Herpesvirus-mediated systemic delivery of nerve growth factor.
Sustained systemic dissemination of therapeutic proteins from peripheral sites is an attractive prospect for gene therapy applications. Replication-defective genomic herpes simplex virus type 1 (HSV-1) vectors were evaluated for their ability to express nerve growth factor (NGF) as a model gene product both locally and systemically. Intra-articular inoculation of NGF expression vectors in rabbits resulted in significant increases in joint lavage and blood plasma NGF that persisted for 1 year. A rhesus macaque injected intra-articularly displayed a comparable increase in plasma NGF for at least 6 months, at which time the serum NGF levels of this animal were sufficient to cause differentiation of PC12 cells in culture, but not to increase footpad epidermis innervation. Long-term reporter transgene expression was observed primarily in ligaments, a finding confirmed by direct inoculation of patellar ligament. Patellar ligament inoculation with a NGF vector resulted in elevated levels of circulating NGF similar to those observed following intra-articular vector delivery. These results represent the first demonstration of sustained systemic release of a transgene product using HSV vectors, raising the prospect of new applications for HSV-1 vectors in the treatment of systemic disease.
Wolfe
D
D
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Goins
W F
WF
Kaplan
T J
TJ
Capuano
S V
SV
Fradette
J
J
Murphey-Corb
M
M
Robbins
P D
PD
Cohen
J B
JB
Glorioso
J C
JC
D000818:Animals; D004817:Epidermis / Q000294:innervation; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D007763:Lac Operon; D008022:Ligaments / Q000378:metabolism; D008253:Macaca mulatta; D020932:Nerve Growth Factor / Q000097:blood / Q000235:genetics*; D016716:PC12 Cells; D011817:Rabbits; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019076:Transgenes
D020932:Nerve Growth Factor