@article{5b75b3422f0e4985bda9d7088c2d87fd,
title = "RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention",
abstract = "A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.",
author = "Donnelly, {Christopher J.} and Zhang, {Ping Wu} and Pham, {Jacqueline T.} and Heusler, {Aaron R.} and Mistry, {Nipun A.} and Svetlana Vidensky and Daley, {Elizabeth L.} and Poth, {Erin M.} and Benjamin Hoover and Fines, {Daniel M.} and Nicholas Maragakis and Tienari, {Pentti J.} and Leonard Petrucelli and Traynor, {Bryan J.} and Jiou Wang and Frank Rigo and Bennett, {C. Frank} and Seth Blackshaw and Rita Sattler and Rothstein, {Jeffrey D.}",
note = "Funding Information: This work was funded by grants from NIH (J.D.R.), P2ALS (J.D.R.), Muscular Dystrophy Association (J.D.R.), The Judith and Jean Pape Adams Charitable Foundation (R.S.), ALS Association (R.S.), the Johns Hopkins Brain Science Institute, The Ansari ALS Center for Cell Therapy and Regeneration Research at Johns Hopkins, The Alzheimer Drug Discovery Foundation and the Association for Frontotemporal Degeneration, The Finnish Academy, The Sigrid Juselius Foundation, the Helsinki University Central Hospital, Robert Packard Center for ALS Research, Maryland Stem Cell Research Fund (C.J.D.), Intramural Research Programs of the US National Institutes of Health (NIH) (B.T.), and National Institute on Aging (B.T.). We would like to thank the Johns Hopkins Deep Sequencing and Microarray Core for the valuable insight on high-throughput experimental design and analysis. Dr. Phillip Wong provided data analysis and interpretation. Dr. Lyle Ostrow provided human tissue demographics. Additional technical and reagent support was graciously provided by Meredith Davitt, Uma Balasubramanian, Conover Talbot Jr., Dr. Tania Gendron, and Dr. Jean-Phillipe Richard. J.D.R, R.S., C.J.D., F.R., and C.F.B. have patents pending on antisense therapeutics and associated genetic biomarkers. B.T. has patents pending for the diagnostic and therapeutic uses of the C9ORF72 hexanucleotide repeat expansion. The remaining authors have no competing financial interests. ",
year = "2013",
month = oct,
day = "16",
doi = "10.1016/j.neuron.2013.10.015",
language = "English (US)",
volume = "80",
pages = "415--428",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",
}