Abstracts

Expression of Two SCN1A Antisense RNAs in Brain Specimens of Children and Adolescents Suggest a Role for SCN1A Regulation

Abstract number : 1.082
Submission category : 2. Translational Research / 2A. Human Studies
Year : 2021
Submission ID : 1826076
Source : www.aesnet.org
Presentation date : 12/9/2021 12:00:00 PM
Published date : Nov 22, 2021, 06:51 AM

Authors :
ingo Borggraefe, MD - Ludwig Maximilians University, Munich; marius schneider – Metabolic Biochemistry, Biomedical Center Munich – Ludwig-Maximilians-University, Munich, Germany; Johanna Scheuermann – Metabolic Biochemistry, Biomedical Center Munich – Ludwig-Maximilians-University, Munich, GermanyUniversity of Munich; Veronika Mueller – Metabolic Biochemistry, Biomedical Center Munich – Ludwig-Maximilians-University, Munich, Germany; Miriam Vogt – ISAR Bioscience GmbH, Planegg, Germany.; antje hentrich – Munich Medical Research School – Ludwig-Maximilians-University, Munich, Germany; Thomas Kremer – Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, – F Hoffmann-La Roche Ltd., Basel, Switzerland; Sebastian lugert – Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel – F Hoffmann-La Roche Ltd., Basel, Switzerland; Friedrich Metzger – Versameb AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland; Manfred Kudernatsch – Clinic for Neurosurgery, Schoen-Klinik Vogtareuth, Germany.; Gerhard Kluger – Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen-Klinik Vogtareuth, Germany and Paracelsus Medical University, Salzburg, Austria; Till Harlieb – Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen-Klinik Vogtareuth, Germany and Paracelsus Medical University, Salzburg, Austria; Soheyl Noachtar – Department of Neurology and Epilepsy Center – Ludwig-Maximilians-University, Munich, Germany; christian Vollmar – Department of Neurology and Epilepsy Center – Ludwig-Maximilians-University of Munich, Germany; Mathias Kunz – Department of Neurosurgery – Ludwig-Maximilians-University, Munich, Germany; Joerg Tonn – Department of Neurosurgery – Ludwig-Maximilians-University, Munich, Germany; Roland Coras – Department of Neurpathology – University of Erlangen; Ingmar Blümcke – Department of Neuropathology – University of Erlangen; Claudia Pace – Institute of Pharmacology, Toxicology, and Pharmacy – Ludwig-Maximilians-University, Munich, Germany; Florian Heinen – Division of Pediatric Neurology, Developmental Medicine Social Pediatrics, Department of Pediatrics – Ludwig-Maximilians-University, Munich, Germany; Christoph Klein – Department of Pediatrics – Ludwig-Maximilians-University, Munich, Germany; Heidrun Potschka – Institute of Pharmacology, Toxicology, and Pharmacy – Ludwig-Maximilians-University, Munich, Germany

Rationale: Enhancing SCN1A gene expression by antisense oligonucleotides directed against Cis-acting SCN1A related long non-coding RNAs was recently shown to ameliorate the sodium channel dysfunction both in vitro and in a mouse model of Dravet syndrome (DS). The aim of the present study was to gain information about the expression of this potential target antisense RNAs during brain development and across the age range, and about its regional distribution in different brain areas.

Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues through different age groups in pediatric patients who underwent surgery for drug resistant epilepsy. RNA from brain tissues was extracted and isolated according to previously described protocols. Levels of mRNA of SCN1A and its related lncRNA RNAs SCN1A-dsAS (downstream antisense) and lncRNA SCN1A-usAS (upstream antisense) were evaluated by quantitative RT-PCR.

Results: We investigated brain specimens of a total of 18 patients (for summary of demographic data, see the table). The SCN1A related antisense RNAs SCN1A-dsAS and SCN1A-usAS were widely expressed within the brain of pediatric patients (Fig A-C). Expression patterns revealed a negative correlation of SCN1A-dsAS (R2=0.52, p< 0.001) and a positive correlation of lncRNA SCN1A-usAS (R2=0.52, p< 0.001) with SCN1A mRNA. We detected no difference in the expression patterns of SCN1A, SCN1A-dsAS and SCN1A-usAS with respect to lobar location and sex. Furthermore, there was no correlation of either transcript expression with age at surgery, age of epilepsy onset and epilepsy duration.

Conclusions: The present findings suggest a role of SCN1A-dsAS in suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, our data support SCN1A-dsAS as an interesting target candidate for the development of antisense oligonucleotide (AntagoNAT) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

Funding: Please list any funding that was received in support of this abstract.: This study was funded by Roche Ltd, Basel, Switzerland.

Translational Research