|Year : 2012 | Volume
| Issue : 1 | Page : 4-12
Diabetic macular edema: Current and emerging therapies
Adam S Wenick, Neil M Bressler
Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine and Hospital, Baltimore, MD, USA
|Date of Web Publication||20-Jan-2012|
Neil M Bressler
Maumenee 752; Johns Hopkins Hospital; 600 N. Wolfe Street; Baltimore, MD 21287-9227
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Diabetic macular edema is a leading cause of vision impairment among people within the working- age population. This review discusses the pathogenesis of diabetic macular edema and the treatment options currently available for the treatment of diabetic macular edema, including for focal/grid photocoagulation, intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor agents. The biologic rationale for novel therapeutic agents, many of which are currently being evaluated in clinical trials, also is reviewed.
Keywords: Diabetic Macular Edema, Focal/Grid Photocoagulation, Intravitreal Corticosteroids
|How to cite this article:|
Wenick AS, Bressler NM. Diabetic macular edema: Current and emerging therapies. Middle East Afr J Ophthalmol 2012;19:4-12
|How to cite this URL:|
Wenick AS, Bressler NM. Diabetic macular edema: Current and emerging therapies. Middle East Afr J Ophthalmol [serial online] 2012 [cited 2015 Aug 5];19:4-12. Available from: http://www.meajo.org/text.asp?2012/19/1/4/92110
| Introduction|| |
An estimated 346 million people are affected by diabetes worldwide in 2011, and the number of people with diabetes is expected to double from 2005 to 2030.  Diabetic retinopathy (DR) is the leading cause of vision loss of working-age adults,  and diabetic macular edema (DME) is the most frequent cause of vision loss related to diabetes. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found the 14-year incidence of DME in type I diabetics to be 26%.  Similarly the Diabetes Control and Complications Trial (DCCT) reported that 27% of type I diabetic patients develop DME within 9 years of onset.  An even higher incidence of macular edema has been reported in older patients with type 2 diabetes (reviewed in  ).
Argon laser photocoagulation has been the mainstay of treatment for macular edema since the publication of the results of the Early Treatment Diabetic Retinopathy Study, which showed an approximate 50% reduction in the rate of moderate vision loss at 3 years following laser photocoagulation compared to no treatment.  However, for patients with center involved macular edema, the risk of moderate vision loss at 3 years remained 15% with treatment.  Since the publication of ETDRS, the DCCT and United Kingdom Prospective Diabetes Study (UKPDS) have demonstrated that tight glycemic and blood pressure control decrease the risk of microvascular complications of diabetes, including DR and vision loss. ,,,, As intensive blood pressure and blood sugar control have become the standard of care, visual outcomes have improved, but recent studies from the Diabetic Retinopathy Clinical Research Network (DRCRnet) indicate that even with the guidelines of tight glycemic and blood pressure control, 12-13% of patients with foveal centered diabetic macular edema who undergo focal/grid laser lose 10 or more ETDRS letters after 2-3 years of follow-up. Additionally, with a baseline median vision of 20/50-20/63, only 36-44% of patients gained 10 or more ETDRS letters at 2-3 years of follow-up, indicating the need for improved treatment modalities. ,,
Within the last 5 years, the use of intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor (VEGF) agents have come into common clinical practice for the management of diabetic macular edema and several recent randomized clinical trials have shown improved effectiveness of ranibizumab compared to focal/grid laser. ,, In this review, we briefly discuss the pathogenesis of diabetic macular edema and the treatment options currently available for the treatment of diabetic macular edema. We then review the biologic rationale for novel therapeutic agents, many of which are currently being evaluated in clinical trials.
| Pathogenesis of Diabetic Macular Edema|| |
The pathogenesis of diabetic macular edema involves the breakdown of the blood-retinal barrier (BRB), which is composed of an inner BRB and an outer BRB. The inner BRB is comprised of tight junctions between retinal vascular endothelial cells as well as retinal glial cells (astrocytes and Mόller cells), creating a barrier that is normally impermeable to proteins.  The outer BRB is formed by tight junctions between retinal pigment epithelial (RPE) cells. Diabetic macular edema is thought to be caused primarily by the breakdown of the inner BRB, though evidence does exist that outer BRB dysfunction may play a role in DME (reviewed in  ). Breakdown of the BRB allows for extravasation of proteins and other solutes from capillaries into the extracellular space. This causes a shift in the balance of hydrostatic and oncotic pressure, favoring the accumulation of fluid within the extracellular space and the development of macular edema.  The mechanisms leading to the breakdown of the BRB in diabetes are complex and are extensively reviewed elsewhere, ,,, but some of the key factors are described below.
Some of the earliest changes seen histologically in the diabetic retina are leukocyte adhesion to capillaries as well as accumulation of advanced glycation end products (AGEs).  These changes contribute to activation of inflammatory mediators and endothelial cell death. Endothelial cell death contributes to the breakdown of the BRB and can lead to increasing ischemia. In addition to cell loss, breakdown of endothelial cell tight junctions also occurs (reviewed in , ). Another histologic change associated with the development of diabetic retinopathy is loss of pericytes, which are cells that are associated with capillaries and are located outside of the blood-retinal barrier. Amongst their functions are the stabilization blood vessels. Loss of pericytes may be related to accumulation of AGEs and to the presence of inflammatory mediators and is associated with the formation of microaneurysms and the breakdown of the BRB. , A more extensive discussion of some of the molecular pathways involved with the development of DME is d further in detail with regards to specific therapeutic targets in the subsections later in this review.
| Current Treatments Options for Diabetic Macular Edema|| |
As noted above, laser photocoagulation had been the mainstay of treatment for DME for almost for the past 25 years, since the publication of photocoagulation results from the ETDRS.  The mechanisms of action of focal/grid laser are not well understood and are not discussed in this review. However, the technique involves placement of light, small (around 50 micron) laser burns only within thickened areas of the macula, including direct (focal) treatment of microaneurysms as well as spots scattered approximately two to three burn widths apart (grid) within other areas of edema not accounted for by microaneurysms. While it previously was used as a monotherapy, focal/grid laser is used in conjunction with anti-VEGF therapy, typically when DME persists and is not continuing to improve after at least 6 months of monthly injections of anti-VEGF therapy. It is added to anti-VEGF therapy if the eye has not had complete laser (focal/grid) treatment to all areas of microaneurysms within areas of edema and grid treatment to all other areas of edema, provided it has been at least 3 to 4 months since any prior focal/grid laser. Macular laser for DME likely will continue to be part of the management of DME in selected patients, especially in the developing world, as its lower cost and less intensive management requirements compared to newer treatment modalities still make laser photocoagulation a preferred therapy in some clinical settings.
In addition to the traditional argon or diode laser used for macular photocoagulation, several newer laser technologies are being evaluated. One of these is a navigated laser photocoagulator (NAVILAS) that integrates a scanning laser slit camera with fluorescein angiography and employs computer aided steering of the laser. It has recently been demonstrated that this laser system has increased accuracy for placement of laser compared to standard manual technique,  but whether this increased accuracy will translate into better clinical results or not, has yet to be determined.
Other newer laser technologies include subthreshold diode-laser micropulse technology , and selective retina therapy (SRT),  which aims at minimizing retinal and RPE tissue damage. A recent randomized clinical trial demonstrated superior results for the primary endpoint of visual acuity for high-density subthreshold diode-laser micropulse photocoagulation compared to standard modified ETDRS laser at 1 year.  Encouraging results have also been reported for SRT,  but this treatment modality has not been directly compared to focal/grid laser as employed by the ETDRS or more recently by the DRCR Network. Further phase II/III studies are underway to evaluate these treatment modalities. ,
Because of our understanding of the central role that VEGF plays in the development of DME and of anti-VEGF therapy for the treatment of DME (discussed below), targeted scatter laser photocoagulation to areas of capillary non-perfusion anterior to the posterior pole is under evaluation as a potential treatment for DME. While peripheral scatter laser photocoagulation was not found to be beneficial for the treatment of DME in the ETDRS study,  in this protocol all areas of mid-peripheral retina were treated regardless of perfusion status. The development of ultra-wide field imaging with fluorescein angiography  allows for the identification of and selective treatment to areas of ischemic retina.  Treatment in this fashion may allow for better visual outcomes or less frequent administration of intravitreal agents.
Mounting evidence exists that inflammation plays a significant role in the development of diabetic macular edema. As noted above, leukostasis is central to the development of diabetic retinopathy. Through the release of free radicals and enzymes, leukocytes can directly damage endothelial cells and increase the permeability of the BRB.  Leukocytes also release a variety of cytokines that act through signaling pathways, leading to increased vascular permeability. Cytokines involved in leukocyte-mediated damage include VEGF, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (reviewed in  ). Intercellular adhesion molecule-1 (ICAM-1) is a cell-to-cell adhesion molecule that plays a major role in leukostasis. In animal models of diabetic retinopathy, inhibition of ICAM-1 with antibodies prevents leukocyte adhesion and prevents the breakdown of the BRB, which is further evidence of the central role played by leukocytes in the development of DME. 
Given the apparent role of inflammation in the pathogenesis of DME, steroids have more recently been utilized for the treatment of DME. Their mode of action may be largely through their ability to inhibit the expression of VEGF. , Two recent randomized controlled trials by the DRCR.net have shed light on the role that steroids should play in the treatment of DME. ,,,, In the first of these studies, the use of focal/grid laser was compared to treatment with 1 mg or 4 mg of intravitreal triamcinolone, with retreatment possible every four months in each arm of the study. At the four month follow-up the triamcinolone arms showed superiority in terms of visual acuity, at one year the treatments appeared equivalent and at the 2-year primary endpoint laser was found to be superior to either of the intravitreal steroid arms. These results held with 3 years of follow-up. ,, In the second of these trials, focal/grid laser alone was compared to 4 mg of intravitreal triamcinolone plus laser. Two additional arms utilized intravitreal ranibizumab, an anti-VEGF agent and are discussed further in the next section below. Similar to the previous study, the triamcinolone plus laser arm showed superiority compared to laser alone in terms of visual acuity at 24 weeks follow-up. However, at one and two years, the treatments appeared fairly equivalent in terms of visual acuity outcome, but with increased rates of cataract and elevated intraocular pressure in the triamcinolone plus laser group. , In the subgroup of patients who were pseudophakic at baseline, the triamcinolone plus laser arm appeared superior to the laser alone treatment and equivalent to the treatment arms utilizing anti-VEGF therapy discussed in the following section. , In light of these results, due to the increased rate of elevated intraocular pressure and formation of cataract in the triamcinolone plus laser group, the authors of this review only consider use of intravitreal steroids plus focal/grid laser in clinical practice in pseudophakic patients who are unable to follow-up monthly for intravitreal anti-VEGF therapy. However, these results were within a subgroup in which the entire group did not show a benefit with intravitreal corticosteroids, the eyes were not randomized within the pseudophakic eyes (so that other factors could have led to outcomes which were superior to focal/grid laser and seemingly equivalent to anti-VEGF therapy), the eyes were more likely to have additional visits for management of increased intraocular pressure and the number of treatments with anti-VEGF therapy appeared to be two to three per year after the first year of treatment. In light of these results, especially the increased rate of elevated intraocular pressure and formation of cataract in the triamcinolone plus laser group, the authors of this review typically consider use of intravitreal steroids plus focal/grid laser in clinical practice in pseudophakic patients who have not responded to monthly intravitreal anti-VEGF therapy for at least 6 months who then had additional focal/grid laser and continued injections for at least another 4 months.
Sustained release steroid delivery systems offer the possibility of less frequent dosing and in a phase II trial, beneficial results have been seen at the 90-day endpoint.  In light of the results of the DRCR.net studies above, sustained release steroid drug delivery systems may have limited benefit for the treatment of DME. They may however have a role in difficult to treat DME in post-vitrectomy eyes. 
The VEGF family is a sub-group of growth factors that include VEGF-A, B, C, D, E and placental growth factor (PlGF). VEGF-A is the member of this family that is most critical with regards to the pathogenesis of ocular disease and its signaling induces angiogenesis as well as increased vascular permeability. ,, PlGF also appears to play a lesser role.  VEGF-A exists in at least nine isoforms due to alternative splicing, with six major isoforms. The VEGF-A165 isoform is the predominant isoform and appears to be the most important in the pathogenesis of ocular disease, including DME. The isoforms vary in their affinity to bind heparin, causing some isoforms to be strictly bound to extracellular matrix (ECM) and other forms to be freely diffusible. VEGF-A165 has intermediate heparin binding ability. The isoforms that bind heparin and therefore have affinity for ECM can undergo proteolytic cleavage and become freely diffusible. 
VEGF-A is the ligand of 2 major receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2. The function of VEGFR-1 is still not completely clear. In addition to VEGF-A, it also binds PlGF and appears to be involved in monocyte chemotaxis as well as the induction of matrix metalloproteinase-9 (MMP-9),  discussed further below. The VEGFR-2 appears to be the primary receptor responsible for angiogenesis, mitogenesis and induction of vascular permeability.  PlGF has also been implicated in the induction of increased vascular permeability  as well as increase in the permeability of RPE cells.  However, in other animal models, it appears to act as an anti-permeability factor. 
VEGF-A expression can be induced by hypoxia via the transcription factor hypoxia-inducible factor (HIF) and it increases vascular permeability via a number of downstream effects. VEGF-A induces phosphorylation of the tight junction proteins occludin and zonula occludens-1, leading to disruption of tight junctions. , VEGF-A can also induce phosphorylation and subsequent destabilization of vascular endothelial cadherin, an endothelial cell-cell adhesion molecule.  Each of these effects leads to increased vascular permeability. Additionally, VEGF has been shown to induce the formation of vesiculo-vacuolar organelles (VVOs) within endothelial cells, which can form into transendothelial cell pores, allowing for the passage of large molecules and fluid through endothelial cells. ,, In addition to its more direct effects on vascular permeability, VEGF indices the expression of ICAM-1. As noted above this is critical to leukostasis which can lead to endothelial cell loss, release of free radicals and release of numerous inflammatory cytokines. , Further, ischemia induced by leukostasis and endothelial cell death can in turn further increase the expression of VEGF.
Because of its central role in the pathogenesis of DME, VEGF was a logical target for therapy. Several anti-VEGF agents are available. The first anti-VEGF agent used in ophthalmology was pegaptanib (OSI Pharmaceuticals, Long Island, NY, USA), which is based on a 28-nucleotide ribonucleic acid aptamer that binds to the VEGF-A165 isoform and was initially approved for the treatment of neovascular age-related macular degeneration.  Its use has largely been supplanted by the development of ranibizumab (Genentech, Inc., South San Francisco, CA, USA), a fragment antigen binding (Fab) anti-VEGF agent that neutralizes all isoforms of VEGF-A.  Bevacizumab (Genentech, Inc., South San Francisco, CA, USA), a humanized monoclonal antibody that binds to all isoforms of VEGF-A, was developed in 1996 and first used for the treatment of human cancers.  It has also come into widespread clinical use in the treatment of retinal disease.
In the recent study by the DRCRnet, discussed above, , in addition to the laser only and laser plus triamcinolone arms of the study, two additional arms using ranibizumab with either prompt or deferred laser were included. Each of the ranibizumab arms showed superior outcomes compared to the laser alone or laser plus triamcinolone groups. , Results of another large randomized control trial demonstrated similar results for ranibizumab in the treatment of DME. , Promising results for the treatment of DME have also been reported for the use of bevacizumab in a large retrospective and one smaller prospective study ,, and for pegaptanib in a randomized control trial. 
Another anti-VEGF agent that has been developed and is pending FDA approval for neovascular age-related macular degeneration is VEGF trap-eye. VEGF trap-eye (Regeneron, Tarrytown, NY, USA) consists of the VEGF binding portions of the human VEGFR-1 and VEGFR-2 fused to the Fc portion of the human immunoglobulin-G1. In addition to having high affinity to all isoforms of VEGF-A, it also binds to PlGF. A recent phase II study has also demonstrated superiority of VEGF trap-eye for the treatment of DME compared to laser at 24 weeks.  KH902 (Kanghong Biotech, Chengdu, China) is a similar molecule that incorporates different domains from the VEGFR-1 and -2 and is currently in phase I/II trials for DME.  Its likely that each of these above therapeutics may require monthly or bimonthly intravitreal injections.
AAV2-sFLT01 (Genzyme, Cambridge, MA, USA) is a replication deficient adeno-virus expressing VEGFR-1. It offers the possibility of more sustained VEGF blockade. It is currently in phase I safety trial in patients with neovascular age-related macular degeneration. 
| Additional Targets and Emerging Therapies|| |
Mammalian target of rapamycin (mTOR) is a tyrosine kinase that forms two different binding complexes, TORC1 and TORC2. Its activation induces the expression of HIFs, including HIF1-α. HIF1-α controls the expression of over 60 genes, including VEGF.  Rapamycin (sirolimus) as well as the related drug everolimus inhibit the TORC1 mTOR complex. A recent phase I/II study of five adult patients demonstrated the safety of subconjunctival rapamycin for the treatment of DME.  Currently, a phase II dose-ranging study is underway for the treatment of DME.  Palomid 529 is another mTOR inhibitor that affects both TORC1 and TORC2. It is currently undergoing the phase I safety trials for the treatment of neovascular AMD with either intravitreal or subconjunctival injection. , Its safety and efficacy to treat DME has not yet been examined.
Protein kinase C
Protein kinase C (PKC) is a family of serine threonine kinases that are activated by growth hormones. At least 13 isoforms exist.  The PKC-β2 isoforms appear to play an important role in increased vascular permeability due to VEGF and inhibitors of this isoform of PKC reduce VEGF induce leakage of fluorescein.  VEGF signaling leads to membrane translocation of several PKC isoforms, including PKC-β2 . PKC is also activated by diacylglycerol, whose levels are increased in diabetes due to increased glycolysis related to hyperglycemia. PKC activation leads to increased vascular permeability. In animal models, administration of ruboxistaurin (RBX), a PKC-β specific inhibitor, has been shown to block more than 95% of VEGF's effect on increased vascular permeability.  In addition to its effects on vascular permeability, PKC-β activation also induces ICAM-1 levels, stimulating leukocyte chemotaxis and leukostasis and it also decreases blood flow via induction of endothelin expression. ,
The PKC-β specific inhibitor RBX, has been evaluated in several large, multicenter, randomized control trials with regards to its effect on diabetic retinopathy. , In one of these phase III studies 685 subjects with advanced non-proliferative diabetic retinopathy were randomized to placebo or 32 mg/day of RBX and followed for at least 3 years. , With consultation with the FDA, the primary end point was changed from progression of diabetic retinopathy to the incidence of sustained moderate vision loss (3 ETDRS lines on two consecutive study visits). The rate of moderate visual loss was 9% in the placebo group and 5.5% (P=0.034) in the RBX group. Improvement in visual acuity from baseline was more common in the treatment group and focal laser was less frequent in the treatment group. The second large, double-masked, randomized, multicenter trial examined the efficacy of RBX on DME progression. , In this study 686 subjects with DME outside of the fovea and no previous laser were randomized to 3 different doses of RBX or placebo. In this study, the primary end point, decrease in the progression of DME into the center of the macula or laser treatment, was not met. Due to the modest results of the first study and failing to meet the study endpoint in the second of these studies, RBX was not approved by the FDA for DME. In subgroup analysis, however, when considering eyes with long-standing, severe DME, use of RBX decreased visual acuity loss by 30% compared to placebo (17 versus 24 letter loss). ,
RBX and other PKC inhibitors still may play a role in the treatment of DME in certain clinical situations or possibly as part of combination therapy. Further investigation is required.
Also downstream of VEGFR activation is the Ras/Raf/Mek/Erk signaling cascade that partly mediates VEGF's effects on vascular permeability. A number of inhibitors of this cascade, including Vatalanib (Novartis), Pazopanib (GlaxoSmithKline), AL39324 (Alcon) and AG013958 (Pfizer) have undergone phase 1 and phase II testing for the treatment of neovascular age related macular degeneration and iCo-007, an antisense oligonucleotide targeting c-Raf, has undergone phase I trial for the treatment of DME.
As detailed above, ICAM-1, plays a critical role in leukostasis in diabetic retinopathy and its inhibition in animal models of diabetes blocks increased vascular permeability.  It exerts this action through binding with lymphocyte function antigen-1 (LFA-1). SAR 1118 is a LFA-1 inhibitor. In animal models of diabetes, topical administration of this drug has been shown to reach the retina and decrease leukostasis and breakdown of the BRB.  Topical administration has been shown to be well tolerated in phase I trials.  Further investigation is needed to determine if SAR 1118 or other ICAM-1 or LFA-1 inhibitors will be safe and effective for the treatment of DME.
MMPs are a family of proteinases that cleave structural components of ECM as well as other proteins, including growth factors.  As noted above MMPs can release ECM-bound VEGF-A. Their activation can contribute to the breakdown of the BRB by degrading ECM proteins as well as by releasing growth factors. Independent of their action as antibiotics, the tetracycline family of antibiotics can inhibit MPPs.  In addition to inhibiting MMPs, minocycline has also been shown to be neuroprotective against excitotoxicity , and has been shown to normalize levels of aquaporin 4, VEGF and interleukin 1β levels in a rodent model of DR.  Three separate studies have shown beneficial effect of minocylcine in terms of decreasing the permeability of the RBR and reducing diabetes related cytokine production in animal models of DR. ,, It is not clear from these studies whether these effects of minocylcine are mediated by inhibition of MMPs. A phase I/II clinical trial is currently recruiting patients to assess the safety and efficacy of minocyline in patients with DME. 
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors are ligand gated ion channels that are made up of following five subunits, α1-10, β1-4, γ, and ε (reviewed in  ). As homomeric and heteromeric pentamers can form, numerous subtypes exist. They can be activated by either acetylcholine or nicotine. Vascular endothelial cells contain nAChRs and can also produce acetylcholine. Nicotine has been shown to cause increased vascular permeability in the brain, largely through activation of endothelial α7-Nicotinic acetylcholine receptors (nAChRs).  Campochiaro et al., recently published reports of a multicenter phase I/II clinical trial assessing the safety and efficacy of topical mecamylamine, a nonspecific nAChR antagonist, for the treatment of chronic DME.  Mecamylamine was first approved for use as an oral antihypertensive in the 1950s and has a good safety profile. In this study, a topical eye drop was used to minimize systemic side effects. High levels of mecamylamine can be detected in the rabbit retina after topical application of this drop. In this study of 23 patients, 8 patients showed improvement, 9 showed equivocal results and 4 patients showed worsening that could be convincingly attributed to the drug used in this study. The authors hypothesize that differential expression of nAChR subtypes, whose actions can oppose each other, may be responsible for these varied results.  Mecamylamine may prove to be beneficial to a subset of patients with DME and more specific nAChR antagonist may provide more uniformly beneficial results.
Receptor for Advanced Glycation End-Products
Chronic hyperglycemia leads to the formation of AGEs. AGEs bind to Receptor for Advanced Glycation End-Products (RAGE) which can lead to expression of VEGF, ICAM-1, TNF-α, RAGE and a number of other inflammatory mediators whose pathogenesis in DME are described above (reviewed in  ). Several RAGE inhibitors have become available. PF-04494700 (TTP488) is an oral formulation of a small molecule inhibitor of RAGE. Phase II trials have been completed in patients with Alzheimer's and have demonstrated its safety. 
The components of the Renin-angiotensin system (RAS) have been identified in the retina (reviewed in ,, ). The RAS appears to be upregulated in diabetic retinas and angiotensin II (ANG II) can directly stimulate the secretion of VEGF. Angiotensin converting enzyme (ACE)-inhibitors can reduce the overexpression of VEGF seen in animal models of diabetes. ,, ANG II, through binding of the angiotensin type 1 (AT1) receptor, can also induce the expression of P-selectin, ICAM-1, VCAM-1, monocyte chomoattractant protein type 1.  Based on animal models, the renin inhibitor, aliskiren (Novartis, East Hanover, NJ, USA) may have beneficial effects on DME and DR. 
Despite the potential of medications targeting the RAS, results of the Diabetic Retinopathy Candesartan Trials (DIRECT) were disappointing with regards to the effect of candesartan, an AT1 receptor blocker, on DME. ,
It is likely that combinations of the above therapies that target different pathways or different steps of the same pathways will yield the best results for the treatment of DME. Several therapeutics have been developed, which alone can inhibit multiple targets in these signaling cascades. TG100572 and TG100801 a prodrug of TG100572 (TargeGen/Sanofi-Aventis, Paris, FRA) is a multi-targeted kinase inhibitor that targets the VEGFR 1 and 2, fibroblast growth factor receptor 1 and 2, platelet derived growth factor receptor β, as well as a numerous members of the Src family of kinases, some of which are downstream in the VEGF signaling pathway.  TG100801 when administered topically to rabbit eyes was shown to achieve high levels of the drug in the retina and choroid. Topical application was shown to significantly reduce fluorescein leakage in rat model of branch retinal vein occlusion.  This compound or other multi-targeted inhibitors may offer the benefits of combined therapies with administration of a single drug.
| Conclusions|| |
The etiology of DME is multifactorial. Understanding of key aspects of the pathogenesis and molecular pathways involved in the development of DME has led to the development of improved therapies for DME that have come into use in clinical practices over the past several years. Additional promising therapeutic agents are currently being evaluated in clinical trials and additional molecular targets exist. Combined therapies targeting multiple pathways may yield synergistic treatment responses.
| References|| |
|1.||World Health Organization Diabetes Fact Sheet Number 312. Available from: http://www.who.int/mediacentre/factsheets/fs312/en/. [cited in 2011]. |
|2.||Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998;105:998-1003. |
|3.||Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII: The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology 1998;105:1801-15. |
|4.||Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology 1995;102:647-61. |
|5.||Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: Pathogenesis and treatment. Surv Ophthalmol 2009;54:1-32. |
|6.||Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-806. |
|7.||The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. |
|8.||UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65. |
|9.||UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. |
|10.||UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13. |
|11.||Diabetic Retinopathy Clinical Research Network (DRCR.net); Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51. |
|12.||Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77,e35. |
|13.||Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609-14. |
|14.||Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-25. |
|15.||Cunha-Vaz JG, Travassos A. Breakdown of the blood-retinal barriers and cystoid macular edema. Surv Ophthalmol 1984;28 Suppl:485-92. |
|16.||Ehrlich R, Harris A, Ciulla TA, Kheradiya N, Winston DM, Wirostko B. Diabetic macular oedema: Physical, physiological and molecular factors contribute to this pathological process. Acta Ophthalmol 2010;88:279-91. |
|17.||Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica. Journal international d'ophtalmologie. Int J Ophthalmol 2010;224 Suppl 1:8-15. |
|18.||Singh A, Stewart JM. Pathophysiology of diabetic macular edema. Int Ophthalmol Clin 2009;49:1-11. |
|19.||Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP. Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 2001;158:147-52. |
|20.||Ciulla TA, Harris A, Latkany P, Piper HC, Arend O, Garzozi H, et al. Ocular perfusion abnormalities in diabetes. Acta Ophthalmol Scand 2002;80:468-77. |
|21.||Hammes HP, Lin J, Renner O, Shani M, Lundqvist A, Betsholtz C, et al. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002;51:3107-12. |
|22.||Kozak I, Oster SF, Cortes MA, Dowell D, Hartmann K, Kim JS, et al. Clinical evaluation and treatment accuracy in diabetic macular edema using navigated laser photocoagulator NAVILAS. Ophthalmology 2011;118:1119-24. |
|23.||Lavinsky D, Cardillo JA, Melo LA Jr, Dare A, Farah ME, Belfort R Jr. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Investig Ophthalmol Visual Sci 2011;52:4314-23. |
|24.||Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol 2005;89:74-80. |
|25.||Roider J, Liew SH, Klatt C, Elsner H, Poerksen E, Hillenkamp J, et al. Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2010;248:1263-72. |
|26.||Evaluation of the Effects of Selective Photocoagulation for the Treatment of Diabetic Macular Edema (SRT). Available from: http://clinicaltrials.gov/ct2/show/NCT01355692. [cited in 2011]. |
|27.||Micropulse 577 nm Laser Photocoagulation Versus Conventional 532 nm Laser Photocoagulation for Diabetic Macular Oedema (UMDMO). Available from: http://clinicaltrials.gov/ct2/show/study/NCT01045239. [cited in 2011]. |
|28.||Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology 1991;98 Suppl 5:S766-85. |
|29.||Manivannan A, Plskova J, Farrow A, Mckay S, Sharp PF, Forrester JV. Ultra-wide-field fluorescein angiography of the ocular fundus. Am J Ophthalmol 2005;140:525-7. |
|30.||Reddy S, Hu A, Schwartz SD. Ultra Wide Field Fluorescein Angiography Guided Targeted Retinal Photocoagulation (TRP). Semin Ophthalmol 2009;24:9-14. |
|31.||Schroder S, Palinski W, Schmid-Schonbein GW. Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy. Am J Pathol 1991;139:81-100. |
|32.||Miyamoto K, Khosrof S, Bursell SE, Rohan R, Murata T, Clermont AC, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Nat Acad Sci U S A 1999;96:10836-41. |
|33.||Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol 1998;341:309-15. |
|34.||Nauck M, Roth M, Tamm M, Eickelberg O, Wieland H, Stulz P, et al. Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is down regulated by corticosteroids. Am J Respir Cell Mol Biol 1997;16:398-406. |
|35.||Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115:1447-9,e1-10. |
|36.||Ip MS, Bressler SB, Antoszyk AN, Flaxel CJ, Kim JE, Friedman SM, et al. A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for diabetic macular edema: Baseline features. Retina 2008;28:919-30. |
|37.||Haller JA, Kuppermann BD, Blumenkranz MS, Williams GA, Weinberg DV, Chou C, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010;128:289-96. |
|38.||Boyer DS, Faber D, Gupta S, Patel SS, Tabandeh H, Li XY, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31:915-23. |
|39.||Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab: An anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006;26:859-70. |
|40.||Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: Review. Blood Cells Mole Dis 2007;38:258-68. |
|41.||Miyamoto N, de Kozak Y, Jeanny JC, Glotin A, Mascarelli F, Massin P, et al. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: Potential implication in the pathogenesis of diabetic retinopathy. Diabetologia 2007;50:461-70. |
|42.||Cai J, Wu L, Qi X, Shaw L, Li Calzi S, et al. Placenta growth factor-1 exerts time-dependent stabilization of adherens junctions following VEGF-induced vascular permeability. PloS One 2011;6:e18076. |
|43.||Dvorak AM, Feng D. The vesiculo-vacuolar organelle (VVO): A new endothelial cell permeability organelle. J Histochem Cytochem 2001;49:419-32. |
|44.||Feng D, Nagy JA, Pyne K, Hammel I, Dvorak HF, Dvorak AM. Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation 1999;6:23-44. |
|45.||Fine SL, Martin DF, Kirkpatrick P. Pegaptanib sodium. Nat Rev Drug Discov 2005;4:187-8. |
|46.||Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, et al. Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2009;116:2175-81,e1. |
|47.||Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do DV, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2010;117:2146-51. |
|48.||Arevalo JF, Sanchez JG, Lasave AF, Wu L, Maia M, Bonafonte S, et al. Intravitreal Bevacizumab (Avastin((R))) for Diabetic Retinopathy at 24-months: The 2008 Juan Verdaguer-Planas Lecture. Curr Diabetes Rev 2010;6:313-22. |
|49.||Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, Brito M, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: The Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology 2009;116:1488-97, 1497 e1. |
|50.||Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: Report 2. Ophthalmology 2010;117:1078-86 e2. |
|51.||Sultan MB, Zhou D, Loftus J, Dombi T, Ice KS; Macugen 1013 Study Group. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011;118:1107-18. |
|52.||Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, et al. The DA VINCI study: Phase 2 Primary results of VEGF trap-eye in patients with diabetic macular edema. Ophthalmology 2011;118:1819-26. |
|53.||Safety and efficacy by multiple injection of KH902 in patients with diabetic macular edema (DME) (Frontier-1). Available from: http://clinicaltrials.gov/ct2/show/NCT01324869. [cited in 2011]. |
|54.||Safety and tolerability study of AAV2-sFLT01 in patients with neovascular Age-Related Macular Degeneration (AMD). Available from: http://clinicaltrials.gov/ct2/show/NCT01024998. [cited in 2011]. |
|55.||Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22. |
|56.||Krishnadev N, Forooghian F, Cukras C, Wong W, Saligan L, Chew EY, et al. Subconjunctival sirolimus in the treatment of diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2011;249:1627-33. |
|57.||Dose ranging study of an ocular sirolimus (Rapamycin) formulation in patients with diabetic macular edema. Available from: http://clinicaltrials.gov/ct2/show/NCT00656643. [cited in 2011]. |
|58.||Palomid 529 in patients with neovascular age-related macular degeneration. Available from: http://clinicaltrials.gov/ct2/show/NCT01271270. [cited in 2011]. |
|59.||Phase I Study of Palomid 529 a Dual TORC1/2 Inhibitor of the PI3K/Akt/mTOR Pathway for Advanced Neovascular Age-Related Macular Degeneration (P52901). Available from: http://clinicaltrials.gov/ct2/show/NCT01033721. [cited in 2011]. |
|60.||Danis RP, Sheetz MJ. Ruboxistaurin: PKC-beta inhibition for complications of diabetes. Exp Opin Pharmacother 2009;10:2913-25. |
|61.||Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997;46:1473-80. |
|62.||PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: Thirty-month results of the randomized PKC-DMES clinical trial. Arch Ophthalmol 2007;125:318-24. |
|63.||Aiello LP, Clermont A, Arora V, Davis MD, Sheetz MJ, Bursell SE. Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Investig Ophthalmol Vis Sci 2006;47:86-92. |
|64.||PKC-DRS2 Group, Aiello LP, Davis MD, Girach A, Kles KA, Milton RC, et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 2006;113:2221-30. |
|65.||Davis MD, Sheetz MJ, Aiello LP, Milton RC, Danis RP, Zhi X, et al. Effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema. Investig Ophthalmol Vis Sci 2009;50:1-4. |
|66.||Rao VR, Prescott E, Shelke NB, Trivedi R, Thomas P, Struble C, et al. Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR). Investig Ophthalmol Vis Sci 2010;51:5198-204. |
|67.||Semba CP, Swearingen D, Smith VL, Newman MS, O'Neill CA, Burnier JP, et al. Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults. J Ocul Pharmacol Ther 2011;27:99-104. |
|68.||Bhatt LK, Addepalli V. Attenuation of diabetic retinopathy by enhanced inhibition of MMP-2 and MMP-9 using aspirin and minocycline in streptozotocin-diabetic rats. Am J Trans Res 2010;2:181-9. |
|69.||Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, et al. Minocycline reduces pro inflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 2005;54:1559-65. |
|70.||Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 2001;21:2580-8. |
|71.||Zhang Y, Xu G, Ling Q, Da C. Expression of aquaporin 4 and Kir4.1 in diabetic rat retina: Treatment with minocycline. J Int Med Res 2011;39:464-79. |
|72.||A pilot study for the evaluation of minocycline as a microglia inhibitor in the treatment of diabetic macular edema. Available from: http://clinicaltrials.gov/ct2/show/study/NCT01120899. |
|73.||D'Hoedt D, Bertrand D. Nicotinic acetylcholine receptors: An overview on drug discovery. Expert Opin Ther Targets 2009;13:395-411. |
|74.||Abbruscato TJ, Lopez SP, Mark KS, Hawkins BT, Davis TP. Nicotine and cotinine modulate cerebral microvascular permeability and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells. J Pharma Sci 2002;91:2525-38. |
|75.||Campochiaro PA, Shah SM, Hafiz G, Heier JS, Lit ES, Zimmer-Galler I, et al. Topical mecamylamine for diabetic macular edema. Am J Ophthalmol 2010;149:839-51 e1. |
|76.||Stitt AW. AGEs and diabetic retinopathy. Investig Ophthalmol Vis Sci 2010;51:4867-74. |
|77.||Sabbagh MN, Agro A, Bell J, Aisen PS, Schweizer E, Galasko D. PF-04494700, an oral inhibitor of receptor for advanced Glycation end products (rage), in Alzheimer disease. Alzheimer Dis Assoc Disord 2011;25:206-12. |
|78.||Wilkinson-Berka JL, Fletcher EL. Angiotensin and bradykinin: Targets for the treatment of vascular and neuro-glial pathology in diabetic retinopathy. Curr Pharma Design 2004;10:3313-30. |
|79.||Wilkinson-Berka JL, Tan G, Binger KJ, Sutton L, McMaster K, Deliyanti D, et al. Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat. Diabetologia 2011;54:2724-35. |
|80.||Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: Randomized, placebo-controlled trials. Lancet 2008;372:1394-402. |
|81.||Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): A randomized placebo-controlled trial. Lancet 2008;372:1385-93. |
|82.||Doukas J, Mahesh S, Umeda N, Kachi S, Akiyama H, Yokoi K, et al. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol 2008;216:29-37. |