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,
M.A. Faghihi,
O. Khorkova,
C. Wahlestedt
Affiliations
J. Hsiao
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
T.Y. Yuan
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
M.S. Tsai
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
C.Y. Lu
Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan
Y.C. Lin
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
M.L. Lee
Dep. Clinical Laboratory Science and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
S.W. Lin
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
F.C. Chang
Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan
H. Liu Pimentel
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
C. Olive
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
C. Coito
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
G. Shen
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
M. Young
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
T. Thorne
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
M. Lawrence
RxGen, 100 Deepwood Drive, Hamden, CT 06517, USA
M. Magistri
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
M.A. Faghihi
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
O. Khorkova
OPKO Health Inc., 10320 USA Today Way, Miramar, FL 33025, USA
C. Wahlestedt
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
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.
