Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome
Journal
EBioMedicine
Journal Volume
9
Pages
257_277
Date Issued
2016
Author(s)
Hsiao J.
Yuan T.Y.
Tsai M.S.
Lu C.Y.
Lin Y.C.
Lee M.L.
Chang F.C.
Liu Pimentel H.
Olive C.
Coito C.
Shen G.
Young M.
Thorne T.
Lawrence M.
Magistri M.
Faghihi M.A.
Khorkova O.
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. ? 2016 The Authors
SDGs
Other Subjects
animal model; Article; electroencephalography; gene expression; gene sequence; genetic disorder; genetic transfection; human; human cell; human tissue; immunohistochemistry; molecular cloning; mouse; nonhuman; phenotype; priority journal; real time polymerase chain reaction; reverse transcription polymerase chain reaction; seizure; severe myoclonic epilepsy in infancy; skin biopsy; upregulation; allele; animal; animal behavior; antagonists and inhibitors; brain; cell line; chemistry; Chlorocebus aethiops; conformation; diagnostic imaging; disease model; gene targeting; genetics; hippocampus; in vitro study; interneuron; metabolism; molecular genetics; myoclonus epilepsy; nucleotide sequence; patch clamp technique; pathology; physiology; sequence alignment; sequence analysis; temperature; transgenic mouse; Vero cell line; videorecording; antisense oligonucleotide; long untranslated RNA; sodium channel Nav1.1; Alleles; Animals; Base Sequence; Behavior, Animal; Brain; Cell Line; Cercopithecus aethiops; Disease Models, Animal; Electroencephalography; Epilepsies, Myoclonic; Gene Expression; Gene Knock-In Techniques; Hippocampus; Humans; In Vitro Techniques; Interneurons; Mice; Mice, Transgenic; Molecular Sequence Data; NAV1.1 Voltage-Gated Sodium Channel; Nucleic Acid Conformation; Oligonucleotides, Antisense; Patch-Clamp Techniques; Phenotype; Real-Time Polymerase Chain Reaction; RNA, Long Noncoding; Sequence Alignment; Sequence Analysis, RNA; Temperature; Up-Regulation; Vero Cells; Video Recording
Type
journal article