Proliferating endothelial cell-specific expression of IGF-I receptor ribozyme inhibits retinal neovascularization.
Insulin-like growth factor-I (IGF-I) and its receptor (IGF-IR) are essential for normal ocular development and are expressed in numerous ocular cell types including lens epithelial cells, retinal pigment epithelial cells, Müller cells and endothelial cells. Endothelial cell proliferation is a common feature of proliferative retinopathies and involves abnormal growth of blood vessels within and on the surface of the retina. In an effort to inhibit the formation of these aberrant blood vessels, we cloned an IGF-IR ribozyme into an expression vector that limits expression of the ribozyme to proliferating endothelial cells. An endothelin enhancer and Cdc6 promoter chimera drives expression of the IGF-IR ribozyme. This promoter limited retinal expression of the reporter gene to proliferating endothelial cells in two mouse models of proliferative retinopathy. In addition, expression of the IGF-IR ribozyme by this promoter inhibited aberrant retinal angiogenesis in both models while preserving normal vessels. These results demonstrate the feasibility of IGF-IR ribozyme expression in a selective manner for safer treatment of abnormal angiogenesis associated with retinopathy.
Shaw
L C
LC
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
Pan
H
H
Afzal
A
A
Calzi
S L
SL
Spoerri
P E
PE
Sullivan
S M
SM
Grant
M B
MB
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D017075:Laser Coagulation; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011401:Promoter Regions, Genetic; D016337:RNA, Catalytic / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000473:pathology / Q000628:therapy*; D014162:Transfection / Q000379:methods
D016337:RNA, Catalytic; D008156:Luciferases; D017526:Receptor, IGF Type 1