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

Adenoviridae Animals Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Dysfunction / genetics Electroencephalography Epilepsy, Temporal Lobe / complications Female Gene Editing / methods Hippocampus / metabolism Kv1.1 Potassium Channel / biosynthesis Male Membrane Potentials / genetics Mice Neurons / physiology Primary Cell Culture Transfection Up-Regulation
CRISPR epilepsy gene promoter gene therapy potassium channels

Journal

Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537

Informations de publication

Date de publication:
01 03 2020
Historique:
received: 23 08 2019
revised: 31 12 2019
accepted: 14 01 2020
pubmed: 5 3 2020
medline: 7 7 2020
entrez: 5 3 2020
Statut: ppublish

Résumé

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-clonic seizures in a model of temporal lobe epilepsy, and rescued cognitive impairment and transcriptomic alterations associated with chronic epilepsy. The focal treatment minimizes concerns about off-target effects in other organs and brain areas. This study provides the proof-of-principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability.

Identifiants

DOI: 10.1093/brain/awaa045 PMID: 32129831 PMC: PMC7089667
pubmed: 32129831
pii: 5780426
doi: 10.1093/brain/awaa045
pmc: PMC7089667
doi:

Substances chimiques

Kv1.1 Potassium Channel 147173-20-4

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

891-905

Subventions

Organisme : Medical Research Council
ID : MR/L01095X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L01095X/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 209807/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 212285/Z/18/Z
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

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Auteurs

Gaia Colasante (G)

San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.

Yichen Qiu (Y)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Luca Massimino (L)

San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.

Claudia Di Berardino (C)

San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.

Jonathan H Cornford (JH)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Albert Snowball (A)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Mikail Weston (M)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Steffan P Jones (SP)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Serena Giannelli (S)

San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.

Andreas Lieb (A)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Stephanie Schorge (S)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.
Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK.

Dimitri M Kullmann (DM)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Vania Broccoli (V)

San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.
CNR Institute of Neuroscience, Via Vanvitelli 32, 20129, Milan, Italy.

Gabriele Lignani (G)

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

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Classifications MeSH

Recherchemedicale.com › Virus › Virus à ADN › Adenoviridae › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Eucaryotes › Animaux › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées en tandem › Clustered regularly interspaced short palindromic repeats › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Diagnostic › Techniques et procédures diagnostiques › Électrodiagnostic › Électroencéphalographie › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Syndromes épileptiques › Épilepsie temporale › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Techniques d'investigation › Techniques génétiques › Génie génétique › Édition de gène › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Hippocampe › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux potassiques › Canaux potassiques voltage-dépendants › Canaux potassiques de la superfamille Shaker › Canal potassique Kv1.1 › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Potentiels de membrane › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Cellules › Neurones › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture cellulaire › Culture de cellules primaires › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Phénomènes génétiques › Recombinaison génétique › Transfection › In vivo CRISPRa decreases seizures and rescues...
Recherchemedicale.com › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › In vivo CRISPRa decreases seizures and rescues...