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.
authors.affiliation: Department of Neurology, Johns Hopkins University, 855 N Wolfe Street, Rangos 2-270, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University, 855 N Wolfe Street, Rangos 2-270, Baltimore, MD 21205, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Donnelly
authors.forename: Ping-Wu
authors.initials: PW
authors.lastname: Zhang
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Pham
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Haeusler
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Heusler
authors.forename: Nipun A
authors.initials: NA
authors.lastname: Mistry
authors.forename: Svetlana
authors.initials: S
authors.lastname: Vidensky
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Daley
authors.forename: Erin M
authors.initials: EM
authors.lastname: Poth
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hoover
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fines
authors.forename: Nicholas
authors.initials: N
authors.lastname: Maragakis
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.forename: Rita
authors.initials: R
authors.lastname: Sattler
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000073885:C9orf72 Protein; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D057180:Frontotemporal Dementia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D016601:RNA-Binding Proteins; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D016376:Oligonucleotides, Antisense; D011506:Proteins; D016601:RNA-Binding Proteins; D018698:Glutamic Acid; D012313:RNA; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase