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Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates

A Corrigendum to this article was published on 04 April 2013

This article has been updated

Abstract

Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of 2 × 1012 vector genome (vg) per 3–6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases.

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  • 04 April 2013

    This article has been corrected since online publication and a corrigendum is also printed in this issue.

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Acknowledgements

This work was supported by generous grants from Hannah’s Hope Fund (to SJG), Award Number UL1RR025747 from the National Center for Research Resources (to SJG), the Senator Paul D Wellstone Muscular Dystrophy Cooperative Research Center Grant U54-AR056953 (to RJS), NIH Research Grant 5R01AI072176-05 (to RJS) and NIH Research Grant NS35633 (to TJM), as well as a kind gift from the Jasper Against Batten Foundation at Partnership for Cures (for support of SJG’s research). We are extremely thankful to MPI Research for the quality and timeliness of the work and for help with study design; in particular, we would like to acknowledge the roles of Mark Johnson, Missy Peet and David Serota. We thank the UNC Vector Core, in particular Josh Grieger, for technical assistance with vector production. We also thank Lavanya Bachaboina, Huijing Sun and Erica Jones for help with tissue sectioning and IHC, Brendan Fitzpatrick and Jennifer Coleman in Mark Zylka’s laboratory (UNC) for help with intrathecal mouse injections and Swati Yadav and Hung-Jui ‘Sophia’ Shih for running qPCR reactions. We would also like to acknowledge Jim Wilson’s group at the University of Pennsylvania for the discovery of AAV9, and thank Xiao Xiao at UNC and the UNC Vector Core for providing the AAV9 helper plasmid.

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Correspondence to S J Gray.

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Gray, S., Nagabhushan Kalburgi, S., McCown, T. et al. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 20, 450–459 (2013). https://doi.org/10.1038/gt.2012.101

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Keywords

  • AAV
  • cerebrospinal fluid
  • brain
  • spinal cord
  • non-human primate

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