Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.
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.
Ludwig 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.
Jie
J
Jiang
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Qiang
Q
Zhu
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Tania F
TF
Gendron
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Shahram
S
Saberi
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Melissa
M
McAlonis-Downes
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Amanda
A
Seelman
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Jennifer E
JE
Stauffer
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Paymaan
P
Jafar-Nejad
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Kevin
K
Drenner
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Derek
D
Schulte
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Seung
S
Chun
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Shuying
S
Sun
Ludwig 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.
Shuo-Chien
SC
Ling
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Brian
B
Myers
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Jeffery
J
Engelhardt
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Melanie
M
Katz
Ludwig 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.
Michael
M
Baughn
Department 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.
Oleksandr
O
Platoshyn
Department 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.
Martin
M
Marsala
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Andy
A
Watt
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Charles J
CJ
Heyser
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
M Colin
MC
Ard
Laboratory 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.
Louis
L
De Muynck
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Lillian M
LM
Daughrity
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
Deborah A
DA
Swing
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
Lino
L
Tessarollo
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Chris J
CJ
Jung
Department 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.
Arnaud
A
Delpoux
Department 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
DT
Utzschneider
Department 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
SM
Hedrick
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Pieter J
PJ
de Jong
German Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians University and Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen Strasse 17, 81377 Munich, Germany.
Dieter
D
Edbauer
Laboratory 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.
Philip
P
Van Damme
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Leonard
L
Petrucelli
Institute of Psychiatry, King's College London, London WC2R 2LS, UK.
Christopher E
CE
Shaw
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
C Frank
CF
Bennett
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Sandrine
S
Da Cruz
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
John
J
Ravits
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Frank
F
Rigo
Ludwig 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.
Don W
DW
Cleveland
Ludwig 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.
Clotilde
C
Lagier-Tourenne
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D057180:Frontotemporal Dementia / Q000188:drug therapy* / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism*
D000073885:C9orf72 Protein; C000606498:C9orf72 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D016376:Oligonucleotides, Antisense; D012313:RNA