A lentiviral strategy for highly efficient retrograde gene transfer by pseudotyping with fusion envelope glycoprotein.
The lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) is used extensively in gene therapy trials of neurological and neurodegenerative diseases. Retrograde axonal transport of viral vectors offers a great advantage to the delivery of genes into neuronal cell bodies that are situated in regions distant from the injection site. Pseudotyping of HIV-1-based vectors with selective variants of rabies virus glycoprotein (RV-G) increases gene transfer via retrograde transport into the central nervous system. Because large-scale application for gene therapy trials requires high titer stocks of the vector, pseudotyping of a lentiviral vector that produces more efficient retrograde transport is needed. In the present study, we developed a novel vector system for highly efficient retrograde gene transfer by pseudotyping an HIV-1 vector with a fusion envelope glycoprotein (termed FuG-B) in which the cytoplasmic domain of RV-G was substituted by the corresponding part of vesicular stomatitis virus glycoprotein. The FuG-B pseudotype shifted the transducing property of the lentiviral vector and enhanced the retrograde transport-mediated gene transfer into different brain regions innervating the striatum with greater efficiency than that of the RV-G pseudotype in mice. In addition, injection of the FuG-B-pseudotyped vector into monkey striatum (caudate and putamen) allowed for highly efficient gene delivery into the nigrostriatal dopamine system, which is a major target for gene therapy of Parkinson's disease. Our strategy provides a powerful tool for the treatment of certain neurological and neurodegenerative diseases by promoting retrograde gene delivery via a lentiviral vector.
Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan.
Shigeki
S
Kato
Kenta
K
Kobayashi
Ken-ichi
K
Inoue
Masahito
M
Kuramochi
Tomoaki
T
Okada
Hiroyuki
H
Yaginuma
Kinjiro
K
Morimoto
Takashi
T
Shimada
Masahiko
M
Takada
Kazuto
K
Kobayashi
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics*; D003342:Corpus Striatum / Q000378:metabolism / Q000821:virology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics*; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D011820:Rabies virus / Q000378:metabolism; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000235:genetics*
D000956:Antigens, Viral; D006023:Glycoproteins; D014759:Viral Envelope Proteins; C064951:glycoprotein G, Rabies virus