title: Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems.
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.
authors.affiliation: Experimental Fetal Medicine Group, National University of Singapore, Singapore.
authors.forename: C N
authors.initials: CN
authors.lastname: Mattar
authors.forename: S N
authors.initials: SN
authors.lastname: Waddington
authors.forename: A
authors.initials: A
authors.lastname: Biswas
authors.forename: N
authors.initials: N
authors.lastname: Johana
authors.forename: X W
authors.initials: XW
authors.lastname: Ng
authors.forename: A S
authors.initials: AS
authors.lastname: Fisk
authors.forename: N M
authors.initials: NM
authors.lastname: Fisk
authors.forename: L G
authors.initials: LG
authors.lastname: Tan
authors.forename: A A
authors.initials: AA
authors.lastname: Rahim
authors.forename: S M K
authors.initials: SM
authors.lastname: Buckley
authors.forename: M H
authors.initials: MH
authors.lastname: Tan
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: M
authors.initials: M
authors.lastname: Choolani
authors.forename: J K Y
authors.initials: JK
authors.lastname: Chan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D008251:Macaca; D009836:Oligodendroglia / Q000378:metabolism; D017933:Peripheral Nervous System / Q000378:metabolism*; D011247:Pregnancy; D012160:Retina / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D049452:Green Fluorescent Proteins