On-demand cell-autonomous gene therapy for brain circuit disorders.
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
04 11 2022
04 11 2022
Historique:
entrez:
15
11
2022
pubmed:
16
11
2022
medline:
19
11
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36378958
doi: 10.1126/science.abq6656
pmc: PMC7613996
mid: EMS158742
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
523-532Subventions
Organisme : Wellcome Trust
ID : 212285
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V034758/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W005204/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_16063
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L01095X/1
Pays : United Kingdom
Organisme : MRF
ID : MRF_MRF-007-0004-STD-KULLM
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S011005/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V013556/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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