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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Change history
06 October 2022
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41587-022-01497-7
References
Burghes, A.H. & Beattie, C.E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci. 10, 597–609 (2009).
Foust, K.D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009).
Gao, G. et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J. Virol. 78, 6381–6388 (2004).
McCarty, D.M. et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 10, 2112–2118 (2003).
Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).
McGovern, V.L., Gavrilina, T.O., Beattie, C.E. & Burghes, A.H. Embryonic motor axon development in the severe SMA mouse. Hum. Mol. Genet. 17, 2900–2909 (2008).
MacKenzie, A.E. & Gendron, N.H. Tudor reign. Nat. Struct. Biol. 8, 13–15 (2001).
Gavrilina, T.O. et al. Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum. Mol. Genet. 17, 1063–1075 (2008).
Azzouz, M. et al. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J. Clin. Invest. 114, 1726–1731 (2004).
Avila, A.M. et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J. Clin. Invest. 117, 659–671 (2007).
Hastings, M.L. et al. Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Sci. Transl. Med 1, 5–14 (2009).
Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17, 1187–1196 (2009).
Le, T.T. et al. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum. Mol. Genet. 14, 845–857 (2005).
Butchbach, M.E., Edwards, J.D. & Burghes, A.H. Abnormal motor phenotype in the SMNDelta7 mouse model of spinal muscular atrophy. Neurobiol. Dis. 27, 207–219 (2007).
Kong, L. et al. Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J. Neurosci. 29, 842–851 (2009).
Wang, X. et al. Decreased synaptic activity shifts the calcium dependence of release at the mammalian neuromuscular junction in vivo. J. Neurosci. 24, 10687–10692 (2004).
Cifuentes-Diaz, C. et al. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. Hum. Mol. Genet. 11, 1439–1447 (2002).
Kariya, S. et al. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum. Mol. Genet. 17, 2552–2569 (2008).
Murray, L.M. et al. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum. Mol. Genet. 17, 949–962 (2008).
Narver, H.L. et al. Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann. Neurol. 64, 465–470 (2008).
Clark, K.R. et al. Gene transfer into the CNS using recombinant adeno-associated virus: analysis of vector DNA forms resulting in sustained expression. J. Drug Target. 7, 269–283 (1999).
Duan, D. et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J. Virol. 72, 8568–8577 (1998).
Nakai, H. et al. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J. Virol. 75, 6969–6976 (2001).
Saunders, N.R., Joakim Ek, C. & Dziegielewska, K.M. The neonatal blood-brain barrier is functionally effective, and immaturity does not explain differential targeting of AAV9. Nat. Biotechnol. 27, 804–805, author reply 805 (2009).
Kota, J. et al. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci. Transl. Med 1, 6–15 (2009).
Koerber, J.T. et al. Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Mol. Ther. 17, 2088–2095 (2009).
Maheshri, N., Koerber, J.T., Kaspar, B.K. & Schaffer, D.V. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat. Biotechnol. 24, 198–204 (2006).
Asokan, A. et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat. Biotechnol. 28, 79–82 (2010).
Pyatt, R.E., Mihal, D.C. & Prior, T.W. Assessment of liquid microbead arrays for the screening of newborns for spinal muscular atrophy. Clin. Chem. 53, 1879–1885 (2007).
Monani, U.R. et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn−/− mice and results in a mouse with spinal muscular atrophy. Hum. Mol. Genet. 9, 333–339 (2000).
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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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.
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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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