Novel therapeutic targets in diabetic macular edema: Beyond VEGF

Abstract

The leading cause of major vision loss in diabetic persons is diabetic macular edema (DME). The hallmark feature of diabetic retinopathy is the alteration of the blood-retinal barrier (BRB). Inflammation plays a crucial role in DME with involvement of several chemokines and cytokines including vascular endothelial growth factor (VEGF). VEGF is a potent cytokine and vaso-permeability factor that has been targeted in multiple, large clinical trials. Multiple anti-VEGF drugs are widely used in the treatment of diabetic macular edema (DME) as the first line of treatment, and have been shown to be effective in vision improvement and prevention of vision loss. However, many DME patients do not show complete response to anti-VEGF drugs despite multiple intravitreal injections with these drugs. Also, the effect seems to be transient in those responders, and many patients do not show complete resolution of fluid. This article summarizes the mechanisms other than VEGF, and how these novel factors can be targeted as promising therapies of DME.

Region‐specific ischemia, neovascularization and macular oedema in treatment‐naïve proliferative diabetic retinopathy

“…Since NPIfpz is the strongest parameter representing ischemia of the entire retina in PDR, a binary classification of NPIfpz was utilized to compare the binary classification of DME. 22 First, regional anatomic and pathophysiologic characteristics of macula may be determining factors of DME. These NPIfpz values were chosen to represent severe ischemia in this PDR cohort.…”

“…It is possible that in addition to the ischemia/VEGF mechanism, there are other critical factors and mechanisms of DME formation. 22 First, regional anatomic and pathophysiologic characteristics of macula may be determining factors of DME. In contrast to peripheral retina, the cr contains the highest density retina vessels (excluding the foveal avascular zone), 23 and vessels with excessive diameter and length.…”

DME Management – Current Perspective and Therapeutic Strategies

“…The BOULEVARD study is a phase 2 trial comparing RO6867461 with ranibizumab. However, disappointing results have been seen in investigations of the use of another monoclonal antibody to Ang-2, Nesvacumab (Regeneron, New York, NY), which was being coadministered with aflibercept in the RUBY study and hence further development is suspended [74,75].…”

“…Intravitreal injection with kallikrein or bradykinin increases retinal vascular permeability. KVD001 (Kalvista Pharmaceutical, Cambridge, MA), an intravitreally administered plasma kallikrein inhibitor, has shown promising results in a phase 1 trial in patients with DME with improvements in visual acuity and decreased retinal thickness [74]. Squalamine is a small molecule antiangiogenic drug delivered as 0.2% eye drops (OHR-102; Ohr Pharmaceutical, New York, NY).…”

Cytokines and Growth Factors as Predictors of Response to Medical Treatment in Diabetic Macular Edema

“…The reasons for this unpredictability are not entirely recognized, representing a significant clinical challenge (Mitchell et al, 2011;Nguyen et al, 2012). One possible explanation is that not only VEGF is implicated in the DME pathogenesis but other numerous inflammatory cytokines and signalling pathways are also implicated (Urias et al, 2017).…”