Specific gene expression in unmyelinated dorsal root ganglion neurons in nonhuman primates by intra-nerve injection of AAV 6 vector

Abstract

Adeno-associated virus 6 (AAV6) has been proposed as a potential vector candidate for specific gene expression in pain-related dorsal root ganglion (DRG) neurons, but this has not been confirmed in nonhuman primates. The aim of our study was to analyze the transduction efficiency and target specificity of this viral vector in the common marmoset by comparing it with those in the rat. When green fluorescent protein-expressing serotype-6 vector was injected into the sciatic nerve, the efficiency of gene expression in DRG neurons was comparable in both species. We found that the serotype-6 vector was largely specific to the pain-related ganglion neurons in the marmoset, as well as in the rat, whereas the serotype-9 vector resulted in contrasting effects in the two species. Neither AAV6 nor AAV9 resulted in DRG toxicity when administered via the sciatic nerve, suggesting this as a safer route of sensory nerve transduction than the currently used intrathecal or intravenous administrative routes. Furthermore, the AAV6 vector could be an optimal serotype for gene therapy for human chronic pain that has a minimal effect on other somatosensory functions of DRG neurons.

Selective RNAi-silencing of Schwann cell Piezo1 alleviates mechanical hypersensitization following peripheral nerve injury

“…AAV serotype 8 with a CMV promoter via direct sciatic nerve injection also transduces SCs; 59 however, other study shows that sciatic nerve injection of AAV8 efficiently transduces sensory neurons. 60 Our data show that, comparable to the other reports, 61 , 62 sciatic nerve injection AAV6 with CBA promoter for transcription induces widespread non-cell specific transgene expression in SCs, afferent axons, sensory neuron somata, and central and peripheral terminals as well as motor neurons in the ventral horn via retrograde transduction ( Fig. 3 ).…”

Distribution of Large and Small Dorsal Root Ganglion Neurons in Common Marmosets

“…Furthermore, transgenic marmoset models of human disease have been developed recently (Sasaki et al, 2009 ; Sato et al, 2016 ; Tomioka et al, 2017 ). Our results add another example to the similarities between marmosets and humans and suggest that marmosets could be an animal model for human peripheral nerve disorders and their treatment (Kudo et al, 2021 ).…”

“…This limitation could be addressed by establishing a non-human primate model for analyzing DRG neuron anatomy and function. To this end, we have established electrophysiological (Umeda et al, 2012 ) and immunohistochemical assays for DRG neurons of non-human primates (Kudo et al, 2021 ). In this short report, we elucidated the size and distribution of DRG neurons in non-human primates and compared them with those of rodent DRG neurons.…”

Mapping of the Sensory Innervation of the Mouse Lung by Specific Vagal and Dorsal Root Ganglion Neuronal Subsets

“…This is consistent with other rAAV2 studies in the mouse lung that failed to trace to DRG neurons ( Su et al, 2021 ), despite the fact that conventional retrograde tracers such as fast blue or DiI identify many lung-labeled DRG afferents ( Kummer et al, 1992 ; Dinh et al, 2004 ; Oh et al, 2006 ; Nassenstein et al, 2010 ). AAV tropism for afferent subsets may be dependent not only on the intrinsic properties of the vector and the neuron ( Mason et al, 2010 ; Jacques et al, 2012 ; Kudo et al, 2021 ) but also perhaps on the properties of the afferent terminal within the specific lung tissue. Given the widespread use of AAVs, more work is needed to explore afferent subset-specific tropism in situ .…”