Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

• DOI: 10.1126/scitranslmed.abb6871
• Publication Date: 2021-01-27T20:16:39Z
• Authors: Lingling Kong; David O. Valdivia; Christian M. Simon; Cera W. Hassinan; Nicolas Delestrée; Daniel M. Ramos; Jae Hong Park; Celeste M. Pilato; Xixi Xu; Melissa Crowder; Chloe C. Grzyb; Zachary A. King; Marco Petrillo; Kathryn J. Swoboda; Crystal Davis; Cathleen M. Lutz; Alexander H. Stephan; Xin Zhao; Marla Weetall; Nikolai A. Naryshkin; Thomas O. Crawford; George Z. Mentis; Charlotte J. Sumner
• Keywords: Motor Neurons; 0303 health sciences; Life Sciences; 610; Mice, Transgenic; Survival of Motor Neuron 1 Protein; Axons; Muscular Atrophy, Spinal; Disease Models, Animal; Mice; 03 medical and health sciences; Medicine and Health Sciences; Animals; Humans; JMG

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence developmentally immature motor neuron axons, many which actively degenerating. We identified similar features in a mouse model SMA, impaired radial growth Schwann cell ensheathment axons began during embryogenesis resulted reduced acquisition myelinated that impeded axon function neonatally. Axons failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into blood. Genetic restoration survival (SMN) expression neurons, not cells or muscle, improved development maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth mice increased already utero was required restore axonal associated maturation, prevent subsequent neonatal degeneration, enhance function. Together, these data reveal cellular basis fulminant worsening patients identify temporal window more effective treatment. These findings suggest minimizing delay is critical achieve optimal therapeutic efficacy.