In Vivo CRISPRa Decreases Seizures and Rescues Cognitive Deficits in a Rodent Model of Epilepsy

Overview

Journal Brain

Publisher Oxford University Press

Specialty Neurology

Date 2020 Mar 5

PMID 32129831

Citations 57

Authors

Gaia Colasante

Yichen Qiu

Luca Massimino

Claudia Di Berardino

Jonathan H Cornford

Albert Snowball

Mikail Weston

Steffan P Jones

Serena Giannelli

Andreas Lieb

Stephanie Schorge

Dimitri M Kullmann

Vania Broccoli

Gabriele Lignani

Affiliations

Soon will be listed here.

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-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.

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