ArticleNeuron2016
Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.
Open access · bronzeAbstract read
In one paragraph
Article in Neuron, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 334 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
334citing papers in PubMed, 1 pooled it
42.0field-weighted citation impact, top 1% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
334 citing papers in PubMed, 1 synthesis or guideline pooled it, 535 citations in OpenAlex.
- Muscle MRI and Muscle Ultrasound Applications in MND/ALS: Academic Insights and Clinical Opportunities.European journal of neurology · 2026Pooled it
- Neural Stem Cell-Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis.Journal of extracellular vesicles · 2026Article
- Designing polymer-peptide conjugates to target dipeptide repeat aggregates implicated in amyotrophic lateral sclerosis.Journal of materials chemistry. B · 2026Article
- Intrathecal (GActa neuropathologica communications · 2026Article
- RAN translation as a dominant pathogenic axis in C9ORF72-associated ALS and FTD models.Molecular neurodegeneration · 2026Review
- Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.Nucleic acids research · 2026Article
- Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.Genes · 2026Review
- Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.Molecular psychiatry · 2026Article
- PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.International journal of molecular sciences · 2026Article
- Intrathecal (GbioRxiv : the preprint server for biology · 2026Article
- Blocking RAN translation without altering repeat RNAs rescuesScience (New York, N.Y.) · 2026Article
- Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases.International journal of molecular sciences · 2026Review
- Targeting Undruggable Proteins: The siRNA Revolution Beyond Small Molecules - Advances, Challenges, and Future Prospects in Therapeutic Innovation.Current gene therapy · 2026Review
- Additive value of early-phase β-Amyloid-PET for the differential diagnosis of non-Alzheimer's disease dementia.NeuroImage. Clinical · 2026Article
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
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- Comparison ofMolecular therapy. Nucleic acids · 2025Article
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- Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.Molecular neurobiology · 2025Article
- Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.Acta neuropathologica communications · 2025Article
274 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
41 authors at 9 institutions in 6 countries.
Jie JiangLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Qiang ZhuLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Tania F GendronDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Shahram SaberiDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Melissa McAlonis-DownesLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Amanda SeelmanLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Jennifer E StaufferDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Paymaan Jafar-NejadIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Kevin DrennerLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Derek SchulteDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Seung ChunIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Shuying SunLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Shuo-Chien LingLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Physiology, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore.
Brian MyersLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Jeffery EngelhardtIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Melanie KatzIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Michael BaughnLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Oleksandr PlatoshynDepartment of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; Neuroregeneration Laboratory, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
Martin MarsalaDepartment of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; Neuroregeneration Laboratory, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 9, 04001 Kosice, Slovakia.
Andy WattIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Charles J HeyserDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
M Colin ArdDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Louis De MuynckLaboratory of Neurobiology, Vesalius Research Center, Experimental Neurology, Department of Neurosciences, KU Leuven/VIB, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
Lillian M DaughrityDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Deborah A SwingMouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
Lino TessarolloMouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
Chris J JungChildren's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Arnaud DelpouxDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Daniel T UtzschneiderDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Stephen M HedrickDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Pieter J de JongChildren's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Dieter EdbauerGerman Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians University and Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen Strasse 17, 81377 Munich, Germany.
Philip Van DammeLaboratory of Neurobiology, Vesalius Research Center, Experimental Neurology, Department of Neurosciences, KU Leuven/VIB, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Christopher E ShawInstitute of Psychiatry, King's College London, London WC2R 2LS, UK.
C Frank BennettIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Sandrine Da CruzLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
John RavitsDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Frank RigoIonis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Don W ClevelandLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dcleveland@ucsd.edu.
Clotilde Lagier-TourenneLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: clagier-tourenne@mgh.harvard.edu.
University of California, San Diego · USLudwig Cancer Research · USIonis Pharmaceuticals (United States) · USMayo Clinic in Florida · USKU Leuven · BENational Cancer Institute · USKing's College London · GBMunich Cluster for Systems Neurology · DESanford Consortium for Regenerative Medicine · US
Funding
VIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BREWER, JAMES B · 1985 to 2018
$55.4MProject 3: Neuropathology of the multi-proteinopathy of c9FTD/ALS.P01NS084974 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2014 to 2024
$17.6MRole of Neurotrophins in the Development of the Mammalian Nervous SystemZIABC010390 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI TESSAROLLO, LINO · 2009 to 2025
$14.2MTransgenic Core FacilityZICBC010903 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI SWING, DEBORAH · 2009 to 2019
$10.2MTraining Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6MTRAINING IN THE NEUROPLASTICITY OF AGINGT32AG000216 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KOO, EDWARD H. · 1992 to 2017
$8.4MTDP-43, RNA Metabolism, and ALS/FTD PathologyR01NS063964 · NINDS · UNIVERSITY OF COLORADO · PI LINK, CHRISTOPHER D. · 2009 to 2019
$3.5MA molecular basis for control of T cell memoryR01AI103440 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HEDRICK, STEPHEN M · 2013 to 2017
$2.3MDeveloping ASO Therapy for Repeat Expanded C9orf72 ALS-FTDR01NS088578 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI RAVITS, JOHN · 2014 to 2018
$2.1MMisregulation of the TDP-43 RNA target, Sortilin, in neurodegenerationR01NS077402 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2011 to 2015
$1.7MSilencing C9or72 with rAAV Mediated RNAiR01NS088689 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI BROWN, ROBERT H., MUELLER, CHRISTIAN · 2014 to 2017
$1.6MUsing RNA signatures for therapy development in neurodegeneration due to C9orf72 expansionsR01NS087227 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI LAGIER-TOURENNE, CLOTILDE · 2014 to 2018
$1.5MNIAID NIH HHS R01 AI103440NIA NIH HHS P50 AG005131NIA NIH HHS T32 AG000216NIGMS NIH HHS T32 GM008666NINDS NIH HHS F32 NS087842NINDS NIH HHS K99 NS091538NINDS NIH HHS P01 NS084974NINDS NIH HHS R01 NS063964NINDS NIH HHS R01 NS077402NINDS NIH HHS R01 NS087227NINDS NIH HHS R01 NS088578NINDS NIH HHS R01 NS088689NINDS NIH HHS R21 NS084528NINDS NIH HHS R21 NS089979
Abstract
Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.
Indexed as
Amyotrophic Lateral SclerosisAnimalsC9orf72 ProteinDNA Repeat ExpansionFrontotemporal DementiaGuanine Nucleotide Exchange FactorsMice, TransgenicNeuronsOligonucleotides, AntisenseRNAC9orf72 ProteinC9orf72 protein, mouseGuanine Nucleotide Exchange FactorsOligonucleotides, AntisenseRNA
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