Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy
Cathleen M. Lutz, … , Margaret L. Winberg, Umrao R. Monani
Cathleen M. Lutz, … , Margaret L. Winberg, Umrao R. Monani
Published July 25, 2011
Citation Information: J Clin Invest. 2011;121(8):3029-3041. https://doi.org/10.1172/JCI57291.
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Research Article

Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment.

Authors

Cathleen M. Lutz, Shingo Kariya, Sunita Patruni, Melissa A. Osborne, Don Liu, Christopher E. Henderson, Darrick K. Li, Livio Pellizzoni, José Rojas, David M. Valenzuela, Andrew J. Murphy, Margaret L. Winberg, Umrao R. Monani

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Figure 3

Restoration of the SMN protein in symptomatic SMA model mice rescues the disease phenotype.

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Restoration of the SMN protein in symptomatic SMA model mice rescues the...
(A) Western blotting reveals disease state levels of spinal cord SMN protein in nontreated P4 animals homozygous for the hybrid allele. (B) NMJ pathology in untreated P4 mutants manifests as poor terminal arborization and NF engorged nerve terminals (arrowheads). (C) Postsymptomatic TM treatment of Cre-ER–positive but not Cre-ER–negative mutant mice overcomes disease-related downturn in growth at P13 and accounts for a significant increase in weight by P17 (n ≥ 16, **P < 0.01, Student’s t test). (D) Improved motor performance in a righting reflex assay (n ≥ 4) following TM treatment at P4. (E) Mutant SMN2;Δ7;Cre-ER;SmnRes/Res mice treated at P4 with TM and sacrificed at P16–P17 express increased SMN protein in nervous as well as nonnervous tissue. Controls were WT (Smn+/+) at the murine Smn locus. (F) NMJs of gastrocnemius muscle of TM-treated mutants exhibit a reduction but not complete absence of pathology at P17 (solid arrowhead), whereas those of untreated mutants become progressively worse, displaying NF swollen nerve terminals (arrows) and immature, plaque-like motor endplates (open arrowheads). (G) Significant increase in the size of the motor endplate of TM-treated mutants compared with those of untreated mutants (100 endplates assessed in each of 3 mice; *P < 0.05; **P < 0.01, Student’s t test). (H) An increase in SMN-mediated snRNP assembly is observed in TM-treated mutants at 4 days after treatment. n = 4, *P < 0.05, Student’s t test. Scale bars: 10 μm (B); 40 μm and 10 μm (enlarged images of NMJs). (F). Data are represented as mean ± SEM.