Anti-VEGF Therapy for Diabetic Retinopathy

In early anti-angiogenesis studies, it was shown that blocking the activity of VEGF with an antiVEGF antibody can reduce iris neovascularization and suppress the formation of new retinal vessels in primates [67, 68]. VEGF is thought to be the key candidate gene involved in promoting the pathology seen in diabetic retinopathy. Therefore, reducing its expression or activity in vivo, provides the rationale for anti-VEGF therapy in retinal vascular diseases associated with new vessel formation such as diabetic retinopathy.

One anti-VEGF molecule widely used is bevacizumab(Avastin,Genentech,Inc.,SanFrancisco, Calif., USA), a recombinant human monoclonal IgG1 antibody that inhibits the activity of all isoforms of human VEGF. Bevacizumab has been approved by the United States Food and Drug Administration for intravenous use to control metastatic colorectal cancer. Initial experimental data on primates suggest that the full-length antibody might not penetrate the inner limiting membrane of the retina [69]; however, follow-up

Fig. 9. Angle neovascularization before and after the injection of bevacizumab. a Before the injection of bevacizumab, rubeosis of angle structures is marked. b Seven days after the injection of bevacizumab, a marked regression of the neovascular vessels can be seen. Reprinted with permission from [81].

studies show that it does penetrate the retinas of rabbits [70] and monkeys [71] within 24 h.

Several case series have been recently published on the off-label use of intravitreal bevacizumab in VEGF-mediated diseases, such as choroidal neovascularization [72], retinal vein occlusion [73], PDR [74–76], cystoid macular edema [77], and neovascular glaucoma [78–80]. In most of these studies, 1.25 mg (0.05 ml) bevacizumab (100 mg/4 ml) was injected into the vitreous of humans and the results were a marked regression of neovascular vessels after 7 days (fig. 9) [81]. When intravitreal injection of bevacizumab was used before vitrectomy for PDR, all patients had less intraoperative bleeding when the neovascular tissues were dissected.

The effect of bevacizumab, however, appears to be transient since most eyes showed signs of a reactivation of the neovascular process 6–8 weeks after injection of the antibody [80]. Bakri et al. [82] measured free bevacizumab after intravitreal injections of 1.25 mg of the compound in rabbits, and reported that the vitreous concentration of bevacizumab declined in a mono-exponential fashion with a half-life of 4.32 days. A concentration >10 μg/ml bevacizumab was maintained in the vitreous humor for 30 days. When the same concentration was injected into the vitreous of eyes with PDR, the levels of VEGF in aqueous humor were significantly reduced at 7 days [81, 83]. We found that VEGF levels were reduced from 676.5 ± 187 pg/ml (mean ± SEM, before injection) to 7.1 ± 7.1 pg/ml (p < 0.005) after 7 days, suggesting that bevacizumab is a potent inhibitor of VEGF expression in the eye. The levels of PEDF in the aqueous humor were not altered in

PDR after injections with bevacizumab [81, 84]; however, in choroidal neovascularization secondary to age-related macular degeneration or pathologic myopia, intravitreal bevacizumab injections reduced aqueous VEGF and increased PEDF levels [85].

Although further studies with larger samples and longer follow-up times are necessary, these studies strongly suggest that intravitreal bevacizumab may be useful for the treatment of PDR. PEDF gene therapy strategies are currently in phase II clinical trials for age-related macular degeneration where neovascularization and retinal degeneration are predominant features in the pathology of this disease. It would be interesting to develop therapeutic strategies that have greater efficacy in reducing vessel growth and limiting damage to the retina in diseases such as diabetic retinopathy by using a combination of anti-VEGF and pro-PEDF compounds.

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