Persistent expression of PEDF in the eye using high-capacity adenovectors.
Ocular neovascularization, the growth of abnormal blood vessels in the eye, is a factor shared by the most common blinding diseases in developed countries. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic and neuroprotective protein that is normally produced in the eye. When delivered via an adenovector, PEDF can block the growth of new blood vessels and trigger the selective regression of abnormal vessels in animal models of ocular disease. Because of the absence of adenoviral genes, high-capacity (HC) adenovectors offer the potential for persistent transgene expression and enhanced tolerability. We have assessed the durability of PEDF expression and the induction of ocular inflammation following delivery of a PEDF-expressing HC adenovector compared to earlier generation vectors. The HC vector mediated prolonged PEDF expression in tissue-cultured pigmented epithelial cells and when delivered by intravitreal injection into the mouse eye. Delivery of first-generation adenovectors resulted in a dose-dependent increase in cytokine/chemokine gene expression, which correlated with the infiltration of inflammatory cells in the eye. In comparison, the levels of inflammatory gene expression and the intraocular infiltrate were substantially reduced following delivery of the HC vector. These results support the development of the HC adenovector gene delivery system for ocular disease.
Chen
Ping
P
GenVec, Inc. Research Department, Gaithersburg, Maryland 20878, USA.
Hamilton
Melissa
M
Thomas
Charles A
CA
Kroeger
Kurt
K
Carrion
Miguel
M
Macgill
Randall S
RS
Gehlbach
Peter
P
Brough
Douglas E
DE
Wei
Lisa L
LL
King
C Richter
CR
Bruder
Joseph T
JT
D000256:Adenoviridae / Q000235:genetics*; D000283:Administration, Intravesical; D000818:Animals; D018925:Chemokines / Q000235:genetics; D005123:Eye / Q000378:metabolism*; D005128:Eye Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
D018925:Chemokines; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor