[VIRTUAL] Killam Seminar Series: Developing Gene-Modifying Therapies for Dravet Syndrome

Supported 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 黑料不打烊 University.

贬辞蝉迟:听Yang Zhou

Developing Gene-Modifying Therapies for Dravet Syndrome

Lori L. Isom

Maurice H. Seevers Professor and Chair of Pharmacology, University of Michigan Medical School

Abstract:听Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure frequency and severity, intellectual disability, and a high risk of SUDEP. Most DS patients carry de novo variants in SCN1A leading to haploinsufficiency of the voltage-gated sodium channel 飦� subunit Nav1.1. Targeted Augmentation of Nuclear Gene Output (TANGO) is an antisense 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 upregulating the wild-type allele. We showed that a single, ICV dose at postnatal day (P)2 of ASO-22, generated using TANGO technology to prevent inclusion of a nonsense-mediated decay exon in Scn1a, exon 20N, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic 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 acts as a surrogate for ASO-22. We tested the effects of a single ICV injection of ASO-84 at P2 on the electrophysiological properties of cortical pyramidal and PV+ fast-spiking interneurons in Scn1a+/- DS and Scn1a+/+ wild-type littermate mice at P21-25. In untreated DS mice, AP firing properties of cortical pyramidal neurons were unchanged compared to controls while AP firing properties of PV+ interneurons showed depolarization block. Sodium current density was reduced in DS PV+ interneurons. The frequency, but not amplitude, of inhibitory post-synaptic currents in DS cortical pyramidal neurons was also reduced, suggesting reduced GABA release from interneurons. ASO-84 ASO administration restored excitability and sodium current density in PV+ DS interneurons and restored GABAergic signaling to cortical pyramidal neurons. Our work provides key mechanisms for further development of precision medicine approaches to treat patients with DS and related developmental and epileptic encephalopathies.

Dr. Isom is the Maurice H. Seevers Professor and Chair of the Department of Pharmacology, Professor of Molecular and Integrative Physiology, and Professor of Neurology at the University of Michigan Medical School. She has served as Director of the Program in Biomedical Sciences and Assistant Dean for Graduate Education in the University of Michigan Medical School. She received her PhD in Pharmacology at Vanderbilt University School of Medicine and then trained as a postdoctoral fellow in the laboratory of Dr. William A. Catterall at the University of Washington. Dr. Isom鈥檚 research program at the University of Michigan focuses on voltage-gated sodium channel function and the roles of sodium channel gene variants in developmental and epileptic encephalopathy (DEE), including Dravet syndrome. Her lab investigates SCN1A, SCN1B, and SCN8A DEE variants in mouse models and in human induced pluripotent stem cell (iPSC) neurons and cardiac myocytes. They developed the first large transgenic animal model of Dravet syndrome, a Scn1a haploinsufficient 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 oligonucleotide precision therapeutic agent for Dravet syndrome, which is now in clinical trials. Dr. Isom is Co-PI of the NINDS-funded EpiMVP Center Without Walls. She serves as PI of the NIH funded, Pharmacological Sciences Training Program T32 grant, co-chairs the Dravet Syndrome Foundation Scientific Advisory Board, served on the Board of the American Epilepsy Society, 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 mentoring, including a NINDS Javits R37 MERIT award and the University of Michigan Rackham Distinguished Graduate Mentoring Award. She is a Fellow of the American Association for the Advancement of Science, a Fellow of the American Society for Pharmacology and Experimental Therapeutics, and a Fellow of the American Epilepsy Society. Dr. Isom was elected to the National Academy of Medicine in 2021 and received the American Epilepsy Society Basic Science Research Award in 2022.