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Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems

Gene Therapy volume 20, pages 69–83 (2013)Cite this article

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Abstract

Correction of perinatally lethal neurogenetic diseases requires efficient transduction of several cell types within the relatively inaccessible CNS. Intravenous AAV9 delivery in mouse has achieved development stage-specific transduction of neuronal cell types, with superior neuron-targeting efficiency demonstrated in prenatal compared with postnatal recipients. Because of the clinical relevance of the non-human primate (NHP) model, we investigated the ability of AAV9 to transduce the NHP CNS following intrauterine gene therapy (IUGT). We injected two macaque fetuses at 0.9 G with 1 × 1013 vg scAAV9-CMV-eGFP through the intrahepatic continuation of the umbilical vein. Robust green fluorescent protein (GFP) expression was observed for up to 14 weeks in the majority of neurons (including nestin-positive cells), motor neurons and oligodendrocytes throughout the CNS, with a significantly lower rate of transduction in astrocytes. Photoreceptors and neuronal cell bodies in the plexiform and ganglionic retinal layers were also transduced. In the peripheral nervous system (PNS), widespread transduction of neurons was observed. Tissues harvested at 14 weeks showed substantially lower vector copy number and GFP levels, although the percentage of GFP-expressing cells remained stable. Thus, AAV9-IUGT in late gestation efficiently transduces both the CNS and PNS with neuronal predilection, of translational relevance to hereditary disorders characterized by perinatal onset of neuropathology.

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Acknowledgements

This work was funded by the Bio-Medical Research Council (06/121/19/450, 09/121/19/597) and National Medical Research Council (CSA/012/2009). CNM was supported by an Overseas Research Fellowship, MC and JKYC were supported by the Clinician Scientist Award (CSA/007/2009 and CSA/012/2009), National Medical Research Council, Singapore, and SNW was part-funded by a European Research grant, ‘SomaBio’. We acknowledge the assistance of Dr Bryan Ogden, Dr Darvi Mitchell, Ms Vivienne Liang, Ms Sheryl Loh and Mr CY Kiong in the care of the animals.

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Authors and Affiliations

  1. Experimental Fetal Medicine Group, National University of Singapore, Singapore

    C N Mattar, A Biswas, N Johana, N M Fisk, L G Tan, M Choolani & J K Y Chan

  2. Institute for Women's Health, University College, London, UK

    S N Waddington, A A Rahim & S M K Buckley

  3. Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore

    X W Ng & J K Y Chan

  4. University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia

    A S Fisk & N M Fisk

  5. DSO National Laboratories, Singapore

    M H Tan & J Lu

  6. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore

    J K Y Chan

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  1. C N Mattar
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Mattar, C., Waddington, S., Biswas, A. et al. Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems. Gene Ther 20, 69–83 (2013). https://doi.org/10.1038/gt.2011.216

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