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

J. Hsiao, T. Y. Yuan, M. S. Tsai, C. Y. Lu, Y. C. Lin, M. L. Lee, S. W. Lin, F. C. Chang, H. Liu Pimentel, C. Olive, C. Coito, G. Shen, M. Young, T. Thorne, M. Lawrence, M. Magistri, Mohammad A Faghihi, O. Khorkova, Claes R Wahlestedt

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StateAccepted/In press - Apr 7 2016

Fingerprint

Long Noncoding RNA
Myoclonic Epilepsy
Gene expression
Brain
Inborn Genetic Diseases
Seizures
Up-Regulation
Voltage-Gated Sodium Channels
Phenotype
Gene Expression
Untranslated RNA
Oligonucleotides
Antisense RNA
Genes
Brain Diseases
Interneurons
Primates
Alleles
Mutation
Therapeutics

Keywords

  • AntagoNAT
  • Dravet syndrome
  • Long non-coding RNA
  • Natural antisense transcript
  • Oligonucleotide-based compound
  • SCN1A

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome. / Hsiao, J.; Yuan, T. Y.; Tsai, M. S.; Lu, C. Y.; Lin, Y. C.; Lee, M. L.; Lin, S. W.; Chang, F. C.; Liu Pimentel, H.; Olive, C.; Coito, C.; Shen, G.; Young, M.; Thorne, T.; Lawrence, M.; Magistri, M.; Faghihi, Mohammad A; Khorkova, O.; Wahlestedt, Claes R.

In: EBioMedicine, 07.04.2016.

Research output: Contribution to journalArticle

Hsiao, J, Yuan, TY, Tsai, MS, Lu, CY, Lin, YC, Lee, ML, Lin, SW, Chang, FC, Liu Pimentel, H, Olive, C, Coito, C, Shen, G, Young, M, Thorne, T, Lawrence, M, Magistri, M, Faghihi, MA, Khorkova, O & Wahlestedt, CR 2016, '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. https://doi.org/10.1016/j.ebiom.2016.05.011
Hsiao, J. ; Yuan, T. Y. ; Tsai, M. S. ; Lu, C. Y. ; Lin, Y. C. ; Lee, M. L. ; Lin, S. W. ; Chang, F. C. ; Liu Pimentel, H. ; Olive, C. ; Coito, C. ; Shen, G. ; Young, M. ; Thorne, T. ; Lawrence, M. ; Magistri, M. ; Faghihi, Mohammad A ; Khorkova, O. ; Wahlestedt, Claes R. / Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome. In: EBioMedicine. 2016.
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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.",
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AU - Khorkova, O.

AU - Wahlestedt, Claes R

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