Expression of nerve growth factor in vivo from a defective herpes simplex virus 1 vector prevents effects of axotomy on sympathetic ganglia.
Sympathetic neurons in the superior cervical ganglion (SCG) of adult rats depend on target-derived nerve growth factor (NGF) for maintenance of tyrosine hydroxylase (TH) levels and the noradrenergic neurotransmitter system. Axotomy of a SCG results in NGF deprivation, causing a decline in TH activity; continuous local application of NGF can prevent this decline in TH activity. We now report that injection of a defective herpes simplex virus 1 vector that expresses NGF (pHSVngf) into a SCG can prevent the decline in TH activity that follows axotomy. SCG of adult rats were injected with either pHSVngf virus or pNFlac virus, which expresses Escherichia coli beta-galactosidase. Analysis of RNA from pHSVngf-infected SCG indicated that the NGF gene was efficiently transcribed and processed. Furthermore, 4 days after pHSVngf injection animals underwent axotomy of the virus-injected SCG. After another 10 days, animals were sacrificed and both the injected-axotomized and contralateral control ganglia were assayed for TH activity. Axotomy of SCG injected with pNFlac virus produced a 50% decline in TH activity relative to control ganglia (P = 0.02). In contrast, SCG injected with pHSVngf virus did not show a decline in TH activity following axotomy; instead, these ganglia manifested an 18% increase in TH levels relative to control ganglia. These data demonstrate that herpes simplex virus 1 vectors can be used to modify neuronal physiology in vivo; specifically, expression of a critical gene product by neural cells that do not normally produce it has potential applications for gene therapy.
Federoff
H J
HJ
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461.
Geschwind
M D
MD
Geller
A I
AI
Kessler
J A
JA
D001483:Base Sequence; D002478:Cells, Cultured; D003673:Defective Viruses; D003714:Denervation; D005728:Ganglia, Sympathetic / Q000502:physiology*; D015870:Gene Expression; D005822:Genetic Vectors; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics; D014162:Transfection
D009414:Nerve Growth Factors; D012333:RNA, Messenger