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Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model


Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality; it results from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene1. Humans have a paralogue, SMN2, whose exon 7 is predominantly skipped2, but the limited amount of functional, full-length SMN protein expressed from SMN2 cannot fully compensate for a lack of SMN1. SMN is important for the biogenesis of spliceosomal small nuclear ribonucleoprotein particles3, but downstream splicing targets involved in pathogenesis remain elusive. There is no effective SMA treatment, but SMN restoration in spinal cord motor neurons is thought to be necessary and sufficient4. Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported in severe SMA mouse models and patients5,6,7,8, reflecting autonomic dysfunction or direct effects in cardiac tissues. Here we compared systemic versus CNS restoration of SMN in a severe mouse model9,10. We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection11,12. Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median lifespan by 25 fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals expression, leading to a pronounced reduction in circulating insulin-like growth factor 1 (IGF1), and ASO-10-27 treatment restored IGF1 to normal levels. These results suggest that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate.

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Figure 1: Systemic versus ICV ASO-10-27 injections in SMA mice.
Figure 2: SMN2 splicing and protein expression in mouse tissues after SC injection of ASO-10-27.
Figure 3: Evaluation of affected tissues and motor function.
Figure 4: The IGF1 system is disrupted in SMA mice.


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We gratefully acknowledge support from the Muscular Dystrophy Association, the National Institute of General Medical Sciences and St. Giles Foundation. We thank J. Bu and M. Passini for protocols and advice on NMJ staining, and S. Hearn for assistance with microscope imaging.

Author information




Y.H., A.R.K. and C.F.B. designed the study and wrote the paper. Y.H., K.S., F.R., G. Hung and G. Horev carried out the experiments and analysed the data. All authors read the manuscript.

Corresponding author

Correspondence to Adrian R. Krainer.

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Competing interests

F.R., G. Hung, and C.F.B. may materially benefit either directly or indirectly through stock options. Y.H., K.S. and A.R.K., along with their employer, could materially benefit if a therapeutic for SMA results from this work.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-3, Supplementary Figures 1-15 with legends and an additional reference. (PDF 1843 kb)

Supplementary Movie 1

This movie shows two P7 pups, both untreated. The smaller one is an SMA mouse and the other one is its heterozygous littermate. (MOV 18216 kb)

Supplementary Movie 2

This movie shows five 3-week-old newly weaned mice. Three representative SMA mice that had been treated with subcutaneous ASO administration (SC80) between P0-P3 have shorter tails, and two untreated heterozygous mice have normal tails. (MOV 21283 kb)

Supplementary Movie 3

This movie shows two 3-month-old mice on a Rotarod test with a four-phase acceleration profile. The one that passed the test and has a shorter tail is an SMA mouse from group SC160, and the other mouse is a heterozygote. 36% of SC160 rescued SMA mice passed this test; 33% of heterozygous mice did not pass the test. (MOV 8152 kb)

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Hua, Y., Sahashi, K., Rigo, F. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123–126 (2011).

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