Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN


Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function1. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect 60% of motor neurons when injected intravenously into neonatal mice2,3,4. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA.

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Figure 1: Phenotypic correction of SMA mice injected on P1.
Figure 2: Effects of SMN treatment at P1 on NMJs of adult SMA mice.
Figure 3: Systemic injection of scAAV9-GFP into SMA mice of varying ages.


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This work was supported by NIH/NINDS R21NS064328 to B.K.K., NINDS R01NS038650 to A.H.M.B., NINDS core P30-NS045758, RC2 NS069476-01 and Miracles for Madison Fund to B.K.K. and A.H.M.B. and NINDS P01NS057228 to M.M.R. We thank R. Levine and E. Nurre for expert technical assistance and J. Ward for pathology services.

Author information

K.D.F., M.M.R., A.H.M.B. and B.K.K. designed and executed experiments and wrote the manuscript. V.L.M., X.W, L.B., A.M.H., A.K.B., P.R.M. and T.T.L. contributed to experiments.

Correspondence to Brian K Kaspar.

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Foust, K., Wang, X., McGovern, V. et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 28, 271–274 (2010).

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