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

Abstract：

: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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Kong L,Valdivia DO,Simon CM,Hassinan CW,Delestrée N,Ramos DM,Park JH,Pilato CM,Xu X,Crowder M,Grzyb CC,King ZA,Petrillo M,Swoboda KJ,Davis C,Lutz CM,Stephan AH,Zhao X,Weetall M,Naryshkin NA,Crawford TO,Mentis GZ

doi

10.1126/scitranslmed.abb6871

subject

Has Abstract

pub_date

2021-01-27 00:00:00

issue

578

eissn

1946-6234

issn

1946-6242

pii

13/578/eabb6871

journal_volume

13

pub_type

杂志文章

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