Therapies for DME and Rationale for Combination Therapy
Therapies for DME and Rationale for Combination Therapy
Ang-2 is another cytokine with inflammatory and angiogenic properties that is expressed by EC. Ang-2 levels are regulated at the level of transcription by different cytokines including VEGF, as well as hypoxia and high-glucose levels, and stored in Weibel–Palade bodies before rapid release. It is elevated in eyes with clinically significant DMO as well as proliferative DR (PDR), and is thought to induce loss of vascular endothelial (VE)-cadherin through phosphorylation. Ang-2 may act by exerting a permissive role for supplementing the action of other pro-inflammatory cytokines through sensitisation of ECs to tumour necrosis factor (TNF)-α and subsequent expression of ICAM-1. Similarly, in the presence of VEGF, Ang-2 increases vascular permeability. Recently, You et al have reported that pan-retinal laser photocoagulation reduced the serum levels of Ang-2 and VEGF in diabetic patients with PDR compared with the significantly elevated pre-treatment levels. Another study showed that the changes in serum VEGF and Ang-2 following laser photocoagulation were not significant. It has been suggested that benfotiamine, a vitamin B1 derivative may block three major pathways of hyperglycaemia damage and prevent experimental DR. Yao et al have suggested that high glucose increased Ang-2 transcription through methoxyglyoxal modifications. Benfotiamine has also been reported to have anti-inflammatory effects. Ang-2 is not expressed by pericytes; pericytes express Ang-1 (and not Ang-2), which promote EC survival signalling, maintenance of endothelial barrier and vascular maturation and quiescence and reduces VEGF-stimulated leukocyte adhesion to ECs. Taurine has been reported to inhibit high glucose-induced apoptosis in retinal pericytes through increased Tie-2 expression and downregulation of Ang-2.
Sirolimus (rapamycin), a macrolide antibiotic, has immunosuppressive and anti-proliferative activities through its inhibition of the mammalian target of rapamycin (mTOR). Sirolimus, through its inhibition of mTOR, inhibits VEGF expression and signalling, and downregulates HIF-1A. In addition, sirolimus has been shown to inhibit VEGF-induced microvascular permeability, and reduces protein kinase C (PKC) activity, as well as reduces the expression of inflammatory cytokines. Recently, a phase 1 study of subconjunctival and intravitreal sirolimus in DMO was reported by Dugel et al. No non-ocular adverse events were noted, and the systemic exposure to sirolimus was low. There were no serious ocular adverse events reported. A median BCVA improvement of 4.0 letters was noted at day 14 and maintained for 90 days, associated with a reduction in the CRT of −33 u at day 14 and −68.3 u at day 90. Similarly, Krishnadev et al in their phase I/II study reported sirolimus to be safe when administered subconjunctivally, although the treatment effect was variable. Progress in the development of sirolimus formulations for intraocular delivery (DE-109, Santen Pharma, Osaka, Japan) is encouraging.
Potential Treatments
Angiopoietin (Ang)-2 Blockage
Ang-2 is another cytokine with inflammatory and angiogenic properties that is expressed by EC. Ang-2 levels are regulated at the level of transcription by different cytokines including VEGF, as well as hypoxia and high-glucose levels, and stored in Weibel–Palade bodies before rapid release. It is elevated in eyes with clinically significant DMO as well as proliferative DR (PDR), and is thought to induce loss of vascular endothelial (VE)-cadherin through phosphorylation. Ang-2 may act by exerting a permissive role for supplementing the action of other pro-inflammatory cytokines through sensitisation of ECs to tumour necrosis factor (TNF)-α and subsequent expression of ICAM-1. Similarly, in the presence of VEGF, Ang-2 increases vascular permeability. Recently, You et al have reported that pan-retinal laser photocoagulation reduced the serum levels of Ang-2 and VEGF in diabetic patients with PDR compared with the significantly elevated pre-treatment levels. Another study showed that the changes in serum VEGF and Ang-2 following laser photocoagulation were not significant. It has been suggested that benfotiamine, a vitamin B1 derivative may block three major pathways of hyperglycaemia damage and prevent experimental DR. Yao et al have suggested that high glucose increased Ang-2 transcription through methoxyglyoxal modifications. Benfotiamine has also been reported to have anti-inflammatory effects. Ang-2 is not expressed by pericytes; pericytes express Ang-1 (and not Ang-2), which promote EC survival signalling, maintenance of endothelial barrier and vascular maturation and quiescence and reduces VEGF-stimulated leukocyte adhesion to ECs. Taurine has been reported to inhibit high glucose-induced apoptosis in retinal pericytes through increased Tie-2 expression and downregulation of Ang-2.
Sirolimus
Sirolimus (rapamycin), a macrolide antibiotic, has immunosuppressive and anti-proliferative activities through its inhibition of the mammalian target of rapamycin (mTOR). Sirolimus, through its inhibition of mTOR, inhibits VEGF expression and signalling, and downregulates HIF-1A. In addition, sirolimus has been shown to inhibit VEGF-induced microvascular permeability, and reduces protein kinase C (PKC) activity, as well as reduces the expression of inflammatory cytokines. Recently, a phase 1 study of subconjunctival and intravitreal sirolimus in DMO was reported by Dugel et al. No non-ocular adverse events were noted, and the systemic exposure to sirolimus was low. There were no serious ocular adverse events reported. A median BCVA improvement of 4.0 letters was noted at day 14 and maintained for 90 days, associated with a reduction in the CRT of −33 u at day 14 and −68.3 u at day 90. Similarly, Krishnadev et al in their phase I/II study reported sirolimus to be safe when administered subconjunctivally, although the treatment effect was variable. Progress in the development of sirolimus formulations for intraocular delivery (DE-109, Santen Pharma, Osaka, Japan) is encouraging.