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.

Systemic gene delivery to the central nervous system using Adeno-associated virus

“…Consistent with mouse, rat, and cat studies, efficient gene delivery and brain transduction has been reported after systemic injection of rAAV in macaque monkeys (Bevan et al, 2011; Gray et al, 2011b; Dehay et al, 2012; Mattar et al, 2012; Samaranch et al, 2012). Even though some methodological discrepancies between studies prevent a clear comparison of the results, some conclusions can be achieved.…”

“…Even though some methodological discrepancies between studies prevent a clear comparison of the results, some conclusions can be achieved. Systemic administration of rAAV9 to adult monkeys induced mostly glial transduction (Bevan et al, 2011; Gray et al, 2011b; Samaranch et al, 2012) while injection in neonate animals induced neuronal transduction (Dehay et al, 2012; Mattar et al, 2012). Another concern in this field of research involves anti-AAV antibodies, which are commonly present in both non-human primate and humans (Boutin et al, 2010; Calcedo et al, 2011; Gray et al, 2011b; Samaranch et al, 2012).…”

Transduction of the Central Nervous System After Intracerebroventricular Injection of Adeno-Associated Viral Vectors in Neonatal and Juvenile Mice

“…Intravenous delivery is relatively noninvasive and can result in homogeneous vector distribution in the CNS. Several groups have reported on the ability of AAV9 vectors to cross the blood-brain barrier and transduce neurons and astrocytes after intravenous injection into neonatal mice, adult mice, cats, and nonhuman primates (Duque et al, 2009;Foust et al, 2009;Rahim et al, 2011;Mattar et al, 2013). However, a disadvantage of this approach is the high biodistribution of the vector to off-target peripheral tissues, thus potentially compromising the level of expression and treatment efficacy.…”

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

“…Mattar et al also demonstrated efficient neuronal transduction after in utero delivery of AAV9 in non-human primates [91]. Nevertheless, this method presents significant practical concerns related to prenatal diagnostic techniques and the risks associated with the treatment [92].…”