Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice.

Autor: Nguyen QA; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA. qanguyen@stanford.edu., Klein PM; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA. kleinp@stanford.edu., Xie C; CODA Biotherapeutics, 240 East Grand Ave., South San Francisco, CA, 94080, USA., Benthall KN; CODA Biotherapeutics, 240 East Grand Ave., South San Francisco, CA, 94080, USA., Iafrati J; CODA Biotherapeutics, 240 East Grand Ave., South San Francisco, CA, 94080, USA., Homidan J; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA., Bendor JT; CODA Biotherapeutics, 240 East Grand Ave., South San Francisco, CA, 94080, USA., Dudok B; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA.; Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA., Farrell JS; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA., Gschwind T; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA., Porter CL; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA., Keravala A; CODA Biotherapeutics, 240 East Grand Ave., South San Francisco, CA, 94080, USA., Dodson GS; CODA Biotherapeutics, 240 East Grand Ave., South San Francisco, CA, 94080, USA., Soltesz I; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jan 18; Vol. 15 (1), pp. 601. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1038/s41467-024-44853-8
Abstrakt: Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, are appealing methods to constrain overactive neuronal activity. We developed BARNI (Bradanicline- and Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled to an α1 glycine receptor anion pore domain. Here we demonstrate that BARNI activation by the clinical stage α7 nicotinic acetylcholine receptor-selective agonist bradanicline effectively suppressed targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of an inhibitory acetylcholine-based engineered channel activatable by both exogenous and endogenous agonists as a potential therapeutic approach to treating epilepsy.
(© 2024. The Author(s).)
Databáze: MEDLINE
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