Diabetic retinopathy (DR) represents a
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1 THE MOLECULAR BIOLOGY OF DIABETIC RETINOPATHY: OPPORTUNITIES FOR THERAPEUTIC INTERVENTION Lloyd P. Aiello, MD, PhD ABSTRACT Hyperglycemia is the principal underlying cause of diabetic microvascular complications, including diabetic retinopathy (DR). Several complex mechanisms are involved in the pathways leading from hyperglycemia to cellular dysfunction and damage. Hyperglycemiainduced protein kinase C () activation, in particular -β activation, plays a key role in several of these pathways. Therefore, inhibition of β represents a potential therapeutic approach. Vascular endothelial growth factor (VEGF) is a major mediator of retinal neovascularization and vascular permeability in DR. Several anti-vegf therapies are in various stages of development and study. These therapies include aptamers, antibody fragments, sirnas, and intravitreal steroids. Further study will determine the role of these agents in monotherapy or combined therapy for the microvascular damage caused by diabetes. (Adv Stud Ophthalmol. 2006;3(1):8-12) Based on a presentation given by Dr Aiello at a satellite symposium held in conjunction with the AAO Annual Meeting in Chicago, Illinois, on October 15, Associate Professor of Ophthalmology, Harvard Medical School, Director, Beetham Eye Institute, Joslin Center, Boston, Massachusetts. Address correspondence to: Lloyd P. Aiello, MD, PhD, Joslin Center, One Joslin Place, Boston, MA lpaiello@joslin.harvard.edu. Diabetic retinopathy (DR) represents a spectrum of disease, ranging from patients who have diabetes but no evidence of DR through mild, moderate, and severe stages of nonproliferative diabetic retinopathy (NPDR) and progressing to proliferative diabetic retinopathy (PDR). Diabetic macular edema (DME) can occur at any point along this spectrum. In asymptomatic patients with no evidence of DR, there are already a variety of biological changes occurring in the retina. Ophthalmologists can intervene throughout the spectrum of DR to reduce its progression and resultant vision loss. EFFECTS OF ACTIVATED PROTEIN KINASE C ON DIABETIC RETINOPATHY Hyperglycemia is thought to be the principal underlying cause of diabetic microvascular complications, leading to cellular dysfunction and damage through several complex physiologic mechanisms. 1 As Figure 1 illustrates, the hyperglycemic state stimulates synthesis of diacylglycerol, which is a potent activator of protein kinase C (). activation has multiple effects on the microvasculature, including induction of basement matrix protein synthesis, activation of leukocytes and endothelial cells, increased endothelial permeability, cytokine activation, and angiogenesis. 2 Therefore, inhibition may ameliorate hyperglycemia-induced cellular dysfunction and damage, even in the presence of high glycemic levels. At least 13 isoforms of have been identified. 3 Of these isoforms, the β isoform is thought to play the most important role in mediating the microvascular complications of diabetes, including DR. -β overexpression in genetically altered nondiabetic mice has 8 Vol. 3, No. 1 March 2006
2 been associated with the development of the same pathologic changes that occur in DR. 4 Figure 2 shows that the level of activation in human monocytes was associated with the severity of DR. -β activity was progressively higher in monocytes from patients with more severe retinopathy (King GL, Unpublished data, 2005). THERAPEUTIC OPPORTUNITIES -β INHIBITORS Several -β inhibitors are being evaluated in preclinical and early stage clinical trials. More clinical data are currently available for ruboxistaurin (RBX) than for the other agents under investigation. RBX is a highly selective -β inhibitor that is orally bioavail- EFFECT OF VASCULAR ENDOTHELIAL GROWTH FACTOR ON DIABETIC RETINOPATHY The role of vascular endothelial growth factor (VEGF) in the development and progression of DR has been delineated through many animal and human investigations. In one study, intravitreal injection of clinically relevant concentrations of VEGF dramatically increased vascular permeability in rat retinas. 5 Likewise, intraocular injection of VEGF into primate eyes has been shown to cause changes similar to those seen in severe NPDR, including aneurysms and capillary dropout. 6,7 VEGF also has been shown to be expressed in the retinas of patients with diabetes; in some cases, early in the disease. 8 A study measuring VEGF levels in the aqueous and vitreous fluids demonstrated high VEGF levels in the eyes of patients with active PDR compared to VEGF levels in those who had no proliferative disease, diabetes without PDR, or diabetes with quiescent PDR (Figure 3). 9 These animal and human studies suggest that VEGF is an important mediator of retinal neovascularization and vascular permeability under ischemic retinal conditions, such as DR. VEGF acts through several pathways, including activation (Figure 4). 10 These findings suggest that blocking the action of VEGF may be an effective means of preventing many of the changes that occur in DR. SUMMARY On the physiologic level, diabetic complications appear to be the result of hyperglycemia-induced dysfunction. Activated β is thought to mediate much of the vascular dysfunction associated with diabetes. Increased expression of VEGF promotes neovascularization and increased vascular permeability, at least partly through the activation of. Therapies that counter -β and VEGF-mediated dysfunction may alleviate the microvascular damage and complications observed in patients with diabetes. Figure 1. Hyperglycemia-Induced Activation Activation of (Classical Type) Hyperglycemia (palmitate oleate) G-protein coupled receptor α PLC βγ IP 3 G-protein ER PIP 2 Glycerol 3-Phosphate Phosphatidic acid DAG Ca 2+ Phospho-protein ADP ATP Protein ADP = adenosine diphosphate; ATP = adenosine triphosphate; DAG = diacylglycerol; = protein kinase C; PLC = phospholipase C. Figure 2. Severity of DR was Associated with Increased Monocyte Activity activity in monocytes (pmol/min/mg protein) No DM No DR NPDR PDR P <.03. DM = diabetic macular edema; DR = diabetic retinopathy; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; = protein kinase C Advanced Studies in Ophthalmology 9
3 able and taken once daily. In animal studies, RBX has been associated with reductions in retinal neovascularization, diabetes-induced vascular permeability, and the normalization of retinal blood flow. 5,11,12 Studies in rats have demonstrated that intravitreal injection of VEGF is associated with a large increase in retinal vascular permeability. This increase was blocked by the oral administration of RBX for 1 week. 5 The promising results from animal studies have led to various trials of RBX in humans, including 2 double-masked, randomized, placebo-controlled, multidose, multicenter clinical trials. The Protein Kinase C- β Inhibitor Diabetic Retinopathy Study (-DRS) investigated the effect of RBX on DR progression in patients with moderate to severe NPDR who had not had prior cataract surgery or scatter photocoagulation treatment. 13 Although RBX treatment did not prevent DR progression in this study, patients receiving RBX had a reduced risk of moderate vision loss. The Protein Kinase C-β Inhibitor Diabetic Macular Edema Study (-DMES) examined the effect of RBX on DME progression in patients with mild to moderate NPDR and DME present at baseline and no prior focal or pan-retinal photocoagulation. 14 The Cox proportional hazard model in the -DMES trial showed a 36% reduced risk of DME progression to within 100 µ of the macula for patients receiving RBX treatment compared to patients receiving placebo (Figure 5). Although there was no apparent effect on retinopathy progression, Cox hazard analysis showed that RBX treatment was associated with a 70% risk reduction for moderate vision loss compared to placebo (Figure 6). ANTI-VEGF STRATEGIES Studies in murine models of proliferative retinopathy have shown that intravitreal injection of VEGF inhibitors can reduce neovascularization. 15,16 In nonhuman primates, administration of a VEGF inhibitor prevented retinal ischemia-associated iris neovascularization. 17 The results of animal studies spawned several anti-vegf approaches that are now in clinical trials with humans. For example, phase II study results for pegaptanib showing a possible beneficial effect for DME have recently been published, 18 and phase III trials of pegaptanib for treatment of DME are beginning. Trials of ranibizumab, VEGF trap, and bevacizumab for DME are under way. Bevacizumab is already being used off-label in some cases. Figure 3. VEGF Concentration was Higher in the Ocular Fluids of Patients with Active PDR VEGF, ng/ml No proliferative diseases = Aqueous fluid = Vitreous fluid = Mean without PDR quiescent PDR active PDR PDR = proliferative diabetic retinopathy; VEGF = vascular endothelial growth factor. Reprinted with permission from Aiello et al. N Engl J Med. 1994;331: Copyright 1996 Massachusetts Medical Society. Figure 4. Model of VEGF-Mediated Microvascular Damage Mechanism of VEGF Action PI3 Kinase Permeability α,β,δ VE GF KDR PLCγ PLCγ-P PIP2 DAG & IP3 Neovascularization DAG = diacylglycerol; = protein kinase C; PLC = phospholipase C; VEGF = vascular endothelial growth factor. Data from Xia et al Vol. 3, No. 1 March 2006
4 INTRAVITREAL STEROIDS Steroids have multiple effects on the diabetic retina, including the potential to prevent the release of VEGF or increase its degradation. Several phase II and phase III clinical trials of intravitreal steroids are under way or completed. Preliminary data suggest that intravitreal steroids reduce retinal edema in a time-limited manner, but that this reduction is not consistently associated with improved visual acuity There are several potential risks associated with intravitreal steroid administration, including endophthalmitis, cataract formation, and elevation of intraocular pressure. The Diabetic Retinopathy Clinical Research Network is conducting a long-term study of more than 470 patients to investigate the effects of a preservative-free steroid formulation in the eye. Patients will be treated with laser photocoagulation or with 1-mg or 4-mg triamcinolone acetonide injections, and they will be followed for 3 years. 22 SUMMARY Studies suggest that -β and VEGF inhibition may prevent microvascular damage or complications that occur in the retina of patients with diabetes. RBX treatment has been associated with a reduced risk for moderate vision loss and reduced DME progression in patients with microvascular complications from diabetes. Clinical trials of several VEGF inhibitors and intravitreal steroids are also under way. CONCLUSIONS New therapies aimed at preventing or ameliorating the development of diabetic microvascular complications, including DR, are under investigation. Understanding the roles of key mediators, such as β and VEGF, have helped develop strategies to block their action and may be instrumental in preventing diabetes-associated vision loss. Preclinical and clinical studies have led to the development of -β inhibitors, anti-vegf approaches, and intravitreal steroid use, all of which hold great promise. However, further clinical trials will determine the appropriate role of these new therapies in clinical care. Figure 5. -β Inhibition was Associated with a Reduced Risk of DME Progression Cox Proportional Hazard Model for DME Progression to within 100 microns of the center of the macula -DMES Body mass index (>30) Baseline VA (<80) Treatment (32 mg RBX) ACE/AII use (Y) Mean BP (>105 mm Hg) Study eye (Severe) HBA 1c (>10.0%) (type 2) P = % Risk Reduction in DME Progression P = Hazard ratio ACE = angiotensin-converting enzyme; BP = blood pressure; DME = diabetic macular edema; HbA 1c = hemoglobin A 1c ; = protein kinase C; -DMES = Protein Kinase C-β Inhibitor Diabetic Macular Edema Study; RBX = ruboxistaurin; VA = visual acuity. Data from Aiello et al. 14 Figure 6. -β Inhibition was Associated with a Reduced Risk of Moderate Vision Loss Nitrates (Y) Gender (Male) ACEI/AII use (Y) High LDL cholesterol or triglycerides Age (>55) Antibiotic use (Y) Tobacco use (Y) Baseline VA (<80) Cox Proportional Hazard Model for Risk of Moderate Visual Loss -DMES P =.02 P =.02 Treatment (32 mg RBX) P = % Risk Reduction in Moderate Visual Loss Hazard ratio P =.03 P =.009 ACEI = angiotensin-converting enzyme inhibitor; LDL = low-density lipoproteins; = protein kinase C; -DMES = Protein Kinase C-β Inhibitor Diabetic Macular Edema Study; RBX = ruboxistaurin; VA = visual acuity. Reprinted with permission from. 2005;54: Copyright 2005 American Association. Advanced Studies in Ophthalmology 11
5 REFERENCES 1. Sheetz MJ, King GL. Molecular understanding of hyperglycemia s adverse effects for diabetic complications. JAMA. 2002;288: Ishii H, Koya D, King GL. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med. 1998;76: Way KJ, Chou E, King GL. Identification of -isoform-specific biological actions using pharmacological approaches. Trends Pharmacol Sci. 2000;21: King GL. [abstract]. The Association for Research in Vision and Ophthalmology. In press. 5. Aiello LP, Bursell SE, Clermont A, 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 ;46: Tolentino MJ, McLeod DS, Taomoto M, et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol. 2002;133: Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103: Lutty GA, McLeod DS, Merges C, et al. Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol. 1996;114: Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331: Xia P, Aiello LP, Ishii H, et al. Characterization of vascular endothelial growth factor s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest. 1996;98: Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by -beta inhibition with LY Invest Ophthalmol Vis Sci. 1998;39: Aiello LP. Invest Ophthalmol Vis Sci. In press. 13. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (-DRS) multicenter randomized clinical trial ;54: Aiello LP, Davis M, Milton R, et al. Initial results of the Protein Kinase C-β Inhibitor Diabetic Macular Edema Study (- DMES) [abstract]. Diabetologia. 2003;46(suppl 2):A Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995;92: Robinson GS, Pierce EA, Rook SL, et al. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci U S A. 1996;93: Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemiaassociated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114: Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an antivascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112: Chieh JJ, Roth DB, Liu M, et al. Intravitreal triamcinolone acetonide for diabetic macular edema. Retina. 2005; 25: Jonas JB, Martus P, Degenring RF, et al. Predictive factors for visual acuity after intravitreal triamcinolone treatment for diabetic macular edema. Arch Ophthalmol. 2005;123: Patelli F, Fasolino G, Radice P, et al. Time course of changes in retinal thickness and visual acuity after intravitreal triamcinolone acetonide for diffuse diabetic macular edema with and without previous macular laser treatment. Retina. 2005;25: Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for diabetic macular edema. Available at: steroid/protbinfo.html. Accessed November 15, Vol. 3, No. 1 March 2006
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