki Iwamoto,
Hyun Gyung Jang,
Pachamuthu Kandasamy,
Fangjun Liu,
Kenneth Longo,
Jörg Ruschel,
Juili Shelke,
Hailin Yang,
Yuan Yin,
Amy Donner,
Zhong Zhong,
Chandra Vargeese () and
Robert H. Brown
Nature Communications, 2021, vol. 12, issue 1, 1-15 Abstract: Abstract A large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders. Date: 2021 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21112-8 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-021-21112-8 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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