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

doi:10.1126/science.abq6656

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 journal › Article › peer-review

70 Scopus citations

Abstract

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 language	English
Pages (from-to)	523-532
Number of pages	10
Journal	Science
Volume	378
Issue number	6619
DOIs	https://doi.org/10.1126/science.abq6656
State	Published - 4 Nov 2022
Externally published	Yes

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

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Qiu, Y., O’Neill, N., Maffei, B., Zourray, C., Almacellas-Barbanoj, A., Carpenter, J. C., Jones, S. P., Leite, M., Turner, T. J., Moreira, F. C., Snowball, A., Shekh-Ahmad, T., Magloire, V., Barral, S., Kurian, M. A., Walker, M. C., Schorge, S., Kullmann, D. M., & Lignani, G. (2022). On-demand cell-autonomous gene therapy for brain circuit disorders. Science, 378(6619), 523-532. https://doi.org/10.1126/science.abq6656

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title = "On-demand cell-autonomous gene therapy for brain circuit disorders",

abstract = "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.",

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

year = "2022",

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doi = "10.1126/science.abq6656",

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Qiu, Y, O’Neill, N, Maffei, B, Zourray, C, Almacellas-Barbanoj, A, Carpenter, JC, Jones, SP, Leite, M, Turner, TJ, Moreira, FC, Snowball, A, Shekh-Ahmad, T, Magloire, V, Barral, S, Kurian, MA, Walker, MC, Schorge, S, Kullmann, DM & Lignani, G 2022, 'On-demand cell-autonomous gene therapy for brain circuit disorders', Science, vol. 378, no. 6619, pp. 523-532. https://doi.org/10.1126/science.abq6656

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AU - Almacellas-Barbanoj, Amanda

AU - Carpenter, Jenna C.

AU - Jones, Steffan P.

AU - Leite, Marco

AU - Turner, Thomas J.

AU - Moreira, Francisco C.

AU - Snowball, Albert

AU - Shekh-Ahmad, Tawfeeq

AU - Magloire, Vincent

AU - Barral, Serena

AU - Kurian, Manju A.

AU - Walker, Matthew C.

AU - Schorge, Stephanie

AU - Kullmann, Dimitri M.

AU - Lignani, Gabriele

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

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