Retrovirus-mediated gene transfer targeted to retinal photocoagulation sites.
Diabetic retinopathy is a major cause of acquired blindness due to the development of retinal neovascularization and associated traction retinal detachment. It is commonly treated with retinal photocoagulation therapy; however, progression to blindness remains a significant problem. To determine the feasibility of adjunctive anti-angiogenic gene therapy, we evaluated the capability of retroviral vectors, which transfer exogenous genes only into dividing cells, to transfer and express a beta-galactosidase gene selectively into photocoagulation sites. Thirty-five rabbits received 30 retinal photocoagulation burns in the right eye followed 2 days later by beta-galactosidase (G1nBgSvNa) or control (G1XSvNa) vector injection into the subretinal space. Beta-galactosidase expression was observed in the photocoagulation sites from 5 days after vector administration (31.7+/-7.0%) to 12 weeks (6.7+/-3.4%). Immunohistochemical studies of the treated retinas using antibody Ber-MAC3 and anti-cytokeratin antibodies revealed that transduced cells were macrophages and retinal pigment epithelial cells. To determine feasibility in a primate, two monkeys received 10 laser burns in the macula superior to the fovea followed 2 days later by G1nBgSvNa vector. beta-galactosidase expression was found in photocoagulation sites and foveal retina was well preserved. We conclude that gene transfer to retinal photocoagulation sites provides stable expression of the transduced gene with relatively high efficiency. This feasibility study suggests the possibility of transferring genes encoding for anti-angiogenic factors into photocoagulation sites to improve the efficacy of laser photocoagulation therapy.
Murata
T
T
Department of Ophthalmology, Doheny Eye Institute, University of Southern California School of Medicine, Los Angeles 90033, USA.
Hoffmann
S
S
Ishibashi
T
T
Spee
C
C
Gordon
E M
EM
Anderson
W F
WF
Hinton
D R
DR
Ryan
S J
SJ
D000792:Angiography; D000818:Animals; D004195:Disease Models, Animal; D005123:Eye / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D005452:Fluoresceins; D015870:Gene Expression / Q000235:genetics; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008028:Light Coagulation; D008252:Macaca fascicularis; D008297:Male; D008853:Microscopy; D011817:Rabbits; D012160:Retina / Q000737:chemistry / Q000378:metabolism* / Q000601:surgery; D012164:Retinal Diseases / Q000235:genetics / Q000601:surgery; D012190:Retroviridae / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
D005452:Fluoresceins; D019394:Ki-67 Antigen; D001616:beta-Galactosidase