On-demand cell-autonomous gene therapy for brain circuit disorders

Yichen Qiu, Nathanael O’Neill, Benito Maffei, Clara Zourray, Amanda Almacellas-Barbanoj, Jenna C. Carpenter, Steffan P. Jones, Marco Leite, Thomas J. Turner, Francisco C. Moreira, Albert Snowball, Tawfeeq Shekh-Ahmad, Vincent Magloire, Serena Barral, Manju A. Kurian, Matthew C. Walker, Stephanie Schorge, Dimitri M. Kullmann*, Gabriele Lignani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and “healthy” surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy. We used an immediate early gene promoter to drive the expression of Kv1.1 potassium channels specifically in hyperactive neurons, and only for as long as they exhibit abnormal activity. Neuronal excitability was reduced by seizure-related activity, leading to a persistent antiepileptic effect without interfering with normal behaviors. Activity-dependent gene therapy is a promising on-demand cell-autonomous treatment for brain circuit disorders.

Original languageAmerican English
Pages (from-to)523-532
Number of pages10
Issue number6619
StatePublished - 4 Nov 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.


Dive into the research topics of 'On-demand cell-autonomous gene therapy for brain circuit disorders'. Together they form a unique fingerprint.

Cite this