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Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs

Gene Therapy volume 19, pages 852–859 (2012)Cite this article

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Abstract

Adeno-associated viral vector 9 (AAV9) has recently been shown to penetrate the blood–brain barrier via intravascular administration, making it a good candidate for diffuse gene delivery. However, the potential side effects of systemic delivery are unknown. Intrathecal viral vector administration may be more invasive than intravenous injections, but it requires far less vector and it can be performed on an outpatient basis, making it an ideal route of delivery for clinical translation. A total of 12 domestic farm pigs (<20 kg) underwent a single-level lumbar laminectomy with intrathecal catheter placement for AAV9 delivery. Animals were perfused and the tissue was harvested 30 days after treatment. Gene expression was assessed by anti-green fluorescent protein immunohistochemistry. Although a single lumbar injection resulted in gene expression limited to the lumbar segment of the spinal cord, three consecutive boluses via a temporary catheter resulted in diffuse transduction of motor neurons (MNs) throughout the cervical, thoracic and lumbar spinal cords. We now present the first successful robust transduction of MNs in the spinal cord of a large animal via intrathecal gene delivery using a self-complementary AAV9. These promising results can be translated to many MN diseases requiring diffuse gene delivery.

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Acknowledgements

We thank Cary H Leung, Brenten L Heeke and Lachlan Busby for their help with the immunohistochemistry protocol. We thank Lavanya Bachaboina and Swati Yadav for technical assistance. We acknowledge Jim Wilson's group at the University of Pennsylvania for the discovery of AAV9, and we also thank Xiao Xiao, PhD (UNC) and the UNC Vector Core for providing the AAV9 helper plasmid. This work was supported by Hannah's Hope Fund.

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Authors and Affiliations

  1. Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA

    T Federici, J S Taub, G R Baum, K A Matthews, C R Handy & N M Boulis

  2. Center for Gene Therapy, University of North Carolina, Chapel Hill, NC, USA

    S J Gray, J C Grieger & R J Samulski

  3. Genzyme, Framingham, MA, USA

    M A Passini

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  1. T Federici
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Correspondence to N M Boulis.

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Competing interests

RJS is the founder of Asklepios BioPharmaceutical Inc. MAP is a paid employee of Genzyme. Other authors declare no conflict interests.

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Federici, T., Taub, J., Baum, G. et al. Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther 19, 852–859 (2012). https://doi.org/10.1038/gt.2011.130

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