Research ArticleSpinal Muscular Atrophy

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

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Science Translational Medicine  27 Jan 2021:
Vol. 13, Issue 578, eabb6871
DOI: 10.1126/scitranslmed.abb6871

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The sooner, the better

Gene therapy approaches hold promise for the treatment of spinal muscular atrophy (SMA). However, these therapies showed that variable clinical response and earlier age of treatment initiation are associated with better outcome. Now, Kong et al. studied the pathophysiology of SMA to identify the best approach to maximize treatment efficiency. The authors used tissue from patients and a mouse model and identified developmental delay of motor neuron axons already in the fetus and subsequent early postnatal cell death. In utero therapeutic intervention prevented motor neuron degeneration and improved axonal function and motor behavior in mice. The results suggest that fetal treatment might increase the efficacy of current therapies for treating SMA.


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

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