Therapeutic benefit of MGE progenitor cell transplantation in a rabbit model of Dravet syndrome

Lori L. Isom, PhD – University of Michigan
Scott Baraban, PhD – University of California San Francisco
Jack M. Parent, MD – University of Michigan
Therapeutic benefit of MGE progenitor cell transplantation in a rabbit model of Dravet syndrome
Transformational Science Grant – $500,000, 3 years

Grant Summary:

Dravet syndrome (DS) is a devastating developmental and epileptic encephalopathy that impacts approximately 1 in 16,000 individuals and places significant burdens on their families and caregivers. Importantly, DS is more than seizures. Its complex clinical presentation includes intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, chronic infections, disruptions of the autonomic nervous system, and mood disorders. While all patients with epilepsy are at risk for SUDEP, DS patients have the highest risk, of up to 20%. Despite recent advances in small molecule drug discovery, the majority of DS patients remain intractable. Even if seizures can be controlled, small molecule drugs do not address the non-seizure phenotypes of DS, which are equally devastating to a patient’s quality of life. Clearly, it is essential that we address the underlying genetic cause of DS, which is for most patients, haploinsufficiency of SCN1A. A gene-modifying antisense oligonucleotide therapeutic agent to restore SCN1A expression is currently in clinical trials and viral-delivered gene replacement/enhancement strategies are under development. Here, we propose to exploit an alternative therapeutic strategy that has been successful in mouse models: Medial Ganglionic Eminence (MGE) progenitor cell transplantation to restore healthy fast-spiking interneurons in DS patient brains. While transgenic mice have provided invaluable insights into seizures and some comorbidities associated with DS, mice have critical differences in physiology and neuroanatomy compared to humans and thus are not the most appropriate model to test a cell transplantation-based therapy. In contrast, rabbits, which are larger vertebrates, are more similar to humans than mice and have been successfully utilized to model human diseases, including Alzheimer’s disease. Here we propose to leverage the combined expertise and experience of the Baraban (in MGE transplantation) and Isom (in SCN1A models including transgenic rabbits) laboratories to develop a proof-of-principle disease-modifying cell transplantation-based therapy for DS. The results of this large animal work will strengthen the preclinical foundation for future cell transplantation therapeutic strategies in DS patients.

About the Investigators:

Lori L. Isom, PhD 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. Prior to becoming Chair of Pharmacology she 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’s postdoctoral research included the first cloning, sequencing, and expression of voltage-gated sodium channel SCN1B and SCN2B, encoding b1 and b2 subunits, respectively.

Dr. Isom’s laboratory employs a variety of techniques, including cellular and molecular biology, genetics, and electrophysiology. Highlights of Dr. Isom’s research program include the discovery that sodium channel b subunits, in addition to functioning as ion channel modulators, are multi-functional cell adhesion molecules of the immunoglobulin superfamily that regulate neuronal migration, pathfinding, and fasciculation. She reported the first mutation in SCN1B linked to Dravet syndrome and collaborates with Dr. Jack Parent and Dr. Miriam Meisler to investigate SCN1A, SCN1B, and SCN8A epileptic encephalopathy mutations in mouse models and human induced pluripotent stem cell (iPSC) neurons and cardiac myocytes. Dr. Isom’s lab has published over 90 articles and received $22 million in funding to investigate genetic links between neuronal excitability and epileptic encephalopathy. In addition to her research activities, Dr. Isom serves as PI of an NIH funded T32 grant, co-chairs the Dravet Syndrome Foundation Scientific Advisory Board with Dr. Parent, serves on NIH grant study sections and editorial boards of scientific journals, and has received awards for research and mentoring, including a NINDS Javits R37 MERIT award and the University of Michigan Rackham Distinguished Graduate Mentoring Award. In 2011, she was elected a Fellow of the American Association for the Advancement of Science for her work in Neuroscience and Graduate Education.

Scott C. Baraban, PhD is a Professor of Neurological Surgery and William K. Bowes Jr. Endowed Chair in Neuroscience Research at the University of California, San Francisco. Dr. Baraban’s lab studies the cellular and molecular basis of epilepsy, specifically catastrophic epilepsies of childhood. While some seizures can be controlled with available medications, a large number of pediatric epilepsy patients are medically intractable. Combining pharmacology, genetics, electrophysiology, cell transplantation, and unique zebrafish models of genetic epilepsies they are identifying new treatments for these patients. The first zebrafish models for epilepsy were developed in the Baraban lab over 15 years ago and recent drug screening efforts in a zebrafish model for DS have led to new therapeutic candidates. Publications from the Baraban laboratory (>100) have appeared in Science, Nature Neuroscience, Nature Communications, Journal of Neuroscience, Proceedings of the National Academy of Sciences, and Neuron.

Dr. Baraban is the recipient of awards from the Esther and Joseph Klingenstein Fund, the Sandler Family Supporting Foundation, the UCSF Innovation in Basic Science Award, a EUREKA grant and Javits Neuroscience Award from the NIH. In 2016, he received the Basic Science Research Recognition Award from the American Epilepsy Society. He was co-Chair (with Jack Parent) of the 2014 Gordon Research Conference on epilepsy and Scientific Program Committee Chair for the 2015 AES meeting. He serves on the Scientific Advisory Board of the Dravet Syndrome Foundation and LGS Foundation and as a regular member of CNNT study section at NIH.

Jack M. Parent, MD, is a professor of neurology, director of the Neurodevelopment and Regeneration Laboratory, and co-director of the Comprehensive Epilepsy Center in the University of Michigan Medical School. His current research interests include neural stem cell transplantation to treat brain injury and neurodegeneration, and the modification of adult neural stem cells to promote brain repair after stroke or prevent epilepsy. Dr. Parent earned a Bachelor of Arts degree, with distinction, in human biology from Stanford University and his medical degree from the Yale University School of Medicine. He completed a medical internship and neurology residency at the University of California, San Francisco (UCSF), where he was selected chief resident. He stayed at UCSF for clinical fellowship training in epilepsy and clinical neurophysiology, and postdoctoral training in neuroscience research.

An internationally recognized research leader in the fields of neural stem cell biology, regeneration after brain injury and epilepsy, Dr. Parent established the Neurodevelopment and Regeneration Laboratory at the University of Michigan in 2000. Dr. Parent is a member of the Epilepsy Foundation of America Research Council, the Medical Advisory Board of the Global Ischemia Foundation, the Independent Science Review Panel of the New Jersey Commission on Brain Injury Research, and the National Scientific Advisory Council of the American Federation for Aging Research. He also serves as an associate editor of Neuroscience Letters, and is on the editorial boards of Experimental Neurology and Epilepsy Currents. He has received several awards for his research, including a Junior Investigator Award from the American Epilepsy Society, a Paul Beeson Physician Faculty Scholars in Aging Award, a Dreifuss-Penry Epilepsy Award from the American Academy of Neurology, and a Grass Foundation Award in Neuroscience from the American Neurological Association.

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