New Trends and Therapeutic Approaches for the Management of Diabetic Retinopathy
Diabetes mellitus is a growing epidemic that has become a global public health problem. The long-term complications of diabetes include retinopathy, the leading cause of blindness and visual impairment in adults. Diabetic retinopathy correlates with the duration of diabetes.
Improved medical care of diabetic patients, and therefore increased life expectancy, will result in more instances of diabetes-induced blindness. Several innovative therapeutic approaches address the unmet need to prevent and treat this debilitating consequence of diabetes.
Diabetes mellitus is a global and rising problem, with an estimated 220 million people worldwide currently affected. The diabetic epidemic will account for 300 million people suffering from diabetes in 2025, according to the World Health Organization. Diabetic retinopathy (DR) is a common microvascular complication of diabetes and a leading cause of blindness. After 15 years of diabetes, approximately 2% of people become blind, and about 10% develop severe visual impairment (1).
Forms of diabetic retinopathy include non-proliferative and proliferative diabetic retinopathy. Non-proliferative diabetic retinopathy (NPDR) is associated at early stages with retinal capillary occlusion, pericyte ghosts, capillary cell death, leukostasis, aneurysms, microvascular leakage, haemorrhage and to some extent neuronal cell death.
This results in avascular hypoxic areas that trigger, through the release of hypoxia-inducible factor 1-a (HIF-1a) and vascular endothelial growth factor (VEGF), retinal neovascularisation, a hallmark of proliferative diabetic retinopathy (PDR). Thus, PDR consists in the proliferative growth and formation of new blood vessels that develop from the inner retinal circulation. These new vessels grow beyond the supporting structure of the retina and can even rupture and haemorrhage into the vitreous in response to a rise of the blood pressure.
Consequently, this haemorrhage results in vision loss. The new blood vessels can also cause retinal detachments. Diabetic macular oedema (DME), manifested by the swelling of the retina due to the leakage of fluids from blood vessels into the macula (the highly pigmented spot near the centre of the retina), can occur at any stage of the disease. However, it is more frequently observed in PDR patients. Macular oedema does not cause total blindness but can lead to severe vision loss. PDR and DME account for 9% and 17% of all diagnosed diabetic retinopathy cases, respectively (2).
Current approaches to prevent and slow down the progression of diabetic retinopathy are built around the tight control of glucose and blood pressure, as demonstrated by the United Kingdom Prospective Diabetes study (UKPDS). Intensive metabolic diabetes therapy and blood pressure control lead to a reduction of the progression of diabetic retinopathy (3,4).
Still, patients with diabetes remain at high residual risk for microvascular complications, even if they are treated with optimal standard of care, a factor which certainly underscores the unmet need for novel therapeutic approaches to prevent and treat diabetesinduced blindness (5).
Today, therapies to treat diabetic retinopathy include laser-induced retinal photocoagulation, which still remains the first-line treatment of diabetic retinopathy. It reduces the risk of blindness derived from vitreous haemorrhage or detachment of the retina. This therapy has been shown to be successful for early treatment of proliferative diabetic retinopathy before the bleeding or detachment has progressed too far.
Limitations of laser therapy include a diminished vision field and reduced colour vision and sensitivity. Vitrectomy, the surgical removal of the vitreous gel from the middle of the eye, is often used for patients with more advanced retinal disease. The procedure is intended to prevent the complete detachment of the retina (reviewed in 6).
Existing treatment options for diabetic retinopathy are limited, resulting in a need for new therapeutic approaches to treat this debilitating disease. Current research is focused on understanding the molecular and biochemical mechanisms of the development and progression of diabetic retinopathy. Several pharmacological agents are currently studied for the treatment of diabetic retinopathy. These include local and systemic agents.
Diabetic retinopathy and angiogenesis
Angiogenesis plays a fundamental role in the normal development and pathological process of the eye. Hyperglycaemia, ischaemia and other growth factors can induce vascular endothelial growth factor (VEGF), a glycoprotein that is essential for the formation of the foetal vascular system. VEGF is expressed during embryonic development, and its expression decreases after birth, but it was also found to be highly expressed in rapidly growing tumours.
VEGF is active in a wide variety of processes; it plays a prominent role in ocular neovascularisation and is active in promoting ocular inflammation. VEGF is increased by retinal hypoxia and induces the breakdown of the blood-retinal barrier, thus strategies to block VEGF or its activity in the eye may provide promising treatment options for diabetic retinopathy (6).
One of the first pharmacological approaches for treating diabetic retinopathy targets the vascular endothelial growth factor (VEGF). Anti-VEGF therapies are meanwhile important therapies for the management of several cancer types and other diseases that include wet age-related macular oedema (AMD). The latter is caused by the abnormal growth of blood vessels behind the retina under the macula. Currently, ranibizumab, pegaptanib, bevacizumab and VEGF Trap-Eye are in clinical trials to investigate local (ocular) agents for the management of diabetic retinopathy (7).
Ranibizumab is a recombinant humanised monoclonal antibody fragment that is directed against all isoforms of human VEGF-A. The US Food and Drug Administration (FDA) approved ranibizumab for wet AMD in June 2006, and studies are under way to investigate ranibizumab in DME.
Pegaptanib is a PEGylated (conjugated to polyethylene glycol) neutralising RNA aptamer that specifically targets the VEGF-A165 isoform. Intravitreal Pegaptinib showed some efficacy in DME, and the subset analysis of the Phase II clinical trial also demonstrated a regression of retinal neovascularisation in patients with PDR. Pegaptanib was approved by the FDA for the treatment of exudative AMD in December 2004.
Bevacizumab, approved by the FDA in February 2004 for the treatment of metastatic colorectal cancer, has been used as intravitreal bevacizumab for DME and PDR. Randomised clinical trials have shown that bevacizumab demonstrated favourable short-term anatomic and visual outcomes in patients with DME and short-term efficacy as an adjunct to photocoagulation in patients with PDR. It is noteworthy that some patients with PDR suffered from tractional retinal detachment after intravitreal treatment with bevacizumab (8).
VEGF-Trap-Eye is a recombinant fusion protein that binds all forms of VEGF-A along with the related placental growth factor (PlGF). VEGFTrap- Eye is currently in a Phase II study of a patient population with DME.
Hyperglycaemia is known to increase the formation of diacylglycerol and subsequently activates protein Kinase C (PKC), an upregulator of VEGF. First studies of ruboxistaurin, an orally administered inhibitor targeting protein kinase C (PKC)-, showed that the drug was associated with a reduction of the progression of DME and a reduction of vision loss in patients with DME. The occurrence of visual improvement in patients with non-proliferative retinopathy also increased (9).
Diabetic retinopathy and inflammation
Immunological processes play an important part in diabetic retinopathy. Diabetic retinopathy is characterised by typical features of low-level inflammation such as elevated levels of circulating and vitreous cytokines, chemokines and growth factors. Chronic retinal leukostasis, the increased adherence of leukocytes to the capillary endothelium, leads to vascular leakage and haemorrhage (6).
Thus, targeting inflammation is another investigational approach to target diabetic retinopathy. Corticosteroids, established anti-inflammatory agents, are able to slow the progression of diabetic retinopathy, as demonstrated by a recent study; however, the authors concluded that any treatment used routinely to prevent PDR should have a favourable safety profile considering the high incidence of elevation of intra-ocular pressure and cataracts associated with intravitreal steroids (10). Corticosteroids are injected intravitreally, and various extended-release corticosteroids for the long-term treatment of DME are currently under investigation (ie Iluvien® and Ozurdex®).
The kallikrein-kinin system in diabetic retinopathy
The kallikrein-kinin system (KKS) is a multi-protein system that controls blood circulation and kidney function, and promotes inflammation and pain in pathological conditions. Plasma kallikrein triggers the contact cascade with its major components kallikrein and bradykinin. Kallikrein and the Hagemann factor (factor XIIa) autoactivate each other and subsequently stimulate the conversion of prekallikrein to kallikrein, leading the cleavage of high-molecular-weight kininogen (HMWK) to bradykinin.
The biological downstream effects of the KKS are mediated by bradykinin, a peptide hormone that activates the G-protein coupled receptors (GPCRs), kinin B1 and B2 receptors (B1R and B2R). The B2R is constitutively expressed in vascular and neuronal cells. The inducible B1R plays a major role in neutrophil recruitment and chemotaxis (11-13) (Figure 1).
The activation of the kallikrein-kinin system has been shown to induce a host of proinflammatory responses.
Retinal inflammation is involved in the development of diabetic retinopathy, and accumulating evidence demonstrates a pivotal role for the KKS in the development of diabetic retinopathy. The KKS system is expressed in the human eye (14), and high levels of carbonic anhydrase (CA-1), prekallikrein, IL-1, IL-8, TNF and IL-6 were found in the vitreous of diabetic patients when compared to healthy volunteers. CA-1 induces retinal oedema and haemorrhage through activation of the KKS, and IL-1, IL-8 and glucose upregulate the expression of B1R in vessels and leukocytes (15).
Furthermore, B1R messengerRNA (mRNA) was markedly increased in the retina of rats with streptozotocin (STZ)-induced diabetes (16). Phipps et al were able to show that intravitreous injection of recombinant plasma kallikrein induced retinal oedema and haemorrhage in diabetic rats, whereas systemic treatment with a kallikrein inhibitor reduced retinal vascular leakage (17).
Recent studies have shown that FOV-2304, a non-peptide kinin B1R antagonist, abolished retinal vascular permeability, as well as leukostasis and leukocyte infiltration, hallmarks of diabetic retinopathy, in streptozotocin-induced diabetic rats18. Additionally, diabetes-induced up-regulation of the many mRNAs, such as endothelial nitric oxide synthase (eNOS), nitric oxide (NO), B1R, B2R, VEGF and VEGF receptor type 2, was reversed after seven days eye-drop treatment of FOV-2304 (18).
Current studies are evaluating the convenient and safe eye-drop formulation of FOV-2304 in rabbits, a species with an eye volume similar to the human eye. The pharmacological blockade of the KKS system, in particular the kinin B1R, may provide an innovative and promising treatment approach for diabetic retinopathy (19). DDW
Dr Didier Pruneau joined Fovea Pharmaceuticals in 2006 as head of scientific operations. Fovea Pharmaceuticals, a start-up company specialising in ocular diseases, was acquired by Sanofi-Aventis in October 2009 to build-up the Ophthalmology branch of the group. Before joining Fovea Pharmaceuticals, he successively headed a Cardiovascular Research Unit, a Receptor Pharmacochemistry Group and the Department of Pharmacology of Fournier Pharma that became part of Solvay Pharma in 2005. Didier Pruneau holds a PhD in biochemistry and a masters degree (Valedictorian) in pharmacology from the Paris V University. He was a post-doctoral fellow in cardiovascular pharmacology at Baker Medical Research Institute, Melbourne, Australia. He authored and co-authored 79 peer-reviewed scientific publications and about seventy scientific communications. He has been an invited speaker at various scientific meetings, including Gordon Research Conferences.
1 World Health Organization, G., Diabetes Fact Sheet 321. 2009.
2 Delcourt, C, Massin, P and Rosilio, M. Epidemiology of diabetic retinopathy: expected vs reported prevalence of cases in the French population. Diabetes Metab, 2009. 35(6): p. 431-8.
3 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med, 1993. 329(14): p. 977-86.
4 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131): p. 837-53.
5 Fioretto, P et al. Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol, 2010. 6(1): p. 19-25.
6 Frank, RN. Diabetic retinopathy. N Engl J Med, 2004. 350(1): p. 48-58.
7 Schwartz, SG, Flynn, HW Jr and Scott, IU. Pharmacotherapy for diabetic retinopathy. Expert Opin Pharmacother, 2009. 10(7): p. 1123-31.
8 Arevalo, JF et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol, 2008. 92(2): p. 213-6.
9 Aiello, LP et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology, 2006. 113(12): p. 2221-30.
10 Bressler, NM et al. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol, 2009. 127(12): p. 1566-71.
11 Bockmann, S and Paegelow, I. Kinins and kinin receptors: importance for the activation of leukocytes. J Leukoc Biol, 2000. 68(5): p. 587-92.
12 Duchene, J et al. A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5. J Immunol, 2007. 179(7): p. 4849-56.
13 Ehrenfeld, P et al. Activation of kinin B1 receptors induces chemotaxis of human neutrophils. J Leukoc Biol, 2006. 80(1): p. 117-24.
14 Ma, JX et al. Expression and cellular localization of the kallikrein-kinin system in human ocular tissues. Exp Eye Res, 1996. 63(1): p. 19-26.
15 Bastian, S et al. Interleukin 8 (IL-8) induces the expression of kinin B1 receptor in human lung fibroblasts. Biochem Biophys Res Commun, 1998. 253(3): p. 750-5.
16 Abdouh, M et al. Retinal plasma extravasation in streptozotocin-diabetic rats mediated by kinin B(1) and B(2) receptors. Br J Pharmacol, 2008. 154(1): p. 136-43.
17 Phipps, JA and Feener, EP. The kallikrein-kinin system in diabetic retinopathy: lessons for the kidney. Kidney Int, 2008. 73(10): p. 1114-9.
18 Pouliot, M et al. Topical Treatment With the Kinin B1 Receptor Antagonist, FOV2304, Inhibits Diabetic Retinopathy (DR) in Rats. ARVO 2010, 5611-D732, Fort- Lauderdale, May 2-6, 2010.
19 Pruneau, D et al. Targeting the kallikrein-kinin system as a new therapeutic approach to diabetic retinopathy. Curr Opin Investig Drugs, 2010. 11(5): p. 507-14.