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

Quynh-Anh Nguyen (), Peter M. Klein (), Cheng Xie, Katelyn N. Benthall, Jillian Iafrati, Jesslyn Homidan, Jacob T. Bendor, Barna Dudok, Jordan S. Farrell, Tilo Gschwind, Charlotte L. Porter, Annahita Keravala, G. Steven Dodson and Ivan Soltesz
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Quynh-Anh Nguyen: Stanford University
Peter M. Klein: Stanford University
Cheng Xie: CODA Biotherapeutics
Katelyn N. Benthall: CODA Biotherapeutics
Jillian Iafrati: CODA Biotherapeutics
Jesslyn Homidan: Stanford University
Jacob T. Bendor: CODA Biotherapeutics
Barna Dudok: Stanford University
Jordan S. Farrell: Stanford University
Tilo Gschwind: Stanford University
Charlotte L. Porter: Stanford University
Annahita Keravala: CODA Biotherapeutics
G. Steven Dodson: CODA Biotherapeutics
Ivan Soltesz: Stanford University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44853-8

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