title: Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.
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.
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hsiao
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: T Y
authors.initials: TY
authors.lastname: Yuan
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd., Taipei 100, Taiwan.
authors.forename: M S
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan.
authors.forename: C Y
authors.initials: CY
authors.lastname: Lu
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Dep. Clinical Laboratory Science and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: M L
authors.initials: ML
authors.lastname: Lee
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd., Taipei 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 7, Chung-Shan S. Rd., Taipei 100, Taiwan; Center for Genomic Medicine, National Taiwan University, No. 7, Chung-Shan S. Rd., Taipei 100, Taiwan.
authors.forename: S W
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd., Taipei 100, Taiwan; Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: F C
authors.initials: FC
authors.lastname: Chang
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu Pimentel
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: C
authors.initials: C
authors.lastname: Olive
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: C
authors.initials: C
authors.lastname: Coito
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: G
authors.initials: G
authors.lastname: Shen
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: M
authors.initials: M
authors.lastname: Young
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: T
authors.initials: T
authors.lastname: Thorne
authors.affiliation: RxGen, 100 Deepwood Drive, Hamden, CT 06517, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: Center for Therapeutic Innovation and the Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami 33136, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Magistri
authors.affiliation: Center for Therapeutic Innovation and the Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami 33136, FL, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Faghihi
authors.affiliation: OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: O
authors.initials: O
authors.lastname: Khorkova
authors.affiliation: Center for Therapeutic Innovation and the Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami 33136, FL, USA. Electronic address: CWahlestedt@med.miami.edu.
authors.forename: C
authors.initials: C
authors.lastname: Wahlestedt
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA; D013696:Temperature; D015854:Up-Regulation; D014709:Vero Cells; D014741:Video Recording
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding
keywords: AntagoNAT; Dravet syndrome; Long non-coding RNA; Natural antisense transcript; Oligonucleotide-based compound; SCN1A