Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery.
In this report it is demonstrated for the first time that rabies-G envelope of the rabies virus is sufficient to confer retrograde axonal transport to a heterologous virus/vector. After delivery of rabies-G pseudotyped equine infectious anaemia virus (EIAV) based vectors encoding a marker gene to the rat striatum, neurons in regions distal from but projecting to the injection site, such as the dopaminergic neurons of the substantia nigra pars compacta, become transduced. This retrograde transport to appropriate distal neurons was also demonstrated after delivery to substantia nigra, hippocampus and spinal cord and did not occur when vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors were delivered to these sites. In addition, peripheral administration of rabies-G pseudotyped vectors to the rat gastrocnemius muscle leads to gene transfer in motoneurons of lumbar spinal cord. In contrast the same vector pseudotyped with VSV-G transduced muscle cells surrounding the injection site, but did not result in expression in any cells in the spinal cord. Long-term expression was observed after gene transfer in the nervous system and a minimal immune response which, together with the possibility of non-invasive administration, greatly extends the utility of lentiviral vectors for gene therapy of human neurological disease.
Mazarakis
N D
ND
Oxford Biomedica (UK) Ltd, Medawar Centre, The Oxford Science Park, Oxford OX4 4GA, UK. n.mazarakis@oxfordbiomedica.co.uk
Azzouz
M
M
Rohll
J B
JB
Ellard
F M
FM
Wilkes
F J
FJ
Olsen
A L
AL
Carter
E E
EE
Barber
R D
RD
Baban
D F
DF
Kingsman
S M
SM
Kingsman
A J
AJ
O'Malley
K
K
Mitrophanous
K A
KA
D000818:Animals; D000956:Antigens, Viral; D001370:Axonal Transport / Q000502:physiology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000821:virology; D017931:DNA Primers / Q000737:chemistry; D004279:DNA, Viral / Q000032:analysis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics*; D007124:Immunoenzyme Techniques; D004860:Infectious Anemia Virus, Equine / Q000502:physiology*; D007763:Lac Operon / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D009420:Nervous System / Q000821:virology*; D016133:Polymerase Chain Reaction; D011818:Rabies / Q000821:virology*; D011820:Rabies virus / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D014759:Viral Envelope Proteins / Q000235:genetics*
D000956:Antigens, Viral; D017931:DNA Primers; D004279:DNA, Viral; C028391:G protein, vesicular stomatitis virus; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; C064951:glycoprotein G, Rabies virus