Abstract
Gene transfer through retrograde axonal transport of viral vectors offers a substantial advantage for analyzing roles of specific neuronal pathways or cell types forming complex neural networks. This genetic approach may also be useful in gene therapy trials by enabling delivery of transgenes into a target brain region distant from the injection site of the vectors. Pseudotyping of a lentiviral vector based on human immunodeficiency virus type 1 (HIV-1) with various fusion envelope glycoproteins composed of different combinations of rabies virus glycoprotein (RV-G) and vesicular stomatitis virus glycoprotein (VSV-G) enhances the efficiency of retrograde gene transfer in both rodent and nonhuman primate brains. The most recently developed lentiviral vector is a pseudotype with fusion glycoprotein type E (FuG-E), which demonstrates highly efficient retrograde gene transfer in the brain. The FuG-E–pseudotyped vector permits powerful experimental strategies for more precisely investigating the mechanisms underlying various brain functions. It also contributes to the development of new gene therapy approaches for neurodegenerative disorders, such as Parkinson’s disease, by delivering genes required for survival and protection into specific neuronal populations. In this review article, we report the properties of the FuG-E–pseudotyped vector, and we describe the application of the vector to neural circuit analysis and the potential use of the FuG-E vector in gene therapy for Parkinson’s disease.
Highlights
To understand the mechanisms underlying brain functions controlled through complex neural networks, an analysis of the functions of specific neuronal pathways and cell types forming these complex networks is necessary
A conventional type of the human immunodeficiency virus type 1 (HIV-1)–based lentiviral vector pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G) has a low efficiency for retrograde gene transfer, which can be improved by pseudotyping with selective variants of rabies virus glycoprotein (RV-G; Mentis et al, 2006; Kato et al, 2007; Federici et al, 2009)
To enhance the efficiency of retrograde gene delivery, we previously developed a novel lentiviral vector capable of highly efficient retrograde gene transfer (HiRet) by pseudotyping with fusion glycoprotein type B (FuG-B), which is composed of the extracellular/transmembrane domains of Rabies virus (RV)-G and the intracellular domain of VSV-G (Kato et al, 2011a,b)
Summary
To understand the mechanisms underlying brain functions controlled through complex neural networks, an analysis of the functions of specific neuronal pathways and cell types forming these complex networks is necessary. These analyses highlight that the FuG-E–pseudotyped vector achieves retrograde gene delivery with greater efficiency compared with the NeuRet vector pseudotyped with FuG-C, suggesting the important role of the sequences of the membraneproximal regions of viral envelope glycoproteins in retrograde gene delivery This type of vector provides a powerful experimental strategy to investigate the mechanisms underlying various neural functions more precisely, and it offers a promising genetic tool for gene therapy trials for neurological and neurodegenerative disorders. The FuG-E vector achieves a higher efficiency of retrograde gene delivery compared with the previously developed NeuRet vector, and it permits neuron-specific gene transduction around the injection site in the brain (Kato et al, 2014). Our newly developed FuG-E vector system with these attractive characteristics may serve as a powerful genetic tool in gene therapy trials for Parkinson’s disease
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