2. Academic Validation
  3. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death

Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death

  • Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E8077-E8085. doi: 10.1073/pnas.1804764115.
Kay L Richards 1,  Carol J Milligan 1,  Robert J Richardson 1,  Nikola Jancovski 1,  Morten Grunnet 2 3,  Laura H Jacobson 4 5,  Eivind A B Undheim 6,  Mehdi Mobli 6,  Chun Yuen Chow 7,  Volker Herzig 7,  Agota Csoti 8,  Gyorgy Panyi 8,  Christopher A Reid 1 9,  Glenn F King 10,  Steven Petrou 11 9
Affiliations

Affiliations

  • 1 Ion Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
  • 2 Neuroscience Drug Discovery, H. Lundbeck A/S, DK-2500 Valby, Denmark.
  • 3 Department of Drug Design and Pharmacology, Copenhagen University, DK-2100 Copenhagen, Denmark.
  • 4 Sleep and Cognition Group, Epilepsy Division, Florey Insitute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
  • 5 Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 6 Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 7 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 8 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
  • 9 Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 10 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; [email protected] [email protected].
  • 11 Ion Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia; [email protected] [email protected].
PMID: 30076230 DOI: 10.1073/pnas.1804764115
Abstract

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated Sodium Channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.

Keywords

Dravet syndrome; genetic epilepsy; seizures; spider venom; targeted drug therapy.

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