Retinal neovascularization

Antagonists of integrin av 33 inhibit the growth of new blood vessels into tumors cultured on the chick chorioallantoic membrane without affecting adjacent blood vessels, and also induce tumor regression [7]. Antagonists of av 33 also inhibit angiogenesis in various ocular models of retinal neovascularization [7]. 

Inhibitors of IkBo phosphorylation have been described which irreversibly inhibit cytokine-induced phosphorylation without affecting constitutive phosphorylation. One such compound (Bay 11-7083 ((E)3-[4-f-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to be effective in two animal models of inflammation after intraperitoneal administration [89]. In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory responses, inhibition of the transcription factor NFkB will also have an effect on angiogenesis. Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects. Some of these factors, e.g. IL-8, TNFa and MCP-1 are known to be produced via NFkB-mediated endothelial cell activation [90,91]. The importance of NFKB-mediated responses in pro-angiogenic endothelium was reflected in studies in which the NFkB inhibitor PDTC decreased retinal neovascularization in the eye of mice [92]. 

A total of 113 patients with angiographically proven sub-retinal neovascularization were enrolled into a prospective study of the effects of intravitreal triamcinolone (61). About 30% developed a significant rise in intraocular pressure (at least 5 mmHg) above baseline during the first 3 months. 

Systemic glucocorticoid treatment can cause severe exacerbation of bullous exudative retinal detachment and lasting visual loss in some patients with idiopathic central serous chorioretinopathy (SEDA-20, 374 68). The atypical presentation of this condition can include peripheral retinal capillary nonperfusion and retinal neovascularization. The treatment of choice in patients with idiopathic central serous chorioretinopathy is laser photocoagulation. 

Effective, long lasting treatment of retinal neovascular disorders, including proliferative diabetic retinopathy and proliferative AMD, remains one of the greatest challenges in ophthalmology today. The number of individuals suffering from diabetes has... 

Suganami, E., Takagi, H., Ohashi, H., Suzuma, K., Suzuma, I., Oh, H., Watanabe, D., Ojima, T., Suganami, T., Fujio, Y., Nakao, K., Ogawa, Y., and Yoshimura, N. 2004. Leptin stimulates ischemia-induced retinal neovascularization possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes 53 2443-2448. 

Angiogenesis driven by myocardial hypoxia may permit collateral formation, relief of angina, and minimize tissue damage during myocardial infarction. On the other hand, hypoxic drive to retinal neovascularization can contribute to retinal hemorrhage and blindness. 

A therapeutic strategy could encompass the suppression of protein kinase C activity, thus short-circuiting at least part of the pathway driving VEGF activity in the retina. The initial chemical studied as a protein kinase C inhibitor was known as LY333531 and was found to have very selective inhibition of both [31 and [311 isoforms of protein kinase C. This drug was studied in animal models and was found to reduce VEGF-mediated retinal vascular permeability, increase retinal blood flow, and inhibit retinal neovascularization. 

Fluorescein is evenly injected over 4 to 6 seconds to promote adequate patient tolerance. After waiting approximately 15 seconds for the dye to reach the retina, the photographer takes pictures at approximately 1-second intervals, continuing until fluorescein has coursed through the veins (typically 8 to 10 exposures). Photographs are taken in the late phase, typically 2 to 3 minutes after injection, but may be taken up to 20 minutes after injection to document persistent leakage or pooling of fluorescein (from retinal neovascularization,... 

The primary vision-threatening manifestations of sarcoidosis are uveitis, glaucoma, and optic nerve involvement dry eye (keratoconjunctivitis sicca) is common but of lower risk. Anterior segment findings (including conjunctival granulomas, iris nodules, iridocyclitis, and keratoconjunctivitis sicca) occur in up to 70% of patients. In contrast, posterior uveitis occurs in up to 30% of patients. If only vasculitis, periphlebitis, or retinal neovascularization is considered, the frequency ranges from 4% to 17% of cases. Optic nerve involvement presents in up to 7% of patients. 

Posterior segment disease is unaffected by topical therapy and minimally requires periorbital administration of corticosteroids systemic therapy is needed if the condition is bilateral or sight threatening. Indications for posterior segment treatment include significant vision loss from macular edema or severe vitreitis, choroidal granulomas, optic nerve involvement, or retinal neovascularization. Conversely, if vision remains at 20/40 or better and there are no complicating factors, systemic... 

Retinal neovascularization as a consequence of talc injection can occur in the retinal periphery as neovascu-lar tufts in the shape of sea fens at the junction of the perfused and nonperfused retina.This is a potentially serious complication of talc emboli, because it can lead to retinal detachment, massive vitreal hemorrhage, and optic disc neovascularization. 

Efficacy. Corticosteroids have an inhibitory effect on the growth of fibroblasts (47,48). Triamcinolone acetonide inhibits experimental intraocular proliferation in rabbits (36). Intravitreal injection of 1 mg of triamcinolone significantly reduced both retinal neovascularization and retinal detachment in an experimentally induced rabbit model (36). A 4-mg intravitreal triamcinolone injection inhibited preretinal and optic nerve head neovascularization in a pig model of iatrogenic branch vein occlusion all untreated eyes developed neovascularization by six weeks (49). Intravitreal triamcinolone is also a potent inhibitor of laser-induced CNV in a rat model however, this animal model may not be ideal since laser-induced CNV may be caused by a traumatic repair process or inflammatory response and may be more susceptible to steroids than neovascularization in human disease states (50). In addition, the intravitreal triamcinolone acetonide was administered at the time of laser treatment thus, the treatment may only inhibit new vessel formation and not existing neovascularization. 

LTO could also be applied to retinal neovascularization which occurs in diseases such as diabetes and sickle cell disease. Most of these new vessels which proliferate into the preretinal space and vitreous can be made to regress by pan-retinal thermal photocoagulation. However, in cases of persistent neovascularization, which results in recurrent vitreous hemorrhage, LTO may potentially be used. 

Great interest has been shown in gene-based treatments of ocular neovasculari zation. Many human retinal diseases have either retinal neovascularization or CNV as a final common pathway. Neovascularization results in retinal injury and... 

Robinson G, Pierce E, Rook S, Foley E, Webll R, Smith L. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA 1996 93 4851 4-856. 

Auricchio A, Behling K, O Connor E, et al. Inhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents. Mol Ther 2002 6 490-494. 

Duh EJ, Yang HS, Suzuma I, et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002 43 821-829. 

Raisler BJ, Berns KI, Grant MB, Beliaev D, Hauswirth WW. Adeno-associated virus type-2 expression of pigmented epithelium- derived factor or Kringles 1-3 of angiostatin reduce retinal neovascularization. Proc Natl Acad Sci USA 2002 99 8909-8914. 

AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, also inhibits retinal neovascularization in an animal model (63). Subsequently, a Phase II, randomized, double-masked, placebo-controlled study of the matrix metallopro-tease inhibitor AG3340 in patients with subfoveal CNV associated with AMD was conducted. The outcome of this study, however, was not released and the company decided not to proceed with a Phase III trial. 

Higgins RD, Sanders RJ, Yan Y, Zasloff M, Williams JI. Squalamine improves retinal neovascularization. Invest Ophthalmol Vis Sci 2000 41 1507-1512. 

Garcia C, Bartsch DU, Rivero ME, et al. Efficacy of Prinomastat (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization. Curr Eye Res 2002 24 33-38. 

As discussed previously, corticosteroids downregulate VEGF production in experimental models and possibly reduce breakdown of the blood retinal barrier (15,16). Similarly, corticosteroids have antiangiogenic properties possibly due to attenuation of the effects of VEGF (20,21). These properties of steroids are commonly used. Clinically, triamcinolone acetonide is used locally as a periocular injection to treat cystoid macular edema secondary to uveitis or as a result of intraocular surgery (22,23). In animal studies, intravitreal triamcinolone acetonide has been used to prevent proliferative vitreoretinopathy and retinal neovascularization (24—27). Intravitreal triamcinolone acetonide has been used clinically to treat proliferative vitreoretinopathy and choroidal neovascularization (28-31). 

Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL. The effects of intravitreal triamcinolone acetonide on experimental pre-retinal neovascularization. Graefes Arch Clin Exp Ophthalmol 1993 231 34-40. 

Overall, the safety profile was reassuring and consistent with safety data in other cardiovascular adenoviral gene therapy trials [15,22]. There was no evidence of myocarditis, retinal neovascularization, or angioma formation. 

P3. Penn, J. S., and Rajaratnam, V. S., Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 44, 5423-5429 (2003). 

PPARy is expressed in bovine retinal endothelial cells [49]. In vitro studies found thiazoUdinediones inhibited the effects of vascular endothelial growth factor on migration and proliferation of retinal endothelial cells. In vivo, intravitreous injection of both agents inhibited development of retinal neovascularization. These results indicate that thiazolidinediones may be effective in the treatment of diabetic retinopathy pending further research in humans [49]. 

Murata T, Hata Y, Ishibashi T, et al. Response of experimental retinal neovascularization to thiazo-lidinediones. Arch Ophthalmol. 2001 119(5) 709-717. 

Suzuma K, Takahara N, Suzuma I, et al. Characterization of protein kinase C beta isoform s action on retinoblastoma protein phosphorylation, vascular endothehal growth factor-induced endothelial cell proliferation, and retinal neovascularization. Proc Natl Acad Sci U S A 2002 99 721-726. 

SantuUi RJ, Kinney WA, Ghosh S, DeCorte BL, Liu L, Tuman RWA, Zhou Z, Huebert N, BurseU SE, Clermont AC, Grant MB, Shaw LC, Mousa SA, Galemmo Jr., RA, Johnson DL, Maryanoff BE, Damiano BP. Studies with an orally bio-available aV integrin antagonist in animal models of ocular vasculopathy retinal neovascularization in mice and retinal vascular permeability in diabetic rats. /. Pharmacol. Exp. Ther. 2008 324 894-901. 

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