April 29-30, 2022 | 10 AM - 2 PM EDT each day
If you have any questions during the conference, please send them to our virtual email inbox which we will do our best to monitor in real time: DNSPG4@ninds.nih.gov
Welcome to the Inaugural scientific symposium on De Novo SPG4 hosted by the NIH Intramural Research Program. This conference is co-sponsored by the Office of the Clinical Director of the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute’s Undiagnosed Diseases Program (NHGRI UDP).
The conference will be held virtually on Friday April 29th from 10AM to 2PM EDT and Saturday April 30th from 10AM to 2PM EDT. The conference will be broadcast live (and also archived for those who may want to view in at a later date) on the NIH webcast site https://videocast.nih.gov/.
If you have any questions during the conference, please send them to our virtual email inbox which we will do our best to monitor in real time: DNSPG4@ninds.nih.gov
Mutations in SPAST when they occur de novo seem to lead to a phenotype of childhood-onset cerebral palsy, as distinct from the classic adult-onset spastic paraparesis phenotype of SPG4. The goal of this inaugural meeting is to bring together clinicians, basic scientists, genetic testing companies, and biotech, as well as patients and their families, in order to review what is known about De Novo SPG4, and discuss gaps in knowledge to inform translational research with the goal of therapeutics development.
We look forward to an exciting meeting!
|10:05 AM - 10:15 AM||Nina Schor, NINDS
Ultra-rare Gene-based Therapy (URGenT) Network
|10:15 AM - 1025 AM||Cynthia Tifft, NHGRI
NIH Undiagnosed Diseases Program and Undiagnosed Diseases Network; GM1 gene therapy trial and how the NIH intramural research program is a unique resource for rare diseases and first-in-human treatment trials
Symposium Part 1: Clinical phenotype | Moderator: Katharine Alter (CC/RMD)
|10:25 AM - 10:35 AM||Chris Lorek and Katie Gregg
Why we are convened here today, perspective from 2 parents of young children recently diagnosed with DN SPG4
|10:35 - 10:45 AM||Andrea McDonnell and Erin Dear
An overview of the CureSPG4 Foundation, mission and focus on fundraising to support various research avenues to find a cure SPG4.
|10:45 AM - 11:05 AM||Rebecca Schule (Tubingen, Germany)
Hereditary SPG4 mutations and the adult-onset spastic paraplegia phenotype
|11:05 AM - 11:15 AM||BREAK|
|11:15 AM - 11:30 AM||Ariane Soldatos and Camilo Toro
Clinical cohort from the NIH Clinical Center
|11:30 AM - 11:50 AM||Darius Ebrahimi-Fakhari (Boston Children’s Hospital, Harvard Medical School)
Clinical cohort from Boston Children’s Hospital: Further Evidence for Early-Onset, Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST. The importance of patient registries and standardized data collection through natural history studies to inform future therapeutic clinical trials in rare diseases.
|11:50 AM - 12:05 PM||Michelle Christie
Clinical cohort from Scottish Rite Hospital, Texas
|12:05 PM - 12:35 PM||LUNCH BREAK|
Symposium Part 2: Genetics Moderator: Camilo Toro (NHGRI)
|12:35 PM - 12:55 PM||Jennifer Posey (Baylor College of Medicine)
Why de novo mutations can present a different phenotype than inherited mutations within the same gene
|12:55 PM - 1:15 PM||Heather McLaughlin (Medical Affairs Director, Invitae)
Cerebral Palsy gene panel including SPAST
|1:15 PM - 2:00 PM||Panel discussion / Q&A|
Symposium Part 3: Translational Research | Moderator: May Malicdan (NHGRI)
|10:00 AM - 10:10 AM||Welcome|
|10:10 AM - 10:30 AM||Craig Blackstone (Massachusetts General Hospital)
Patient derived samples and translational research from NIH to MGH, with focus on fibroblasts and iPSCs
|10:30 AM - 10:50 AM||Bryan Traynor (NIH/NIA)
NIH and NCATS pipelines for rare diseases therapeutics including ASOs, other rare disease initiatives such as the N=1 collaborative
|10:50 AM - 11:10 AM||June Li (University of Illinois Chicago)
Differentiating iPSCs derived from children with de novo SPG3A into neurons for compound screening
|11:10 AM - 11:30 AM||Peter W. Baas (Drexel University, Philadelphia)
Mouse models of SPG4
|11:30 AM - 11:50 AM||Eric Samarut (University of Montreal, Canada)
Intersecting in vivo biology and data science to drive mechanistic insights and speed up drug discovery for rare genetic disorder
|11:50 AM - 12:05 PM||Chi-Lun Chang (St Jude’s Children’s Research Hospital)
Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking
|12:05 PM - 12:35 PM||LUNCH|
Symposium Part 4: Therapeutics | Moderator: Ariane Soldatos (NINDS)
|12:35 PM - 12:50 PM||Katharine Alter (NIH)
The importance of rehabilitation therapies
|12:50 PM - 1:10 PM||Miguel Esteves (UMass)
|1:10 PM - 1:25 PM||Jahannaz Dastgir (Director Clinical Research at Applied Therapeutics)
What small pharmaceutical startups are looking for when they consider rare disease therapeutic development
|1:25 PM - 1:45 PM||Panel discussion / Q&A|
|1:45 PM - 2:00 PM||Summary of the meetings and action items/next steps|
Nina F. Schor, MD, PhD is Deputy Director and Acting Scientific Director of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH). Before coming to NIH, Dr. Schor spent 20 years on faculty at the University of Pittsburgh, ultimately becoming the Carol Ann Craumer Professor of Pediatric Research, Chief of the Division of Child Neurology in the Department of Pediatrics, and Associate Dean for Medical Student Research at the medical school. In 2006, Dr. Schor became the William H. Eilinger Chair of the Department of Pediatrics, and Pediatrician-in-Chief of the Golisano Children’s Hospital at the University of Rochester, posts she held until January 2018, when she became Deputy Director of the NINDS. For 27 years, her research on neural crest development and neoplasia was continuously funded by NIH. She currently leads the Division of Intramural Research and the Ultra-Rare GENe-targeted Therapies (URGenT) Network, strategic planning and career development programs at NINDS and serves as a Neurology Director for the American Board of Psychiatry and Neurology.
Cynthia Tifft received her Ph.D. in genetics from the University of Texas Graduate School of Biomedical Science at M.D. Anderson Cancer Center and her M.D. from the University of Texas Health Science Center in Houston. She completed her pediatric residency at Johns Hopkins Hospital and fellowship in Medical Genetics at the National Institutes of Health. Dr. Tifft joined the faculty of the George Washington University School of Medicine at Children's National Medical Center in 1991, becoming chair of the Division of Genetics and Metabolism in 1996. In 2009, she was recruited to the National Human Genome Research Institute as deputy clinical director, where she also directs the Pediatric Undiagnosed Diseases Program. Dr. Tifft's clinical and research interests for many years have been lysosomal disorders affecting the central nervous system. She is the principal investigator of a gene therapy trial for children with GM1 gangliosidosis.
Ariane Soldatos is a physician scientist in the NINDS Intramural Research Program. She is associate investigator on first-in-human clinical treatment trials, including gene therapy, for rare childhood neurodegenerative diseases. She has a clinical research interest in genetic mimics of cerebral palsy and has been involved in the care of a cohort of children with De Novo mutations in SPAST through the NHGRI Undiagnosed Diseases Program. She is passionate about partnering with families of children with rare diseases in navigating the complex landscape of translational rare diseases therapeutics development and advocacy.
Katharine E. Alter is Board Certified in Pediatrics, Physical Medicine and Electrodiagnostic and Neuromuscular Medicine. She is the Medical Director of the NIH Rehabilitation medicine Functional and Applied Biomechanics Section. She has particular expertise in cerebral palsy, spasticity management, and gait analysis in rare neurological diseases.
Camilo Toro is a Neurologist specialized in movement disorders and neurogenetics. He is the Director of the Adult NIH Undiagnosed Diseases Program.
Dr. Malicdan is the Director of the NIH-Undiagnosed Disease Program Translational Laboratory.
Chris Lorek is father of Blair, a 4 year-old girl who has been diagnosed with de novo SPG4. Blair is unable to stand or walk independently, and has had gross and fine motor delays since infancy. She endures a rigorous therapy schedule each week, including physical, occupational, speech and hippo therapies. Chris and his wife Stephanie are working diligently to engage the medical community and raise awareness of this disease in hopes of one day finding a treatment or cure for their daughter.
Katie is the mother of Lilly, a 4 year old girl diagnosed with de novo SPG4 at 22 months of age. She has been in various therapies since 18 months old when an initial diagnosis of cerebral palsy was given. In addition to hippotherapy, occupational and physical therapies, Lilly participates in 3-week intensives 4 times a year. She cannot stand or walk independently and primarily uses a posterior walker or crawls and relies on a wheelchair for longer distances. She is a determined and motivated little girl, just like her family is in helping her to live her best life.
Cuyler and Erin Dear are parents to a 4 year old daughter with de novo SPG4. They co-founded Cure SPG4 Foundation, along with Danny and Andrea McDonnell, with the goal of fundraising and supporting research specific to SPG4. Cuyler and Erin have 4 children and live in San Antonio, Texas, where Cuyler practices as an orthopedic surgeon.
Danny & Andrea McDonnell are the parents of 6 year old Connor, diagnosed with de novo SPG4 at age 3. Feeling like they wanted to directly influence research to support advancements towards a cure, they co-founded Cure SPG4 Foundation, along with the Dear family. The goal of Cure SPG4 Foundation is to fundraise and support research specifically for SPG4. Danny and Andrea McDonnell have 3 boys and live in the suburbs of Chicago.
Dr Rebecca Schüle is a neurogeneticist and is the leader of the Genomics of Rare Movement Disorders research group within the Hertie Institute for Clinical brain research at the University of Tübingen in Germany. She has particular research interest in HSP, including SPG4. She created and developed the Spastic Paraplegia Rating Scale (SPRS). She has undertaken several clinical trials in HSP and has followed the progression of HSP in a cohort of over 600 patients for the last decade. She is coordinating the international TreatHSP network, an association of HSP clinicians and researchers with the aim to develop and implement novel therapies for people affected by HSP.
Dr. Ebrahimi-Fakhari is a pediatric neurologist with special expertise in movement disorders, Department of Neurology, Boston Children’s Hospital. His research interests cover childhood-onset neurogenetic and neurodegenerative diseases. He leads a translational research program that aims to discover novel therapies for childhood-onset forms of hereditary spastic paraplegia and disorders related to the autophagy pathway. Current work covers gene discovery, natural history studies in patients, disease modeling in iPSC-derived neurons and zebrafish, and high-throughput small molecule and functional genomics screens. Work over the last years has focused on the role of adaptor protein complex-mediated protein trafficking in neurons using AP-4-associated hereditary spastic paraplegia (AP4B1, AP4M1, AP4S1, AP4E1) as a tractable model.
Dr. Christie leads a large subspecialty clinic for HSP at Scottish Rite For Children, Dallas, TX, where she also serves as the Director of Neurophysiology. Her research interests include advancing symptomatic and genetic treatments for child and adolescent onset progressive neurogenetic conditions, specifically HSP and Charcot-Marie Tooth, through multidisciplinary care. Current work includes delineating the clinical spectrum and natural history of childhood onset HSP and creating evidenced based surgical and non-surgical treatment protocols in childhood onset HSP.
Dr. Jennifer Posey is an Assistant Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine. Her research interests lie in the relationship between genomic variation and clinical (phenotypic) expression and how this can be leveraged to develop individualized treatment approaches. Dr. Posey leads the Baylor College of Medicine Genomic Research to Elucidate the Genetics of Rare (BCM-GREGoR) research program, and also works with the Undiagnosed Diseases Network (UDN), and the Rare and Atypical DIAbetes NeTwork (RADIANT) consortia. As a physician scientist and a medical and human geneticist, her ultimate goal is to be able to translate our understanding of the relationship between an individual’s genotype and phenotype, or disease trait, into actionable and treatable information in the clinic.
Dr. McLaughlin is a board-certified Clinical Molecular Geneticist by the American Board of Medical Genetics and Genomics and a fellow of the American College of Medical Genetics. Dr. McLaughlin serves as a Medical Affairs Director at Invitae, focusing on biopharma partnerships. Prior to joining Invitae, Dr. McLaughlin was an Associate Director of Clinical Genomics and Cardiogenetics at GeneDx, where she was instrumental in developing their clinical exome sequencing program. She also previously served as an Assistant Laboratory Director at Partners HealthCare Personalized Medicine Laboratory for Molecular Medicine. Dr. McLaughlin obtained a B.S. in Diagnostic Molecular Science from Michigan State University and a Ph.D. in Human Genetics from the University of Michigan. She completed her Clinical Molecular Genetics fellowship at Harvard Medical School. She has clinical expertise in cardiogenetics, connective tissue disorders, neurogenetics, and pediatrics.
Dr. Traynor is a neurologist and a senior investigator at the National Institute on Aging (NIA). He is a member of the NIH Gene Therapy Taskforce. He led the international consortium that identified a pathogenic hexanucleotide repeat expansion in the C9orf72 gene as a cause of a large proportion of ALS and FTD. He received his MD and PhD from the University College Dublin. He also received a Master’s in Medical Science (MMSc) from Harvard-Massachusetts Institute of Technology HST. He completed a neurology residency and fellowship at Massachusetts General Hospital and Brigham and Women’s Hospital in Boston.
Dr. Blackstone received his M.D. and Ph.D. from Johns Hopkins University. After a neurology residency at the Harvard-Longwood Neurology Program, Dr. Blackstone completed a fellowship in clinical movement disorders at the Massachusetts General Hospital. During this time he also conducted postdoctoral research with Morgan Sheng at Harvard Medical School, investigating the functions of proteins implicated in hereditary dystonias. Dr. Blackstone joined NINDS as an investigator in 2001. His NINDS laboratory investigated the cellular and molecular mechanisms underlying hereditary movement disorders. In 2020, Dr. Blackstone became the Chief of the Movement Disorders Division at the Massachusetts General Hospital and Harvard Medical School. Dr. Blackstone's research investigates the pathogenesis of hereditary spastic paraplegias.
Dr. Chi-Lun Chang earned his PhD from the University of Texas Southwestern Medical Center under the mentorship of Dr. Jen Liou, where he studied the molecular basis of inter-organelle lipid and Ca2+ signaling at organelle interface. He then pursued postdoctoral training with Dr. Jennifer Lippincott-Schwartz at Janelia Research Campus, defining the mechanistic regulation of inter-organelle fatty acid transfer and protein trafficking. He joined the faculty at St. Jude in 2021 as an assistant member in the Department of Cell and Molecular Biology. Dr Chang’s research interests include spatial-temporal regulation of energy homeostasis at lipid droplet-organelle contact sites and alteration of inter-organelle communication in neurological diseases.
Dr. Peter Baas is Professor of Neurobiology and Anatomy at Drexel University College of Medicine, where he is also Director of the Graduate Program in Neuroscience and Director of the T32/NIH-funded Training Program in Spinal Cord Injury. Dr. Baas has studied SPG4-HSP for the past 15 years and has focused mainly on the underlying mechanisms of the disease. He has developed the first animal (mouse) model for the disease that includes both loss-of-function and gain-of-function components. With mechanistic insights and mouse models established, he is now primarily focused on developing novel therapies for prevention and treatment of the degenerative symptoms of SPG4-HSP.
Xue-Jun (June) Li received her PhD in Neurobiology and postdoc training in Stem Cell Research. She is an Associate Professor and Michael A. Werckle Endowed Professor in the Department of Biomedical Sciences at the College of Medicine Rockford and the Department of Bioengineering at the University of Illinois at Chicago. Dr Li's research focuses on specifying neuronal subtypes from human pluripotent stem cells and using these stem cell-derived neurons to study motor neuron and axonal degeneration. Particularly, her lab is interested in using stem cell models of hereditary spastic paraplegias to understand the pathogenic mechanisms and to identify potential therapeutics.
Dr Éric Samarut holds a master's degree in science from the École Normale Supérieure in Lyon and a doctorate in molecular aspects of life sciences from the University of Strasbourg. After a postdoctoral fellowship in neurosciences at the University of Montreal, he was recruited as an assistant research professor at the Centre de Recherche du CHU de Montréal (CRCHUM). His research laboratory is interested in understanding the role of genes and pathogenic mutations in rare neurological diseases. His research interests aim to better understand the mechanisms underlying neurological diseases and to develop precision medicine strategies. Dr Éric Samarut also holds a Master’s in Business Administration (MBA) from the School of Management Sciences (UQAM) and is the co-founder of several biotechnology start-ups. In particular, since 2018 he is the co-founder and Chief Scientific Officer of Modelis, a start-up whose mission is to accelerate the discovery of treatments for rare genetic diseases including hereditary Spastic Paraplegia.
Jahannaz Dastgir, DO is a pediatric neurologist specialized in neuromuscular diseases. She is the medical director of the SORD deficiency and PMM2-CDG programs at Applied Therapeutics. She also maintains a part time position as the director of the MDA clinic and pediatric neuromuscular medicine program at Goryeb children’s hospital. She was previously a clinical research fellow at the NIH under the neurogenetic and neuromuscular disorders of childhood section, led by Carsten Bonnemann.
Miguel Sena-Esteves, PhD, is an associate professor of neurology and a member of the Horae Gene Therapy Center. He received his PhD from the University of Porto, Portugal, where he started his work in gene therapy. His laboratory at the University of Massachusetts Medical School (UMMS) focuses on the development of adeno-associated virus (AAV) based gene therapies for lysosomal storage diseases, Huntington’s disease, ALS, FSHD and brain tumors. In addition, his laboratory develops novel AAV capsids to improve targeting, distribution and potent transduction of target tissues in these diseases, with a particular focus on the central nervous system. Dr. Sena-Esteves leads the Tay-Sachs Gene Therapy Consortium with the focus to develop an AAV gene therapy and conduct the first-in-human clinical trial. He is also leading the pre-clinical development efforts for a GM1-gangliosidosis AAV gene therapy in collaboration with Lysogene. In 2011 he received the Outstanding New Investigator Award from the American Society of Gene & Cell Therapy (ASGCT) for his many contributions to the field of gene and cell therapy.