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

Mattar, C. N., Waddington, S. N., Biswas, A., Johana, N., Ng, X. W., Fisk, A. S., Fisk, N. M., Tan, L. G., Rahim, A. A., Buckley, S. M., Tan, M. H., Lu, J., Choolani, M. and Chan, J. K. (2012) Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems. Gene Therapy (Basingstoke), 20 1: 69-83. doi:10.1038/gt.2011.216


Author Mattar, C. N.
Waddington, S. N.
Biswas, A.
Johana, N.
Ng, X. W.
Fisk, A. S.
Fisk, N. M.
Tan, L. G.
Rahim, A. A.
Buckley, S. M.
Tan, M. H.
Lu, J.
Choolani, M.
Chan, J. K.
Title Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems
Language of Title eng
Journal name Gene Therapy (Basingstoke)   Check publisher's open access policy
Language of Journal Name eng
ISSN 0969-7128
1476-5462
Publication date 2012-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/gt.2011.216
Open Access Status Not yet assessed
Volume 20
Issue 1
Start page 69
End page 83
Total pages 15
Place of publication London, Hamps, U.K.
Publisher Nature Publishing Group
Language eng
Subject 1313 Molecular Medicine
1312 Molecular Biology
1311 Genetics
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 × 10 13 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.
Formatted 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.
Keyword Non-human primate
Central nervous system
Intrauterine gene transfer
AAV9
Neuron
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 06/121/19/450
CSA/012/2009
CSA/012/2009
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2013 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 20 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 02 Mar 2012, 20:01:54 EST by Roheen Gill on behalf of UQ Centre for Clinical Research