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Central and peripheral delivered AAV9-SMN are both efficient but target different pathomechanisms in a mouse model of spinal muscular atrophy

Gene Therapy volume 29, pages 544–554 (2022)Cite this article

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Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the SMN1 gene and low SMN protein levels. Although lower motor neurons are a primary target, there is evidence that peripheral organ defects contribute to SMA. Current SMA gene therapy and clinical trials use a single intravenous bolus of the blood-brain-barrier penetrant scAAV9-cba-SMN by either systemic or central nervous system (CNS) delivery, resulting in impressive amelioration of the clinical phenotype but not a complete cure. The impact of scAAV9-cba-SMN treatment regimens on the CNS as well as on specific peripheral organs is yet to be described in a comparative manner. Therefore, we injected SMA mice with scAAV9-cba-SMN either intravenously (IV) for peripheral SMN restoration or intracerebroventricularly (ICV) for CNS-focused SMN restoration. In our system, ICV injections increased SMN in peripheral organs and the CNS while IV administration increased SMN in peripheral tissues only, largely omitting the CNS. Both treatments rescued several peripheral phenotypes while only ICV injections were neuroprotective. Surprisingly, both delivery routes resulted in a robust rescue effect on survival, weight, and motor function, which in IV-treated mice relied on peripheral SMN restoration but not on targeting the motor neurons. This demonstrates the independent contribution of peripheral organs to SMA pathology and suggests that treatments should not be restricted to motor neurons.

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Fig. 1: Peripheral and spinal cord SMN levels in response to ICV and IV scAAV9-cba-SMN injection.
Fig. 2: Impact of ICV and IV scAAV9-cba-SMN injection on motor neuron degeneration in Smn2B/− mice.
Fig. 3: Impact of ICV and IV scAAV9-cba-SMN injection on neuromuscular junction pathology in Smn2B/− mice.
Fig. 4: Impact of ICV and IV scAAV9-cba-SMN on SMA-like pathophysiology.
Fig. 5: Impact of ICV and IV scAAV9-cba-SMN injection on peripheral organ defects in Smn2B/− mice.
Fig. 6: Graphical summary of the rescue of SMA-like pathology after ICV and IV scAAV9-cba-SMN injection of Smn2B/− mice.

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Data availability

Additional data are available from the corresponding author upon request.

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Acknowledgements

The authors thank Dr. Ronald Booth and Adrienne Rowan from the Eastern Ontario Regional Laboratory Association at The Ottawa Hospital for assistance with some of the NfL assays. RK was supported by Muscular Dystrophy Association (USA) (grant number 575466); Muscular Dystrophy Canada; and Canadian Institutes of Health Research (CIHR) (grant number PJT-156379). AR was supported by a CNMD STAR Award from the University of Ottawa Brain and Mind Institute. MOD was supported by Frederick Banting and Charles Best CIHR Doctoral Research Award.

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Authors and Affiliations

  1. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada

    Aoife Reilly, Marc-Olivier Deguise, Ariane Beauvais, Rebecca Yaworski, Niko Hensel & Rashmi Kothary

  2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

    Aoife Reilly, Marc-Olivier Deguise & Rashmi Kothary

  3. Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Canada

    Aoife Reilly, Marc-Olivier Deguise, Niko Hensel & Rashmi Kothary

  4. Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada

    Simon Thebault

  5. Department of Medicine, University of Ottawa, Ottawa, Canada

    Simon Thebault & Rashmi Kothary

  6. Department of Physics, University of Ottawa, Ottawa, Canada

    Daniel R. Tessier & Vincent Tabard-Cossa

  7. Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Bernard L. Schneider

  8. Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne, Geneva, Switzerland

    Bernard L. Schneider

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Contributions

A.R. and R.K. designed research. A.R., M.O.D., A.B., R.Y., S.T., and D.R.T. performed experiments. B.L.S. and V.T.C. provided material support. A.R., M.O.D., and N.H. analyzed the data. A.R., N.H., and R.K. wrote the manuscript with input from all authors. R.K. designed the study.

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Correspondence to Rashmi Kothary.

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Competing interests

R.K. received honoraria and travel accommodations from Roche as an invited speaker at their global and national board meetings in 2019. R.K. and the Ottawa Hospital Research Institute have a licensing agreement with Biogen for the Smn2B/− mouse model. MOD received honoraria and travel accommodations from Biogen for speaking engagements at the SMA Summit 2018 held in Montreal, Canada and SMA Academy 2019 held in Toronto, Canada. These COIs are outside the scope of this study. All other authors have no competing interests to declare.

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Reilly, A., Deguise, MO., Beauvais, A. et al. Central and peripheral delivered AAV9-SMN are both efficient but target different pathomechanisms in a mouse model of spinal muscular atrophy. Gene Ther 29, 544–554 (2022). https://doi.org/10.1038/s41434-022-00338-1

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