Abstract
Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300–1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.
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Acknowledgements
The authors thank and are indebted to the families and patients for making this research possible. Writing and editorial support for the original manuscript was provided by Cadent Medical Communications (New York, NY, USA). Funding was provided by Novartis Gene Therapies, Inc.
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G.T., A.H.M.B., C.H., J.D., B.T.T.C., S.P., B.B., W.K.C., V.L.M., R.F.H., M.C. and C.R.P. performed the experiments. G.T., A.H.M.B., P.K., D.M.S., D.E.F., W.K.C., V.L.M., M.S., F.M., J.R.M. and K.D.F. analyzed the results. K.D.F. supervised the studies.
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J.D., S.P. and B.T.T.C. are employees of Novartis Gene Therapies, Inc. and hold shares in Novartis. B.B., G.T., C.H., D.M.S., D.E.F., P.K. and K.D.F. are former employees of Novartis Gene Therapies, Inc. W.K.C. received honoraria for participation in a scientific advisory board for Regeneron Genetics Center and received grant support from Biogen for a newborn screening study outside of this study. A.H.M.B. is a consultant for Novartis Gene Therapies, Inc., for this study and other work, and conducted research for Exicure, Inc., outside of this study. V.L.M., C.R.P., and M.C. have nothing to disclose. R.F.H. was a consultant for Cunningham Meyer & Vedrine, PC, and Phillips Parker Orbeson & Arnett, PLC, outside of this study. J.R.M. is a consultant for Novartis Gene Therapies, Inc., for this study and other work, and receives honoraria for participation in scientific advisory boards from Novartis Gene Therapies, Inc., for this study and other work. M.S. reports honoraria for participation in scientific advisory boards from Novartis Gene Therapies, Inc., for this study and other work, Biogen and Roche, and for scientific presentation in Biogen-sponsored symposia outside of this study. F.M. reports a grant from Biogen for newborn screening and for registries outside of this study. F.M. also reports honoraria for participation in scientific advisory boards from Novartis Gene Therapies, Inc., for this study and other work, Biogen and Roche, and for scientific presentation at their industry-sponsored symposia outside of this study. Novartis Gene Therapies, Inc., sponsored the STR1VE-US (NCT03306277) and STR1VE-EU studies (NCT03461289).
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Thomsen, G., Burghes, A.H.M., Hsieh, C. et al. Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue. Nat Med 27, 1701–1711 (2021). https://doi.org/10.1038/s41591-021-01483-7
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DOI: https://doi.org/10.1038/s41591-021-01483-7
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