Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome

EBioMedicine. 2016 Jul;9:257-277. doi: 10.1016/j.ebiom.2016.05.011. Epub 2016 May 13.

Abstract

Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.

Keywords: AntagoNAT; Dravet syndrome; Long non-coding RNA; Natural antisense transcript; Oligonucleotide-based compound; SCN1A.

MeSH terms

  • Alleles
  • Animals
  • Base Sequence
  • Behavior, Animal
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Cell Line
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Electroencephalography
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / metabolism
  • Epilepsies, Myoclonic / pathology*
  • Gene Expression
  • Gene Knock-In Techniques
  • Hippocampus / physiology
  • Humans
  • In Vitro Techniques
  • Interneurons / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • NAV1.1 Voltage-Gated Sodium Channel / chemistry
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • NAV1.1 Voltage-Gated Sodium Channel / metabolism*
  • Nucleic Acid Conformation
  • Oligonucleotides, Antisense / metabolism
  • Patch-Clamp Techniques
  • Phenotype
  • RNA, Long Noncoding / antagonists & inhibitors
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Sequence Alignment
  • Sequence Analysis, RNA
  • Temperature
  • Up-Regulation
  • Vero Cells
  • Video Recording

Substances

  • NAV1.1 Voltage-Gated Sodium Channel
  • Oligonucleotides, Antisense
  • RNA, Long Noncoding