Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Clotilde Lagier-Tourenne, Michael Baughn, Frank Rigo, Shuying Sun, Patrick Liu, Hai Ri Li, Jie Jiang, Andrew T. Watt, Seung Chun, Melanie Katz, J. Qiu, Ying Sun, Shuo Chien Ling, Qiang Zhu, Magdalini Polymenidou, Kevin Drenner, Jonathan W. Artates, Melissa McAlonis-Downes, Sebastian Markmiller, Kasey R. HuttDonald P. Pizzo, J. Cady, Matthew B. Harms, Robert H. Baloh, Scott R. Vandenberg, Gene W. Yeo, Xiang Dong Fu, C. Frank Bennett, Don W. Cleveland, J. Ravits

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354 Scopus citations


Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.

Original languageEnglish (US)
Pages (from-to)E4530-E4539
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number47
StatePublished - Nov 19 2013

ASJC Scopus subject areas

  • General


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