BEGIN:VCALENDAR VERSION:2.0 PRODID:-//132.216.98.100//NONSGML kigkonsult.se iCalcreator 2.20.4// BEGIN:VEVENT UID:20250511T045233EDT-0507mBMdO6@132.216.98.100 DTSTAMP:20250511T085233Z DESCRIPTION:\nSupported by the generosity of the Killam Trusts\, The Neuro' s Killam Seminar Series invites outstanding guest speakers whose research is of interest to the scientific community at The Neuro and ºÚÁÏÍø Univers ity.\n\n\nZoom\n\nHost: Yang Zhou\n\n\nDeveloping Gene-Modifying Therapies for Dravet Syndrome\n\nLori L. Isom\n\nMaurice H. Seevers Professor and C hair of Pharmacology\, University of Michigan Medical School\n\nAbstract:  Dravet syndrome (DS) is a developmental and epileptic encephalopathy chara cterized by high seizure frequency and severity\, intellectual disability\ , and a high risk of SUDEP. Most DS patients carry de novo variants in SCN 1A leading to haploinsufficiency of the voltage-gated sodium channel ï¡ sub unit Nav1.1. Targeted Augmentation of Nuclear Gene Output (TANGO) is an an tisense oligonucleotide (ASO) technology that targets naturally occurring\ , non-productive alternative splicing events to reduce non-productive mRNA and increase productive mRNA and protein of the target gene by upregulati ng the wild-type allele. We showed that a single\, ICV dose at postnatal d ay (P)2 of ASO-22\, generated using TANGO technology to prevent inclusion of a nonsense-mediated decay exon in Scn1a\, exon 20N\, increased producti ve Scn1a transcript and Nav1.1 expression and reduced the incidence of ele ctrographic seizures and SUDEP in a DS mouse model. Next\, we investigated an ASO that also targets exon 20N\, ASO-84\, in DS mouse brain\, which ac ts as a surrogate for ASO-22. We tested the effects of a single ICV inject ion of ASO-84 at P2 on the electrophysiological properties of cortical pyr amidal and PV+ fast-spiking interneurons in Scn1a+/- DS and Scn1a+/+ wild- type littermate mice at P21-25. In untreated DS mice\, AP firing propertie s of cortical pyramidal neurons were unchanged compared to controls while AP firing properties of PV+ interneurons showed depolarization block. Sodi um current density was reduced in DS PV+ interneurons. The frequency\, but not amplitude\, of inhibitory post-synaptic currents in DS cortical pyram idal neurons was also reduced\, suggesting reduced GABA release from inter neurons. ASO-84 ASO administration restored excitability and sodium curren t density in PV+ DS interneurons and restored GABAergic signaling to corti cal pyramidal neurons. Our work provides key mechanisms for further develo pment of precision medicine approaches to treat patients with DS and relat ed developmental and epileptic encephalopathies.\n\n\n\nDr. Isom is the Ma urice H. Seevers Professor and Chair of the Department of Pharmacology\, P rofessor of Molecular and Integrative Physiology\, and Professor of Neurol ogy at the University of Michigan Medical School. She has served as Direct or of the Program in Biomedical Sciences and Assistant Dean for Graduate E ducation in the University of Michigan Medical School. She received her Ph D in Pharmacology at Vanderbilt University School of Medicine and then tra ined as a postdoctoral fellow in the laboratory of Dr. William A. Catteral l at the University of Washington. Dr. Isom’s research program at the Univ ersity of Michigan focuses on voltage-gated sodium channel function and th e roles of sodium channel gene variants in developmental and epileptic enc ephalopathy (DEE)\, including Dravet syndrome. Her lab investigates SCN1A\ , SCN1B\, and SCN8A DEE variants in mouse models and in human induced plur ipotent stem cell (iPSC) neurons and cardiac myocytes. They developed the first large transgenic animal model of Dravet syndrome\, a Scn1a haploinsu fficient rabbit. Their body of work has provided preclinical evidence for neuro-cardiac mechanisms of Sudden Unexpected Death in Epilepsy. Dr. Isom collaborated with Stoke Therapeutics to develop the first antisense oligon ucleotide precision therapeutic agent for Dravet syndrome\, which is now i n clinical trials. Dr. Isom is Co-PI of the NINDS-funded EpiMVP Center Wit hout Walls. She serves as PI of the NIH funded\, Pharmacological Sciences Training Program T32 grant\, co-chairs the Dravet Syndrome Foundation Scie ntific Advisory Board\, served on the Board of the American Epilepsy Socie ty\, co-chairs the American Epilepsy Society-NINDS Benchmarks committee\, chaired the NIH ESTA study section\, as well as served on editorial boards of scientific journals. She has received awards for research and mentorin g\, including a NINDS Javits R37 MERIT award and the University of Michiga n Rackham Distinguished Graduate Mentoring Award. She is a Fellow of the A merican Association for the Advancement of Science\, a Fellow of the Ameri can Society for Pharmacology and Experimental Therapeutics\, and a Fellow of the American Epilepsy Society. Dr. Isom was elected to the National Aca demy of Medicine in 2021 and received the American Epilepsy Society Basic Science Research Award in 2022.\n DTSTART:20250513T200000Z DTEND:20250513T210000Z LOCATION:Virtual | Zoom SUMMARY:[VIRTUAL] Killam Seminar Series: Developing Gene-Modifying Therapie s for Dravet Syndrome URL:/neuro/channels/event/virtual-killam-seminar-serie s-developing-gene-modifying-therapies-dravet-syndrome-365199 END:VEVENT END:VCALENDAR