In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy.

Brain : a Journal of Neurology
Gaia ColasanteGabriele Lignani

Abstract

Epilepsy is a major health burden, calling for new mechanistic insights and therapies. CRISPR-mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex vivo. Its translational potential for treating non-genetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR, because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can effectively treat acquired focal epilepsy, focusing on ion channels because their manipulation is known be effective in changing network hyperactivity and hypersynchronziation. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video-EEG telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic-clo...Continue Reading

References

Mar 27, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Cristina RichichiAnnamaria Vezzani
Apr 29, 2006·Nature Genetics·Piero CarninciYoshihide Hayashizaki
May 15, 2008·Brain : a Journal of Neurology·Francesco NoèAnnamaria Vezzani
Sep 26, 2009·Disease Models & Mechanisms·Joost H HeeromaDimitri M Kullmann
Jun 23, 2011·PloS One·Kellen D WindenJerome Engel
Sep 9, 2011·The New England Journal of Medicine·Patrick KwanMartin J Brodie
Apr 21, 2012·Briefings in Bioinformatics·Helga ThorvaldsdóttirJill P Mesirov
Jun 12, 2012·Nature Medicine·Eva M Jimenez-MateosDavid C Henshall
Sep 1, 2012·Nature Protocols·Gerard M J BeaudoinJyothi Arikkath
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Nov 14, 2012·Science Translational Medicine·Robert C WykesDimitri M Kullmann
Jan 24, 2013·Nature Communications·Esther Krook-MagnusonIvan Soltesz
Oct 9, 2013·Epilepsy & Behavior : E&B·Michele Simonato
Nov 23, 2013·Nature Protocols·Marianne LegerThomas Freret
Jan 15, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lluis SamaranchKrystof S Bankiewicz
Mar 19, 2014·Nature Reviews. Neurology·Dimitri M KullmannRobert C Wykes
May 29, 2014·Nature Communications·Dennis KätzelDimitri M Kullmann
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Apr 24, 2015·Frontiers in Neuroinformatics·Gonçalo LopesAdam R Kampff
Jun 15, 2015·Journal of Neuroscience Methods·Robert C WykesVincent Magloire
Sep 16, 2015·Molecular and Cellular Biology·Marie F La Russa, Lei S Qi
Dec 15, 2015·Nature Reviews. Neuroscience·Matthias Heidenreich, Feng Zhang
Dec 17, 2015·Nature Reviews. Molecular Cell Biology·Antonia A DominguezLei S Qi
May 25, 2016·Current Gene Therapy·Atze T DasBen Berkhout
Sep 7, 2016·Nature Methods·Wei Leong ChewGeorge M Church
Nov 17, 2016·Nature·Keiichiro SuzukiJuan Carlos Izpisua Belmonte
Feb 15, 2017·Proceedings of the National Academy of Sciences of the United States of America·Umesh VivekanandaDimitri M Kullmann
May 6, 2017·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gareth MorrisGabriele Lignani
Jul 22, 2017·Frontiers in Neurology·Fei TangBjörn Bauer
Sep 9, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Giuseppe MorabitoVania Broccoli
Dec 12, 2017·Cell·Hsin-Kai LiaoJuan Carlos Izpisua Belmonte
May 17, 2018·Nature Communications·Mazhar Adli
Jul 11, 2018·Nature Medicine·Andreas LiebDimitri M Kullmann
Oct 23, 2018·Experimental Neurology·Nicole A HawkinsJennifer A Kearney
Jan 4, 2019·Nature Communications·Jichao SunSubhojit Roy

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Citations

Apr 26, 2020·International Journal of Molecular Sciences·Maria Cristina D'AdamoPaola Imbrici
Jul 18, 2020·Frontiers in Cellular Neuroscience·Gabriele LignaniVincenzo Marra
Sep 4, 2020·Journal of Neurochemistry·Thomas J TurnerGabriele Lignani
Feb 24, 2021·Disease Models & Mechanisms·Grant F MarshallCatherine M Abbott
Mar 27, 2021·Brain : a Journal of Neurology·Katerina HristovaAlfredo Gonzalez-Sulser
May 25, 2021·Epilepsy Currents·Jacy L Wagnon
Jun 29, 2021·Revue neurologique·T Marissal
May 18, 2021·Epilepsy Currents·Barbara C JobstWilliam Davis Gaillard
Jul 9, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jenna C Carpenter, Gabriele Lignani
Oct 30, 2021·Frontiers in Genome Editing·Amy McTagueManju A Kurian

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Datasets Mentioned

BETA
GSE133930

Methods Mentioned

BETA
PCR
classifier predictions
acetylation
RNAseq
transfection
RNA-Seq

Software Mentioned

Prism
ZEN
ENSEMBL
GraphPad
Open Source Instruments
R
custom
SPSS
Windows
Integrative Genome Viewer ( IGV )

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