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RETRACTED ARTICLE: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN

Nature Biotechnology volume 28, pages 271–274 (2010)Cite this article

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This article was retracted on 06 October 2022

This article has been updated

Abstract

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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Acknowledgements

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.

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Author notes

  1. Xueyong Wang and Vicki L McGovern: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA

    Kevin D Foust, Lyndsey Braun, Adam K Bevan, Amanda M Haidet & Brian K Kaspar

  2. Wright State University, Dayton, Ohio, USA

    Xueyong Wang & Mark M Rich

  3. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA

    Vicki L McGovern, Thanh T Le, Arthur H M Burghes & Brian K Kaspar

  4. Integrated Biomedical Graduate Program, The Ohio State University, Columbus, Ohio, USA

    Adam K Bevan, Amanda M Haidet, Arthur H M Burghes & Brian K Kaspar

  5. The Mannheimer Foundation, Inc., Homestead, Florida, USA

    Pablo R Morales

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Contributions

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.

Corresponding author

Correspondence to Brian K Kaspar.

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The authors declare no competing financial interests.

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Supplementary Figs. 1–7 and Supplementary Table 1 (PDF 7851 kb)

Supplementary Movie (MOV 5968 kb)

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Foust, K., Wang, X., McGovern, V. et al. RETRACTED ARTICLE: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 28, 271–274 (2010). https://doi.org/10.1038/nbt.1610

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  • DOI: https://doi.org/10.1038/nbt.1610

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