Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factor.

Neovascularization leads to blindness in numerous ocular diseases, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and sickle cell disease. More effective and stable treatments for ocular neovascularization are needed, yet there are major limitations in the present animal models. To develop primate models of diabetic retinopathy and choroidal neovascularization, rhesus monkeys were injected subretinally or intravitreally with an adeno-associated virus (AAV)-2 vector carrying the cDNA encoding human vascular endothelial growth factor (VEGF). Overexpression of VEGF was measured by intraocular fluid sampling over time. Neovascularization was evaluated by ophthalmoscopy through angiography, optical coherence tomography, and ultimately histopathology. Overexpression of VEGF through AAV2 results in rapid development of features of diabetic retinopathy or macular edema, depending on the targeted cell type/mode of production of VEGF and diffusion of VEGF. Nonhuman primate models will be useful in testing long-term safety and efficacy of novel therapeutic agents for blinding neovascular diseases.

[1]  L. Yıldız,et al.  Submacular surgery for choroidal neovascularization secondary to optic nerve drusen. , 2003, American journal of ophthalmology.

[2]  R. Ali,et al.  Gene therapy for ocular angiogenesis. , 2003, Clinical science.

[3]  J. Bennett,et al.  Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. , 2003, Molecular vision.

[4]  John I. Loewenstein,et al.  Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. , 2003, Ophthalmology.

[5]  P. Rakoczy,et al.  Enhanced recombinant adeno-associated virus-mediated vascular endothelial growth factor expression in the adult mouse retina: a potential model for diabetic retinopathy. , 2003, Diabetes.

[6]  W. Manning,et al.  AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat. , 2003, Investigative ophthalmology & visual science.

[7]  Yoshinori Mitamura,et al.  Vitreous levels of placenta growth factor and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. , 2002, Diabetes care.

[8]  M. Matsumura,et al.  Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. , 2002, American journal of ophthalmology.

[9]  P. Campochiaro,et al.  AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. , 2002, Investigative ophthalmology & visual science.

[10]  T. Aleman,et al.  Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Lutty,et al.  Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. , 2002, American journal of ophthalmology.

[12]  R. Ali,et al.  Inhibition of retinal neovascularisation by gene transfer of soluble VEGF receptor sFlt-1 , 2002, Gene Therapy.

[13]  T. Cox,et al.  Safety and pharmacokinetics of intravitreal 2-methoxyestradiol implants in normal rabbit and pharmacodynamics in a rat model of choroidal neovascularization. , 2002, Experimental eye research.

[14]  P. Campochiaro,et al.  Pigment epithelium‐derived factor inhibits retinal and choroidal neovascularization , 2001, Journal of cellular physiology.

[15]  R. Duvoisin,et al.  Recombinant angiostatin prevents retinal neovascularization in a murine proliferative retinopathy model , 2001, Gene Therapy.

[16]  N. McIntosh,et al.  A novel model of retinopathy of prematurity simulating preterm oxygen variability in the rat. , 2000, Investigative ophthalmology & visual science.

[17]  K. Csaky,et al.  Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. , 2000, Investigative ophthalmology & visual science.

[18]  D. Hinton,et al.  Natural history of choroidal neovascularization induced by vascular endothelial growth factor in the primate , 2000, Graefe's Archive for Clinical and Experimental Ophthalmology.

[19]  T. Aleman,et al.  Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Ivana K. Kim,et al.  Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. , 1999, Investigative ophthalmology & visual science.

[21]  M. Mandai,et al.  Inhibitory effect of TNP-470 on experimental choroidal neovascularization in a rat model. , 1999, Investigative ophthalmology & visual science.

[22]  I. Constable,et al.  Generation and characterization of a recombinant adenovirus expressing vascular endothelial growth factor for studies of neovascularization in the eye. , 1999, Australian and New Zealand journal of ophthalmology.

[23]  A. Cideciyan,et al.  Relation of optical coherence tomography to microanatomy in normal and rd chickens. , 1998, Investigative ophthalmology & visual science.

[24]  P. Campochiaro,et al.  Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. , 1998, Experimental eye research.

[25]  P. Campochiaro,et al.  Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. , 1997, The American journal of pathology.

[26]  S. Seregard,et al.  Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. , 1996, Investigative ophthalmology & visual science.

[27]  G. Lutty,et al.  Localization of vascular endothelial growth factor in human retina and choroid. , 1996, Archives of ophthalmology.

[28]  E. Kohner,et al.  Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. , 1996, The British journal of ophthalmology.

[29]  L. Aiello,et al.  Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  L. Aiello,et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. , 1994, The New England journal of medicine.

[31]  J. Penn,et al.  Exposure to Alternating Hypoxia and Hyperoxia Causes Severe Proliferative Retinopathy in the Newborn Rat , 1994, Pediatric Research.

[32]  Joan W. Miller,et al.  Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. , 1994, The American journal of pathology.

[33]  T. Dryja,et al.  Transgenic mice with a rhodopsin mutation (Pro23His): A mouse model of autosomal dominant retinitis pigmentosa , 1992, Neuron.

[34]  Matthew A. Thomas,et al.  Surgical management of subfoveal choroidal neovascularization. , 1992, Ophthalmology.

[35]  J. Fujimoto,et al.  Optical Coherence Tomography , 1991, LEOS '92 Conference Proceedings.

[36]  D. Ingber,et al.  Potent anti-angiogenic action of AGM-1470: comparison to the fumagillin parent. , 1991, Biochemical and biophysical research communications.

[37]  C. Puliafito,et al.  A new model of experimental choroidal neovascularization in the rat. , 1989, Archives of ophthalmology.

[38]  R. Machemer,et al.  Experimental subretinal hemorrhage in rabbits. , 1982, American journal of ophthalmology.

[39]  James M. Wilson,et al.  Isolation of highly infectious and pure adeno-associated virus type 2 vectors with a single-step gravity-flow column. , 2001, Human gene therapy.

[40]  R. Danis,et al.  Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531. , 1998, Investigative ophthalmology & visual science.

[41]  E S Gragoudas,et al.  Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. , 1996, Archives of ophthalmology.

[42]  J. Folkman,et al.  Increased Vascular Endothelial Growth Factor Levels in the Vitreous of Eyes With Proliferative Diabetic Retinopathy , 1995 .

[43]  Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. , 1991, Archives of ophthalmology.

[44]  Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Macular Photocoagulation Study Group. , 1990, Archives of ophthalmology.

[45]  N. Bressler,et al.  Persistent and recurrent neovascularization after krypton laser kphotocoagualation for neovascular lesions fo age-related macular degenration , 1990 .

[46]  Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Macular Photocoagulation Study Group. , 1986, Archives of ophthalmology.