Online Seminar: Optimizing therapeutic efficacy in spinal muscular atrophy

This seminar is intended for the personnel and students at the University of Oxford and the Oxford University Hospitals Foundation Trust.

Online Seminar – please register for the Zoom event

Over the last 5 years, three gene targeting therapeutics have been approved for patients with SMA.  Despite distinct routes of administration and biodistributions, all show substantially greater efficacy when delivered very early.  In order to characterize the mechanisms that may underlie this optimal therapeutic window, we examined SMA and age-matched control human tissues collected during expedited autopsies.  We observed high survival motor neuron (SMN) protein expression levels during fetal stages of development that decreased perinatally suggesting a particular requirement for SMN during prenatal development.  Parallel histological characterization of motor neuron axons in human and SMA mouse ventral roots indicated that impairments of motor axon radial growth and Schwann ensheathment began in utero and were followed by rapid degeneration postnatally.  In SMA mice, in utero treatment with small molecule SMN2 splice modifiers was required to more fully restore motor axonal maturation programs and prevent axon degeneration.  Together these studies provide a cellular basis for the fulminant worsening of infantile onset SMA patients and emphasize that minimizing neonatal treatment delay is essential to achieve optimal outcomes.  These studies also provide a rationale for exploring fetal treatment of patients with the most severe forms of SMA.

Charlotte graduated with a bachelor of arts in ecology and evolutionary biology from Princeton University. She attained her medical degree from Perelman School of Medicine at the University of Pennsylvania and was an intern in internal medicine at University of California, San Francisco where she completed her residency in neurology. She further completed a fellowship in neuromuscular disease at John Hopkins School of Medicine, followed by a fellowship in neurogenetics in Kenneth Fischbeck’s lab at the National Institute of Neurological Disorders and Stroke. Charlotte joined the faculty at John Hopkins University as an assistant professor of neurology and later became co-director of the Charcot Marie Tooth Disease Clinic. In 2011, Charlotte became associate professor of neurology and neuroscience, and is currently professor of neurology at Johns Hopkins University since 2019.