Eric J. Kremer, PhD- Institut de Génétique Moléculaire de Montpellier
Moran Rubinstein, PhD- Tel Aviv University
Else A. Tolner, PhD- Leiden University Medical Center
Ethan M. Goldberg, MD, PhD- The Children’s Hospital of Philadelphia
Molecular characterization of the therapeutic effect of exogenous NaV1.1
Transformational Science Grant- $500,000 over 3 years
Funding for this grant was supported by Dance for Dravet
Grant Summary from the Investigators: The original notion of “gene therapy” was to replace a defective gene with a functional copy. Although conceptually simple and straightforward for some organs, diseases of the brain, especially those that impact neurodevelopment, create additional challenges. Indeed, neurons are the most structurally diverse and specialized cell type in the body with numerous functionalities, which creates therapeutic challenges.
We developed a gene transfer approach in DS mice that, to date, is one of the most effective. However, our approach did not follow the dogma that only some neuron types (inhibitory, not excitatory) should be targeted. We now want to explore the “How? and Why?”. What did our therapy change in the mouse brain? Has our therapy affected the gene being activated throughout the neuronal networks? How does exogenous NaV1.1 activity affect the function of neurons? How long do we need to provide exogenous NaV1.1 activity to prevent the inception and maintenance of the disease state? Can our results provide fundamental and mechanistic insight to allow alternative approaches and outside the box thinking?
Equally important, we corrected many of the most life-threatening and debilitating symptoms, including seizures, sudden death, and cognitive function. Here, we will further determine if our approach corrected more subtle comorbidities, including sleep deficits. The restoration of the latter would strongly contribute to improving the lives of patients with DS. These are among the ambitious goals of our research proposal.
About the Investigators:
Eric J. Kremer, PhD, is an Inserm Director of Research (Class E), and a principal investigator and the director adjoint of the Institute de Genetique Moleculaire de Montpellier (IGMM, home to 18 research teams). Inserm (Institut National de la Santé et de la Recherche Médicale) is the French public research organization dedicated to biological, medical and human health research, covering the pathway from bench to bedside.
Eric received his Ph.D. from the University of South Carolina chemistry department, and then trained with Grant Sutherland and Rob Richards at the Adelaide Women & Children’s Hospital (South Australia), working on the genetic basis of the Fragile X syndrome.
After moving to France, Eric’s lab has focused on three themes: innate immune responses to adenoviruses; the role of a cell adhesion molecule called “CAR” in adenovirus uptake and its physiological role in adult neurogenesis; and the development of gene transfer vectors that target neurons in the central and peripheral nervous system. While working with Moran Rubinstein (Tel Aviv), the latter theme led to development of a gene therapy approach for Dravet syndrome that not only addresses seizures and SUDEP, but also behavior comorbidities. Eric has co-authored more than 130 articles; coordinated multiple national, European, transatlantic, and Australasian consortia; has been a member of the EMA vaccine advisory panel; guest editor for PNAS; and recipient of the Dean’s award at USC and South Australian Innovation award.
Moran Rubinstein is an Associate Professor in the Department of Human Molecular Genetics and Biochemistry at the Faculty of Medical & Health Sciences, Tel Aviv University. She received her Ph.D. from Tel Aviv University and completed her postdoctoral training in the lab of Dr. William A. Catterall at the University of Washington.
Dr. Rubinstein’s research is focused on uncovering the neuronal mechanisms underlying developmental epilepsies and neurodevelopmental disorders, with a particular emphasis on developing innovative therapeutic approaches. These include viral-mediated genetic therapies aimed at ameliorating the epileptic and non-epileptic phenotypes.
The lab employs a range of experimental approaches to explore disease mechanisms and the therapeutic potential of treatments. These include examining the functional impact of ion channel mutations at the cellular level, as well as ex vivo and in vivo electrophysiological techniques in mouse models to assess how disease-causing mutations disrupt cellular and network neuronal activity in microcircuits, neuronal processing, and global brain oscillations. The lab also integrates behavioral paradigms in mouse models to connect these physiological findings to the developmental and cognitive phenotypes associated with neurodevelopmental disorders.
Ethan Goldberg is Associate Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and Departments of Neurology and Neuroscience at The University of Pennsylvania Perelman School of Medicine. He is an Attending Physician and Director of the Epilepsy NeuroGenetics Initiative (ENGIN) at CHOP where he specializes in the diagnosis and care of children with complex neurological disorders including epilepsy, developmental delay/intellectual disability, and autism spectrum disorder. His biomedical research lab studies basic mechanisms of childhood epilepsy and other neurodevelopmental disorders, with a particular interest in ion channelopathies and how genetic variation in ion channel genes leads to human disease. His lab uses a range of approaches including: human and mouse genetics; ion channel, cellular and synaptic neurophysiology; pharmacology; induced pluripotent stem cell technology and cell-based therapy; behavior; and imaging approaches including two-photon microscopy in experimental systems.
Else A. Tolner, PhD, is Assistant Professor and faculty staff member at the department of Neurology at the Leiden University Medical Centre (LUMC), the Netherlands. She is leading a neurophysiology laboratory within the Human Genetics department, equipped with various video-EEG systems for in vivo translational studies on brain activity and physiological changes in transgenic mouse models of epilepsy and hemiplegic migraine.
Dr. Tolner obtained her PhD in 2005 on neuroplasticity processes in epilepsy from the University of Amsterdam, under supervision of late Prof. Fernando Lopes da Silva. As postdoctoral researcher she studied cortical network dynamics in epilepsy, in the lab of late Prof. Uwe Heinemann at the Charité, Berlin, and afterwards at Helsinki University in the team of Prof. Kai Kaila. She started her neurophysiology lab at the LUMC in 2011 within the team of Prof. Arn van den Maagdenberg, funded by an institutional tenure-track fellowship. She has received various sources of funding for her epilepsy and SUDEP studies through a Marie Curie Career Integration Grant (2011), CURE SUDEP award (2014) and Dutch League against Epilepsy Grants (2016; 2022).
Dr. Tolner has published >50 papers on preclinical and clinical findings in the field of epilepsy and migraine, that include identification of brainstem depolarization as critical mechanism in genetic models with risk for sudden death. Her current research focuses on uncovering pathophysiological mechanisms and therapeutic targets for epilepsy and co-morbid (hemiplegic) migraine, including overlapping features. By close collaboration with clinical partners at the LUMC and abroad, she integrates data from functional studies in the transgenic animal models with EEG findings from patients with epilepsy or migraine. Ongoing preclinical epilepsy studies concern identification of EEG indicators for seizure risk and treatment response in the Dravet Scn1a knock-out model, and investigation of epilepsy features in models of Alternating Hemiplegia of Childhood and Alzheimer’s disease.
