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

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

Science (American Association for the Advancement of Science), 2022-11, Vol.378 (6619), p.523-532 [Periódico revisado por pares]

United States: The American Association for the Advancement of Science

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Título:
On-demand cell-autonomous gene therapy for brain circuit disorders
Autor: Qiu, Yichen ; O'Neill, Nathanael ; Maffei, Benito ; Zourray, Clara ; Almacellas-Barbanoj, Amanda ; Carpenter, Jenna C ; Jones, Steffan P ; Leite, Marco ; Turner, Thomas J ; Moreira, Francisco C ; Snowball, Albert ; Shekh-Ahmad, Tawfeeq ; Magloire, Vincent ; Barral, Serena ; Kurian, Manju A ; Walker, Matthew C ; Schorge, Stephanie ; Kullmann, Dimitri M ; Lignani, Gabriele
Assuntos: Animals ; Brain ; Brain - metabolism ; Circuits ; Closed loops ; Epilepsy ; Epilepsy - genetics ; Epilepsy - therapy ; Excitability ; Gene therapy ; Genetic Therapy ; Humans ; KCNA1 protein ; Kv1.1 Potassium Channel - genetics ; Mental disorders ; Mice ; Neurons ; Neurons - physiology ; Potassium ; Seizures - genetics ; Seizures - metabolism ; Seizures - therapy ; Switches
É parte de: Science (American Association for the Advancement of Science), 2022-11, Vol.378 (6619), p.523-532
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Present address: Department of Pharmaceutics, The Hebrew University of Jerusalem, Jerusalem, Israel.
Descrição: 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.
Editor: United States: The American Association for the Advancement of Science
Idioma: Inglês

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

United States: The American Association for the Advancement of Science

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