Milestone 1: To provide leadership and expertise for the planning, development, coordination, and overall administration of EpiMVP.
Drs. Isom and Parent co-direct the Administrative Core and are responsible for the fiscal administration of the program. They also oversee the distribution of scientific core resources to the Projects, manage the website, coordinate investigator and Steering Committee meetings, provide fiscal oversight and reporting, assure compliance with all guidelines of participating institutions and NIH by each Project and Core and manage interactions with the External Scientific Advisory Committee.
Milestone 2: To oversee reporting of CWOW activities within its membership and to NINDS and to disseminate information regarding EpiMVP findings to a broad constituency, from scientists to clinicians to patients and families.
Presenting findings from EpiMVP projects to the research community, healthcare professionals, and patients/families is our priority.
Milestone 3: To help train and mentor the next generation of scientists to advance the understanding and treatment of genetic epilepsies.
EpiMVP synergizes outstanding teams of mentors and mentees, indicative of the very strong historical track record of our group in the mentoring of graduate students, postdoctoral fellows and junior faculty. We will use EpiMVP resources to expand this mentorship to additional postdoctoral trainees.
Lori L. Isom, PhD
Co-PI and Co-Director of EpiMVP, is the Maurice H. Seevers Professor and Chair of Pharmacology at Michigan Medicine, as well as the PI and Director of the U-M Pharmacological Sciences Training Program. Prior to becoming Chair of Pharmacology, she served as Director of the U-M Program in Biomedical Sciences (PIBS), an umbrella program that is a national leader in collaborative, diverse, interdisciplinary graduate education across multiple departments and colleges. She also served for four years as Michigan Medicine Assistant Dean for Recruitment and Pre-Candidate Graduate Education, helping to set a national standard for innovative recruitment of highly qualified, diverse (including underrepresented and differently abled) students to 14 PhD-granting programs.
Isom’s research program focuses on the mechanism of pediatric inherited epilepsy and cardiac arrhythmia due to mutations in genes encoding voltage-gated sodium channels. She is committed to the U-M 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. She is particularly proud of her 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 25 years, her laboratory has trained 16 predoctoral students, 16 postdoctoral fellows, 8 visiting scholars, 5 master’s degree students, 1 PREP student and more than 30 undergraduate researchers who have gone on to become successful MD, PhD and MSTP students.
In 2011, she was elected a fellow of the AAAS for her contributions to both Neuroscience and Graduate Education. In addition, she serves as a permanent member and chair of the Electrical Signaling, Ion Transport and Arrhythmias (ESTA) study section. Isom has significant expertise in Na+ channel biology and the role of Na+ channels in disease.
Starting with her postdoctoral work at the Univ. of Washington with Dr. W.A. Catterall, where she was the first to clone, sequence, and investigate the functions of Na+ channel SCN1B and SCN2B, she has made significant contributions to the Na+ channel field. Her laboratory has investigated the multi-functional roles of Na+ channel α and β subunits for the past >24 years. They 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 β1B splice variant. Her laboratory has expertise in electrophysiology, biochemistry, cell biology, immunofluorescence, electron microscopy, and genetics. She currently serves with Dr. Parent as Co-Chair of the Scientific Advisory Board of the Dravet Syndrome Foundation and is a Board member of the American Epilepsy Society.
Jack M. Parent, MD
Co-PI and Co-Director of EpiMVP, is the William J. Herdman Professor of Neurology and Co-director of the U-M Comprehensive Epilepsy Center. He is a neurologist, epileptologist and neuroscientist with expertise in stem cell biology, adult neurogenesis, and rodent and human pluripotent stem cell models of epilepsy.
His laboratory studies adult neurogenesis in the intact and injured vertebrate brain using rodent and zebrafish models. He has been studying animal models of temporal lobe epilepsy (TLE) for over 20 years. His pioneering work on seizure-induced neurogenesis in the adult brain, begun as a postdoctoral fellow with Dr. Daniel Lowenstein at UCSF, spurred on many labs to study the role of adult hippocampal neurogenesis in epileptogenesis, and the effects of other brain injuries on adult neurogenesis. His laboratory has remained at the forefront of investigations into the role of adult neurogenesis in TLE pathophysiology.
For the past 10 years, Parent has also developed models of genetic epilepsies and other neurological disorders using patient induced pluripotent stem cells (iPSCs) and gene edited iPSCs or human embryonic stem cells (hESCs). His group has generated well over 130 patient and control iPSC lines, and CRISPR gene edited lines from over 35 subjects with disorders that include 11 different genetic epilepsies (Genes: SCN1A, SCN1B, SCN8A, STRADA, PCDH19, CHD2, DEPDC5, SPTAN1, SMC1A, KCNA2, SCL6A1), neuroacanthocytosis and Fragile X Syndrome. His lab has expertise in non-integrating reprogramming methods using episomal vectors, generating retroviral and lentiviral reporter lines, differentiation protocols to generate various cell types (cortical neurons, autonomic neurons, astrocytes and cardiac myocytes) and CRISPR gene editing of iPSCs/hESCs.
Along with Dr. Isom, he has been studying SUDEP mechanisms in Dravet syndrome, SCN1B- and SCN8A-associated epilepsies using patient-derived cardiac myocytes and mouse models. His laboratory also has expertise with 5 different protocols to generate human cerebral organoids (hCOs) from pluripotent stem cells. To date, Parent has mentored or is currently mentoring 7 graduate students, 19 postdoctoral fellows, and 3 K08 awardees. He previously served as a member of NIH CNNT and NST-1 study sections, the latter because he appreciates the importance of training the next generation of scientists. Parent finished a 4-year term as Secretary of the American Neurological Association and a 3-year term on the Board of Directors of the American Epilepsy Society.
He founded (in 2009), chaired and now co-chairs (with Dr. Isom) the Scientific Advisory Board of the Dravet Syndrome Foundation, is a member of the Scientific Advisory Board of the PCDH19 Alliance, and serves as Chief Editor for Epilepsy Currents, and on the editorial boards of the Journal of Experimental Medicine and Brain Plasticity.
EpiMVP Steering Committee:
Lori L. Isom, PhD
Co-Chair, Co-Director
Jack M. Parent, MD
Co-Chair, Co-Director and PI of Project 2
M. Elizabeth Ross, MD
PI of Project 1
Dr. Ross is the Nathan Cummings Professor of Neurology and Neuroscience and Director of the Center for Neurogenetics (CNG) in the Brain and Mind Research Institute, Weill Cornell Medicine.
The CNG supports research into the genetic causes of neurological disorders in children and adults. Either non-syndromic epilepsies or seizure disorders associated with developmental delay and brain malformation comprise a major segment of conditions evaluated in the CNG. The Center has both basic science and clinical arms and operates the biobank for the neurological community at Weill Cornell and currently has fibroblast samples representing VUSs in STXBP1, SYNGAP1, DEPDC5, and CDKL5 that are available for this collaborative program.
Neuroscientist faculty members of the Center investigate the mechanisms underlying pathogenesis of a broad range of conditions. Her own research group, the Laboratory of Neurogenetics and Development, focuses on discovery of gene mutations associated with brain malformations, many of which include epilepsy phenotypes, and investigation of how these genes direct brain construction. Three major projects in her lab encompass: 1) complex genetic interactions that lead to spina bifida, 2) cell cycle regulation and its role in growth and cellular patterning of brain, and 3) regulation of neuronal cytoskeleton, necessary for neuronal movement, synapse formation and turnover that are critical to the function of developing and aging brain. The latter two areas overlap with interneuron deficits and synaptic dysregulation that are intimately related to epilepsy pathogenesis.
These three areas of study are approached from both a basic science perspective, using biochemical, cell biological and mouse genetic tools, and clinical genetics, pursuing genotype-phenotype insights.
Yu Wang, Ph.D.
PI of Project 3
Dr. Wang is an epileptologist and neuroscientist with expertise in epilepsy, neurogenetics and cortical development. The overall goal of his translational research program is to study refractory epilepsies and identify potential novel treatments. Specifically, he utilizes in vivo rodent models to identify genetic mechanisms contributing to malformations of cortical development and seizures.
He has a broad background in molecular genetics and seizure electrophysiology, with training and expertise in a variety of experimental approaches. As a graduate student and postdoctoral fellow in the laboratories of Drs. Joseph LoTurco and Jack Parent, respectively, he carried out numerous molecular and cell biology studies as well as advanced EEG and seizure analysis. At the University of Michigan, where he has established an independent laboratory, he has expanded his research interests to include CRISPR-mediated somatic mutagenesis, quantitative PCR, transcriptome analysis (e.g., bulk RNA sequencing and TRAP-Seq) and in vivo electrophysiology. He has a long-standing interest and expertise in epilepsy and neurodevelopment, and his laboratory has recently generated a novel animal model of somatic Depdc5 loss-of-function that is the first to display highly clinically relevant electroclinical expression to model human focal cortical dysplasia.
Gemma Carvill, Ph.D.
PI of Gene and Variant Curation Core (GVCC)
Dr. Carvill is a geneticist with extensive experience in the use of genomic technologies to study the genetic factors that cause neurodevelopmental disorders, particularly epilepsy. Her laboratory uses genomic, epigenomic and transcriptomic datasets along with computational models to identify specific coding and noncoding genetic variants associated with epilepsy. In addition to identifying these genetic etiologies, her lab uses patient-specific and genome edited iPSC lines to study pathogenic mechanisms in epilepsy.
She is particularly interested in the genes involved in epigenetic mechanisms, including transcription factors and chromatin remodelers. Her research constantly challenges the status quo, by focusing on the long neglected noncoding regions of the genome in patients with epilepsy, as well as expanding the study of epilepsy beyond a ‘channelopathy’. Moreover, supported by the highly competitive NIH Director’s New Innovators Award, she is exploring the utility of cfDNA in genetic diagnosis and as a novel biomarker in epilepsy.
In addition to her established and innovative independent research program, she has an extensive track record of collaborative research with groups across the globe and she has been part of multiple collaborative efforts to identify novel genetic etiologies in epilepsy and other neurological disorders. She has trained graduate, undergraduate and postdoctoral students as well as clinical colleagues and trainees in the use of genomic technologies and computational tools to find genetic causes of neurological disease. She has an outstanding track record of collaborative research and leadership in the field of epilepsy genetics, along with a high level of expertise in the use of genomics and computational approaches.
Michael D. Uhler, Ph.D.
PI of the HETC
Dr. Uhler is Professor of Biological Chemistry and Research Scientist of the Molecular and Behavioral Neuroscience Institute, as well as former director of the Neuroscience Graduate Program of the U-M. He has worked with mouse ES lines and their neuronal differentiation for the past 15 years using viral and transposon vectors. Over the past 10 years, he has used hESC and iPSC lines as models for neuronal differentiation. He collaborates with Drs. Stan Watson and Huda Akil on studies of major depressive disorder mechanisms using patient-specific iPSCs in studies supported by the Pritzker Neuropsychiatric Disorders Consortium. He has generated over 50 iPSC lines from 20 patient and control fibroblast lines using episomal reprogramming vectors. He has also generated 10 CRISPR-derived mutant stem cells lines, often in collaboration with Dr. Parent.
Over the past 10 years, Uhler’s group has met monthly with Dr. Parent’s group to review advances made in each laboratory relevant to human pluriopotent stem cell (hPSC) derivation and neuronal differentiation. He has optimized the generation of excitatory neurons using the Tol2 transposon system for production of stable stem cell lines with tetracycline inducible expression of human neurogenin 2. His laboratory has also generated inhibitory neurons, astrocytes, cerebral organoids and NPCs derived from patient iPSCs.
He has served as the Co-Director of the U-M Human Stem Cell and Gene Editing core with Dr. Parent for the past 4 years. For this application, Uhler will serve as Director of the Human Epilepsy Stem Cell Core (10% effort) and Parent will serve as Co-Director (5% effort) to direct the generation of cellular models including stem cell-derived neural models for the functional characterization of VUS related to the gene sets described in both projects 1 and 2.
Vicky Whittemore, Ph.D.
NINDS Scientific Program Officer
Miriam Leenders, Ph.D.
NINDS Administrative Program Officer
EpiMVP External Scientific Advisory Committee
John Huguenard, MD, PhD
Dr. Huguenard is Professor of Neurology and Neurological Sciences with appointments in Neurosurgery and Molecular and Cellular Physiology at Stanford University. His research and training program focuses on cellular/circuit questions relevant to epilepsy and neurodevelopmental disorders. His work has focused on two forms of epilepsy, generalized genetic epilepsies (absence epilepsy) and post-lesional epilepsies. A central theme is the inhibitory system mediated by the neurotransmitter GABA, which can play either seizure-promoting or seizure-suppressing roles, dependent on circuit location.
His work has supported development of synapse-specific (pharmacology) or cell specific (optogenetic) interventions designed to rein in epileptic circuits. His lab uses a variety of innovative methods, including in vitro and in vivo techniques, including LFP and EEG recording in awake animals, whole cell voltage and current clamp intracellular recording in brain slices, ion and neurotransmitter imaging/uncaging, multiphoton microscopy, behavior, and fiber photometry. He has extensive leadership and research training experience, having directed the Stanford Epilepsy Training program for postdoctoral fellows for the last 15 years, and the Stanford Neurosciences PhD program from 2006-2013. He is committed to promoting rigorous research – and was an author on the recent NINDS rigor document regarding pre-clinical research (Landis et al, 2012), chaired the Gordon Research Conference on Epilepsy, served on both foundation and federal research review committees, and was the recent past chair of the NIH CNNT study section.
He is a strong proponent of rigorous and effective training, especially in neurophysiology and epilepsy research, with many of his trainees now principal investigators in the field.
Jozef Gecz, PhD
Dr. Gecz is a human molecular geneticist who focuses on the genetic causes of childhood onset disabilities such as epilepsy, intellectual disability and cerebral palsy. He earned his undergraduate degree in the former Czechoslovakia, spent two years at INSERM as a postdoc in Marseille, France and subsequently 25 years at the Women’s and Children’s Hospital in Adelaide, Australia. In 1996 he cloned the first gene for non-syndromic intellectual disability, FMR2 (now AFF2). He then engaged in many other neurodevelopmental disease gene identification studies. Altogether, he has discovered or contributed to the discovery of more than 200 disease genes, including CDKL5, ARX, PHF6, USP9X, IQSEC2, UPF3B, THOC2, GPKOW, ZSWIM6. and PCDH19. He led an international effort to study PCDH19 in 2008 (Nat Genet 40(6):776-81, 2008) by systematic X-chromosome sequencing.
Since 2008, he has continued to research PCDH19-associated epilepsy and has identified many additional patients and initiated mechanistic work. In 2015 he published a major study showing that patients with PCDH19 mutations are deficient for allopregnanolone (Hum Mol Genet 15;24(18):5250-9, 2015), which has now been independently replicated (Epilepsia 58(6):e91-e95, 2017). This research led his group to propose a Phase 2 Clinical Trial, which is now being conducted by Marinus Pharmaceuticals Inc, ref NCT03865732.
With Prof Paul Thomas at the University of Adelaide, he generated and characterized a mouse Pcdh19 knockout model (Sci Rep 6:26765, 2016; Neuron 97:55-66, 2018). Dr. Gecz has extensive experimental data linking PCDH19 protein to the regulation of gene expression normally under control of nuclear hormone receptors like estrogen and androgen receptor (Hum Mol Genet 26(11):2042-2052,2017). He has completed in vitro and in silico assessments of 322 PCDH19 variants and generated a variant prediction toolbox specific to this epilepsy gene. He matched this with thorough standardized neuropsychiatric assessment of 112 PCDH19 patients including 12 mosaic boys (papers submitted).
Other major epilepsy genes actively studied by his Neurogenetics team are IQSEC2 (mouse model, MS in press), ARX (2x mouse models), and TBL1XR1 (patient cell-based models). As part of his 20+ year collaboration with Prof’s Scheffer and Berkovic (4x consecutive NHMRC Program grants) he continues to pursue novel epilepsy gene discovery as well as a better understanding of epilepsy disease mechanisms. His latest innovation in epilepsies is exploration of cell free DNA and RNA from blood of epilepsy patients.
Sarah Weckhuysen, M.D.
Dr. Weckhuysen is a neurologist with vast experience in both clinical epilepsy and genetic research. As a clinician, she has worked in several tertiary epilepsy centers, including the Epilepsy Center Kempenhaeghe in the Netherlands, and the Hôpital Pitié Salpêtrière in Paris, France. Currently she works as an epileptologist in the University Hospital of Antwerp in Belgium.
Her research focuses on the genetics of (early onset) epilepsies and febrile seizures, and the phenotypical delineation of genetic epilepsy syndromes. She obtained a PhD in genetics of epileptic encephalopathies with the Neurogenetics group of the VIB Department of Molecular Genetics in Antwerp, Belgium, where she is now leading the Epilepsy Division of the group. Her lab’s contributions to epilepsy include many gene discoveries, including the first demonstration that de novo mutations in the sodium channel gene SCN1A cause severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome), and the identification of de novo KCNQ2 mutations in a neonatal epileptic encephalopathy (KCNQ2 encephalopathy). Her research group has been leading and coordinating the European consortium EuroEPINOMICS-RES on genetics of rare epilepsies, including partners from 30 different European epilepsy research centers, and is part of the Epi25 consortium, funded by the NHGRI Centers for Common Disease Genomics grant.
She has built an extensive network of collaborations with clinical epileptologists, giving access to well documented patient cohorts of children with rare epilepsy disorders who are followed on a regular basis and are receiving currently optimal but unfortunately still inadequate treatment. Over the last few years, her group has grown from a genetic research lab to a lab that works from bedside (deep phenotyping of patients) to bench (genetic diagnosis and functional characterization) and back to bedside (therapeutic strategies).
Karen Wilcox, Ph.D.
Dr. Wilcox is Professor and Chair of Pharmacology and Toxicology at the University of Utah. Her laboratory has made key contributions to understanding basic mechanisms of epileptogenesis, the mechanisms of action of anticonvulsant drugs, and the development of animal models to study therapy-resistance to anticonvulsant drugs, including a viral infection model of epilepsy and genetic models of epilepsy.
She has active NIH support to use electrophysiological, calcium imaging, pharmacological, behavioral, genetic, immunoblot, and immunohistochemical techniques in a variety of in vitro preparations and animal models of epilepsy to achieve the goals of her laboratory. Most importanatly for the present application, she serves as Director of the Anticonvulsant Drug Development (ADD) Program at the University of Utah. The ADD Program serves as the contract site of the Epilepsy Therapy Screening Progran at NINDS, of which she is currently the principal investigator, and has made significant contributions over the last 5 decades to the preclinical evaluation of a substantial number of compounds approved for symptomatic treatment of seizure disorders. Thus she has considerable expertise in identifying novel therapeutic targets and the potential for compounds to confer protection against seizures.
Dianalee McKnight, Ph.D., FACMG.
Dr. McKnight is a board-certified clinical molecular geneticist who has been in the genetic diagnostic industry for over 10 years. She served as the director of neurogenetics testing at GeneDx, where she oversaw the design, validation, and performance of diagnostic testing for many neurological conditions including autism, intellectual disability, epilepsy, neuromuscular disorders, and neurodegenerative disorders including ALS/FTD and leukodystrophy. Recently, she moved to Invitae, where she serves as Medical Affairs Director, Emerging Clinical Omics.