Chang and Sarraf VEGF-A. An exploratory study of the use of the VEGF trap in the treatment of ﬁve patients with DME showed a decrease in retinal thickness and improvement in visual acuity, without serious adverse events (Do et al 2007). Protein kinase C Hyperglycemia is an important factor for the development and progression of diabetic retinopathy (Anonymous 1993, 1998a). Hyperglycemia activates protein kinase C (PKC), a family of approximately 13 enzymes, through VEGF by inducing synthesis of diacylglycerol (Aiello 2002). In animal studies, upregulation of the beta-isoform increases retinal vascular permeability and neovascularization (Aiello et al 1997; Xu et al 2004), while inhibition or genetic knockout reduces diabetes-induced retinal permeability and ischemia- induced neovascularization (Danis et al 1998; Suzuma et al 2002). Ruboxistaurin mesylate (LY333531) is an oral PKC B-isozyme selective inhibitor that has been shown to ameliorate diabetic retinopathy in animal models and improve alterations in retinal blood flow from early diabetic retinopathy in human subjects. The Protein Kinase C Inhibitor Diabetic Retinopathy Study (PKC-DRS) was undertaken to determine whether ruboxistaurin reduces that rate of progression of nonproliferative diabetic retinopathy to proliferative retinopathy. (Aiello et al 2006) The results of the study did not support the primary hypothesis. However, when compared to the placebo group, the treatment group had a lower rate of moderate visual loss (5.5% vs. 9%), a greater likelihood to gain 15 letters from baseline and a reduction in the use of focal/grid photocoagulation by 26%. Such ﬁndings suggested that PKC B inhibition may decrease vascular permeability and DME. The Protein Kinase C Inhibitor Diabetic Macular Edema Study (PKC-DMES) was designed to determine the effect of orally-administered ruboxistaurin on DME (Anonymous 2007). In this phase III trial, 686 with DME that did not meet ETDRS-criteria for CSME were randomized to placebo or 4 mg, 16 mg, or 32 mg/day of ruboxistaurin. After 30 months, there was no statistically signiﬁcant difference in the progression to sight-threatening DME or the need for focal/grid photoco- agulation. Octreotide Several lines of evidence support a role for growth hormone in the progression of diabetic retinopathy (Wilkinson-Berka et al 2006). Two phase III studies of the insulin-like growth factor antagonist octreotide have been completed. In one 430 study, monthly intramuscular injections of Sandostatin LAR reduced the progression of DR, but failed to beneﬁt visual acuity or macular edema. However, a second study of similar design failed to show a beneﬁcial effect on any of the outcome measures examined. Vitrectomy In addition to its role in the treatment of proliferative DR and vitreous hemorrhage, vitrectomy has been used for the treatment of DME (Lewis et al 1992). Spontaneous resolution of DME accompanying PVD has been reported. In one study, PVD was more prevalent in diabetics without DME than with DME (Nasrallah et al 1988; Nasrallah et al 1989). Postulated mechanisms of action include relief of traction, removal of cytokines in the vitreous that promote vascular permeability and proliferation, and increasing oxygen diffusion to the retina. A retrospective analysis of 65 eyes undergoing PPV with membrane peeling for DME showed a progressive decrease in mean retinal thickness and an improvement in visual acuity over the four month follow-up period (Yamamoto et al 2001). Highly-puriﬁed hyaluronidase (Vitrase, ISTA) has been studied in phase III clinical trials in the treatment of vitre- ous hemorrhage (Kuppermann et al 2005). While it reduced vitreous hemorrhage and allowed photocoagulation, it did not show an improvement in visual acuity when compared to control. Intraocular Vitrase has been used to induce posterior vitreous detachment, but its role in the treatment of DME is yet to be elucidated. Additional potential targets for future therapy c-Raf kinase The Ras/Raf/MAPK signaling pathway has been impli- cated in angiogenesis in many types of systemic tumors and associated with ocular neovascularization. VEGF has been identiﬁed as a downstream effector of this pathway. Intravitreal injection of an anti-raf-1-kinase antisense oligo- nucleotide inhibited neovascularization in a porcine animal model (Danis et al 2003). 17-aminoallylgeldanamycin, an inhibitor of this pathway currently under investigation as a systemic chemotherapeutic, has been shown to inhibit retinal neovascularization in a mouse model of hypoxia-induced proliferative retinopathy. (Kociok et al 2007) Erythropoietin Erythropoeitin is another hypoxia-induced angiogenic factor that has been implicated in the pathogenesis of DR. Studies Clinical Ophthalmology 2008:2(2)