POSITION TITLE: Maurice H. Seevers Professor and Chair of Pharmacology, University of Michigan Medical School. DEGREE (if applicable)

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1 NAME: ISOM, LORI L. OMB No (Rev. 09/17 Approved Through 03/31/2020) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. era COMMONS USER NAME: LLISOM POSITION TITLE: Maurice H. Seevers Professor and Chair of Pharmacology, University of Michigan Medical School EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Washington University, St. Louis, MO Vanderbilt University, Nashville, TN University of Washington, Seattle, WA A.B. Ph.D. Postdoctoral 05/ / /1993 Chemistry, Biology Pharmacology Pharmacology A. Personal Statement I am the Maurice H. Seevers Professor and Chair of Pharmacology at the University of Michigan Medical School (UMMS). I am the PI and Director of the UM Pharmacological Sciences Training Program (T32) as well as a codirector of the UM Multidisciplinary Cardiovascular Research Training Program (T32). I have extensive experience in graduate education and lead a consistently funded, translational research program. Prior to becoming Chair of Pharmacology, I served for six years as Director of the UM Program in Biomedical Sciences (PIBS), an umbrella program that is a national leader in collaborative, diverse, interdisciplinary graduate education across multiple departments and colleges. I served for four years as UMMS Assistant Dean for Recruitment and Pre-Candidate Graduate Education, helping to set a national standard for innovative recruitment of highly qualified, diverse (including under-represented and differently-abled) students to 14 PhDgranting programs. I have established my reputation as an energetic and innovative leader in graduate education and mentoring. I wrote and promoted the UM Graduate Certificate in Translational Research, developed the UMMS Individualized Development Plan (IDP), participated in the Rackham graduate School Faculty Allies program, developed and directed multiple graduate courses including PHARM 502 (Introduction to Scientific Communication) and PIBS 800 (Seminars in Professional Development). I served for six years as Associate Director of the UM Postbaccalaureate Research and Education Program (PREP) for under-represented students. I served as a leader of the education team of the Ethiopia-Michigan Platform for Advancing Collaborative Engagement and am a member of the UMMS Academy for Educational Excellence and Scholarship. I was a recipient of the UM Distinguished Faculty Award and the Rackham Distinguished Graduate Mentoring Award. My consistently funded research program focuses on the mechanism of pediatric inherited epilepsy and cardiac arrhythmia due to mutations in genes encoding voltage-gated sodium channels. I am currently co-principal investigator on a NIH NINDS Center Without Walls U01 project involving 6 other US institutions. I am committed to the UM mission of training the next generation of physicians and scientists in translational research as well as those who choose other, non-academic career paths after their doctoral training. I am particularly proud of my trainees who have gone on to independent careers, including two who are Assistant Professors at medical schools and a number of others who are currently leading research groups in the pharmaceutical industry, developing innovative products in biotech, specializing in medical writing, working in public health, and teaching in an undergraduate institution. Over the past 21 years, my laboratory has trained 13 graduate students, 17 postdoctoral fellows or visiting scholars, and many undergraduates who have gone on to become successful MD, PhD, and MSTP students. In 2011, I was elected a fellow of the AAAS for my contributions to both Neuroscience and Graduate Education.

2 I have significant expertise in Na + channel biology and the role of Na + channels in disease. Starting with my postdoctoral work at the U of WA with Dr. W.A. Catterall, where I was the first to clone, sequence, and investigate the functions of Na + channel SCN1B and SCN2B (Isom et al, Science 256: , 1992; Isom et al, Cell. 83: , 1995), I have made significant contributions to the Na + channel field. My laboratory at the UM has investigated the multi-functional roles of Na + channel and subunits for the past >20 years. We have generated a number of Na + channel mutant mouse models, reported the first SCN1B mutation causing Dravet Syndrome (DS), and reported the first SCN1B epilepsy mutation in the 1B splice variant. My laboratory has expertise in electrophysiology, biochemistry, cell biology, immunofluorescence, electron microscopy, and genetics. I currently serve on the Scientific Advisory Board of the Dravet Syndrome Foundation. For the past 9 years I have collaborated with Dr. Parent, a clinical epileptologist, stem cell biologist, and neuroscientist who has been studying animal models of epilepsy and mechanisms of epileptogenesis for the past 19 years. His lab has successfully generated ipsc-derived forebrain neurons, cortical neurons, autonomic neurons, and cardiac myoyctes from the fibroblasts of a number of patients with DS and related epileptic encephalopathies caused by SCN1A, SCN8A, and SCN1B mutations, as well as from multiple human controls. Physiological data from these cells generated by our group have suggested previously unrecognized mechanisms for hyperexcitability in DS. We have also published our results of increased Na + current and arrhythmia in SCN1A-, SCN1B-, and SCN8A-linked mouse models of DS. This work is a critical component of a comprehensive and powerful translational program that offers great potential for advancing our understanding of epileptic encephalopathy and SUDEP mechanisms, biomarkers to define at-risk patients, and for the eventual development of preventative interventions. B. Positions and Honors Senior Fellow in Pharmacology, Univ. of WA, (laboratory of William A. Catterall, Ph.D.) Lecturer in Pharmacology, Univ. of WA Assistant Professor of Pharmacology, University of MI Medical School Associate Professor of Pharmacology with tenure, University of MI Medical School 2007-present Professor of Pharmacology, University of MI Medical School Associate Director, Program in Biomedical Sciences, University of MI Medical School Faculty Director, UMMS Postdoctoral Association, University of MI Medical School Director, Program in Biomedical Sciences, University of MI Medical School 2009-present Professor of Molecular and Integrative Physiology, University of MI Medical School Assistant Dean, Graduate Recruitment and Pre-Candidate Education, Univ. of MI Med Sch Interim Chair of Pharmacology, University of MI Medical School 2015-present Professor of Neurology, University of MI Medical School 2015-present Maurice H. Seevers Professor and Chair of Pharmacology, University of MI Medical School Other Experience and Professional Memberships Member, Society for Neuroscience Member, ASPET Member, American Physiological Society Member, UM Medical School Representative, AAMC GREAT Group National Multiple Sclerosis Society Scientific Review Panel B 2006 NIH, Electrical Signaling, Ion Transport, and Arrhythmias (ESTA) Study Section NSF Neuronal and Glial Mechanisms, Ad Hoc reviewer Member, American Epilepsy Society Editorial Board, Journal of Biological Chemistry Dravet Syndrome Foundation Scientific Advisory Board American Epilepsy Society Scientific Program Committee 2012, 2013 NIH, CNTN Special Emphasis Panel 2015 ZNS1 SRB-B 2015 Dept. of Veterans Affairs Summer Review 2015 CNNT Oct ZRG1CVRS-K (02) Dec ESTA, permanent member

3 Honors 2001 American Heart Association Established Investigator Award 2004 Ralph C. Wilson Jr. Medical Research Grant Program Award 2009 Alumni Lecturer Award, University of Washington Department of Pharmacology 2009 University of Michigan Distinguished Faculty Award 2011 Fellow, AAAS 2013 University of Michigan Rackham Graduate School Distinguished Graduate Mentoring Award 2015 Maurice H. Seevers Professorship in Pharmacology 2016 Elected, University of MI Medical School Executive Committee Theodore M. Brody Distinguished Lecturer, Michigan State University Department of Pharmacology and Toxicology C. Contribution to Science 1. As a postdoctoral fellow in the Catterall laboratory at the U of WA I was the first to clone, sequence, and express SCN1B and SCN2B, encoding the voltage-gated sodium channel 1 (1) and 2 (2) subunits, respectively. I showed that 1 and 2 chaperone sodium channel subunits to the plasma membrane and modulate sodium current density and voltage-dependence in heterologous systems. 1. Isom LL, De Jongh KS, Patton DE, Reber BFX, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA. Primary structure and functional expression of the 1 subunit of the rat brain sodium channel. Science. 1992;256: Isom LL, Ragsdale DS, De Jongh KS, Westenbroek RE, Reber BF, Scheuer T, Catterall WA. Structure and function of the 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell. 1995;83: I established my independent research program at the U of MI by demonstrating that, in addition to functioning as sodium channel modulators, 1 and 2 subunits are immunoglobulin superfamily cell adhesion molecules that participate in cell-cell communication (3), cell-matrix communication (4), recruitment of the cytoskeletal protein ankyrin (5), and neuite outgrowth (6). 1 subunits are substrates for fyn kinase and 1 tyrosine phosphorylation regulates its ability to associate with ankyrin. This body of work demonstrated that sodium channel subunits are multifunctional channel modulators and cell adhesion molecules that signal through multiple pathways on multiple time scales. 3. Malhotra JD, Kazen-Gillespie K, Hortsch M, Isom LL. Sodium channel subunits mediate homophilic cell adhesion and recruit ankyrin to points of cell-cell contact. J Biol Chem. 2000;275: Xiao Z-C, Ragsdale DS, Malhorta JD, Mattei LN, Braun PE, Schachner M, Isom LL. Tenascin-R is a functional modulator of sodium channel subunits. J Biol Chem. 1999;274: Malhotra JD, Koopmann MC, Kazen-Gillespie KA, Fettman N, Hortsch M, Isom LL. Structural requirements for interaction of sodium channel 1 subunits with ankyrin. J Biol Chem. 2002;277(29): Davis TH, Chen C, Isom LL. Sodium Channel β1 Subunits Promote Neurite Outgrowth In Cerebellar Granule Neurons. J Biol Chem. 2004;279: My laboratory developed the first Scn2b null mouse model (7). We demonstrated that Scn2b is critical for sodium channel subunit expression at the neuronal plasma membrane (7). In addition, we showed that Scn2b deletion is neuroprotective in a mouse model of multiple sclerosis (8). 7. Chen C, Bharucha V, Chen Y, Westenbroek RE, Brown A, Malhotra JD, Jones D, Avery C, Gillespie PJ, 3rd, Kazen-Gillespie KA, Kazarinova-Noyes K, Shrager P, Saunders TL, Macdonald RL, Ransom BR, Scheuer T, Catterall WA, Isom LL. Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits. Proc Natl Acad Sci U S A. 2002;99(26): PMCID: PMC O'Malley HA, Shreiner AB, Chen GH, Huffnagle GB, Isom LL. Loss of Na+ channel beta2 subunits is neuroprotective in a mouse model of multiple sclerosis. Mol Cell Neurosci. 2009;40(2): PMCID:

4 4. My laboratory developed the first Scn1b null mouse model (9). We were the first to report a human SCN1B mutation linked to the pediatric epileptic encephalopathy, Dravet Syndrome (DS), and to demonstrate that Scn1b null mice model DS with SUDEP (10). We were the first to clone and express the SCN1B splice variant, 1B, and the first to demonstrate that mutations in this splice variant are linked to human epilepsy (11). We showed that Scn1b deletion results in neuronal migration, proliferation, pathfinding, and fasciculation defects in brain that may contribute to neuronal hyperexcitability (12). Thus, we proposed that SCN1B-linked DS involves aberrant sodium current and cell-cell or cell-matrix adhesion. 9. Chen C, Westenbroek RE, Xu X, Edwards CA, Sorenson DR, Chen Y, McEwen DP, O'Malley HA, Bharucha V, Meadows LS, Knudsen GA, Vilaythong A, Noebels JL, Saunders TL, Scheuer T, Shrager P, Catterall WA, Isom LL. Mice lacking sodium channel beta1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture. J Neurosci. 2004;24(16): Patino GA, Claes LR, Lopez-Santiago LF, Slat EA, Dondeti RS, Chen C, O'Malley HA, Gray CB, Miyazaki H, Nukina N, Oyama F, De Jonghe P, Isom LL. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009;29(34): PMCID: Patino GA, Brackenbury WJ, Bao Y, Lopez-Santiago LF, O'Malley HA, Chen C, Calhoun JD, Lafreniere RG, Cossette P, Rouleau GA, Isom LL. Voltage-gated Na+ channel beta1b: a secreted cell adhesion molecule involved in human epilepsy. J Neurosci. 2011;31(41): PMCID: Brackenbury WJ, Yuan Y, O'Malley HA, Parent JM, Isom LL. Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b-null mice and precedes hyperexcitability. Proc Natl Acad Sci U S A. 2013;110(3): PMCID: In collaboration with Dr. Jack Parent, we reported one of the first human induced pluripotent stem cell neuron models of SCN1A-linked DS and suggested a previously unrecognized mechanism for hyperexcitability in DS that involves compensatory upregulation of sodium current in excitatory and inhibitory neurons (13). We were the first to demonstrate increased sodium current and arrhythmia in a mouse model of SCN1A-linked DS (14). In addition, we were the first to show that the SCN1B mouse model of DS exhibits changes in cardiac excitability and arrhythmia (15). Through this work, we have proposed that SUDEP involves arrhythmia in heart and brain. 13. Liu Y, Lopez-Santiago LF, Yuan Y, Jones JM, Zhang H, O'Malley HA, Patino GA, O'Brien JE, Rusconi R, Gupta A, Thompson RC, Natowicz MR, Meisler MH, Isom LL, Parent JM. Dravet syndrome patientderived neurons suggest a novel epilepsy mechanism. Ann Neurol. 2013;74(1): PMCID: Auerbach DS, Jones J, Clawson BC, Offord J, Lenk GM, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL. Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. PLoS One. 2013;8(10):e PMCID: PMC Lopez-Santiago LF, Meadows LS, Ernst SJ, Chen C, Malhotra JD, McEwen DP, Speelman A, Noebels JL, Maier SK, Lopatin AN, Isom LL. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol. 2007;43(5): PMCID: Complete List of Published Work in My Bibliography: n=ascending. D. Research Support ACTIVE U01 NS (J. Noebels) 08/01/ /31/2019 SUDEP Research Alliance: ipsc and Mouse Neurocardiac Models, Application 6 of 7 Application 6 of this SUDEP Research Alliance Centers Without Walls (CWOW) grant proposal, entitled ipsc and Mouse Neurocardiac Models, explores cardiac arrhythmia and autonomic dysfunction as potential causes of Sudden Unexplained Death in Epilepsy (SUDEP). The goals are to determine whether cardiac electrical and/or autonomic abnormalities underlie SUDEP in Dravet Syndrome and to identify biomarkers of SUDEP risk using patient-derived induced pluripotent stem cells, mouse models and clinical data. Role: Co-PI: Isom, Co-PI: Parent CURE SUDEP AWARD (Isom) 09/01/ /31/2017

5 Citizens United for Research in Epilepsy Patient-specific Induced Pluripotent Stem Cell Cardiac Myocytes as Predictors of SUDEP Risk The goals are to determine whether induced pluripotent stem cell-derived cardiac myoctyes from subjects with childhood epileptic encephalopathy due to SCN1B, SCN8A or CHD2 mutations show abnormalities that may predispose to arrhythmia and SUDEP. 1R01NS A1 02/15/ /31/2021 Discovering Epilepsy Mechanisms in Dravet Syndrome The objective of this project is to determine epilepsy mechanisms of SCN1A-linked DS in humans. We will test the central hypothesis that SCN1A haploinsufficiency paradoxically increases INa in excitatory and inhibitory cortical neurons, leading to both intrinsic and synaptic hyperexcitability in DS. Role: Co-PI: Isom, Co-PI: Parent Zogenix, Inc., 07/01/ /30/2017 Use of Dravet Syndrome patient-derived induced pluripotent stem cell cortical neurons to test the effect of ZX-008 on neuronal excitability This contract will use Dravet Syndrome and control patient-derived induced pluripotent stem cells to investigate ZX-008 and currently prescribed anti-epileptic drugs. Role: Co-PI: Lori Isom, Co-PI: Jack Parent 2T32GM /1/2016-6/30/2020 NIH/NIGMS Interdepartmental Training in Pharmacological Sciences The goal of this training program is designed to provide advanced training to students interested in pursuing research careers in the life sciences related to pharmacological research. The training provided to these future researchers will enable them to work on advances in medicine and human health related to drug therapy. 2R37NS A1 (Isom) 03/15/ /31/2021 Role of SCN1B in Inherited Epilepsy The goals are to use mouse models and patient-derived or genome-edited induced pluripotent stem cell models of SCN1B-related Dravet syndrome to discover epilepsy mechanisms. Stoke (Isom) 12/01/ /30/2018 Research Collaboration between the University of Michigan and Stoke Therapeutics The goals are to use antisense oligonucleotides to develop novel therapeutics for Dravet Syndrome.