Chimeric rabies SADB19-VSVg-pseudotyped lentiviral vectors mediate long-range retrograde transduction from the mouse spinal cord

• Published in: Gene therapy 2015-05, Vol.22 (5), p.357-364
• Main Authors: Schoderboeck, L, Riad, S, Bokor, A M, Wicky, H E, Strauss, M, Bostina, M, Oswald, M J, Empson, R M, Hughes, S M
• Format: Article
• Language: English
• Subjects: 42; 42/44; 631/1647/2300; 64; 64/60; Analysis; Animals; Axonal Transport; Biomedical and Life Sciences; Biomedicine; Brain; Brain stem; Care and treatment; Cell Biology; Cells, Cultured; Cellular biology; Cerebral cortex; Fluorescence; Gene Expression; Gene Therapy; Gene transfer; Gene Transfer Techniques; Genes; Genetic transformation; Genetic Vectors - genetics; Glycerol Kinase - genetics; Glycoproteins; Green fluorescent protein; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health aspects; HIV infection; Human Genetics; Hypothalamus; Injection; Lentivirus - genetics; Mice; Mice, Inbred C57BL; Nanotechnology; Neurons; Neurons - metabolism; original-article-enabling-technologies; Promoter Regions, Genetic; Proteins; Rabies; Rabies virus - genetics; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Retrograde transport; Risk factors; Spinal cord; Spinal Cord - cytology; Spinal Cord - metabolism; Stomatitis; Transgenes; Vesicular stomatitis virus; Vesiculovirus - genetics; Viral Envelope Proteins - genetics; Viral Envelope Proteins - metabolism; Virions
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2015.3

Lentiviral vectors have proved an effective method to deliver transgenes into the brain; however, they are often hampered by a lack of spread from the site of injection. Modifying the viral envelope with a portion of a rabies envelope glycoprotein can enhance spread in the brain by using long-range axon projections to facilitate retrograde transport. In this study, we generated two chimeric envelopes containing the extra-virion and transmembrane domain of rabies SADB19 or CVS-N2c with the intra-virion domain of vesicular stomatitis virus. Viral particles were packaged containing a green fluorescent protein reporter construct under the control of the phosphoglycerokinase promoter. Both vectors produced high-titer particles with successful integration of the glycoproteins into the particle envelope and significant transduction of neurons in vitro . Injection of the SADB19 chimeric viral vector into the lumbar spinal cord of adult mice mediated a strong preference for gene transfer to local neurons and axonal terminals, with retrograde transport to neurons in the brainstem, hypothalamus and cerebral cortex. Development of this vector provides a useful means to reliably target select populations of neurons by retrograde targeting.