Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

1.INTRODUCTION

Over 50 years ago, Isaac Michaelson proposed that a soluble “factor X” was responsible for retinal neovascularization.1 The first soluble polypeptide growth factors were not discovered until the mid-1970’s. With regard to retinal and choroidal neovascularization, the first growth factors that were associated with pathological retinal angiogenesis were acidic and basic fibroblast growth factors (aFGF and bFGF), later re-named FGF-1 and FGF- 2.2,3 Subsequently, vascular endothelial growth factor (VEGF), also called vascular permeability factor (VPF),4 was felt to be the major growth factor responsible for retinal and choroidal neovascularization. This was based on the presence of VEGF protein in eyes with retinal neovascularization in proliferative diabetic retinopathy and other diseases5 and the upregulation of its mRNA in neovascular membranes removed surgically from diabetic patients,6 as well as the fact that VEGF expression is enhanced by hypoxia,7 which is thought to be a critical factor in the pathogenesis of neovascularization in the retina.8,9 VEGF protein (but also FGF-1 and FGF-2 proteins) have been found in choroidal neovascular membranes excised surgically from patients with neovascular age-related macular degeneration.10,11 Although VEGF has been central to much current research, both basic and clinical, dealing with the pathogenic mechanisms of diabetic retinopathy and potential therapies, other possible mechanisms and a variety of therapeutic approaches have been considered. This chapter will consider many of the therapies that have been tested or for which clinical evaluation is now in progress. Because a number of these therapies are still under evaluation and no results have been published, many of the references cited below are to news reports and Web announcements of these investigations, rather than to more traditional publications in peer-reviewed biomedical journals.

2.ANTI-VEGF STRATEGIES

The major clinical approaches to treating diabetic retinopathy and other ocular neovascularizing diseases that have arisen from these findings have been attempts to block VEGF synthesis or its actions. Several approaches were suggested by studies in experimental animals with retinal neovascularization produced by neonatal hyperoxia. These included anti-

VEGF antibodies,12 “anti-sense” VEGF RNA,13 and blockade of VEGF action using a VEGF “trap” consisting of a chimeric protein in which an immunoglobulin protein was linked to a VEGF receptor.14 Similar “trap” technology is currently under development in the biotechnology industry.15

The Fab fragment of an anti-VEGF antibody (ranibizumab) is being tested in age-related macular degeneration in a collaboration between two pharmaceutical companies.16 This antibody is undergoing a clinical trial for

the treatment of diabetic macular edema.

Yet another approach to anti-VEGF therapy is the development of pegaptanib, which is a 28-base pair modified RNA-aptamer that binds VEGF. Pegaptanib has been tested in neovascular age-related macular degeneration but is now also undergoing studies in diabetic macular edema. In a Phase II study involving 172 diabetic subjects with macular edema and randomized to receive either a sham intravitreal injection of the vehicle or one of three drug doses, the best-corrected visual acuity of subjects treated with the lowest dose of the drug (0.3 mg) for 36 weeks either remained stable or improved 73%, compared to 51% of subjects who received the sham injection (P = 0.023). Improvements in visual acuity by >/= 10 letters (2 lines) at 36 weeks occurred in 34% of the subjects who received the 0.3 mg dose vs. 10% of those receiving the sham injection (P = 0.003). Higher doses of pegaptanib had a lesser effect on visual acuity during this study.17

Other methods of inhibiting VEGF action include blocking either of its two principal receptors on the endothelial cell plasma membrane or preventing their synthesis. Attempts to use VEGF receptor blockers in cancer therapy have demonstrated some efficacy but considerable toxicity.18 However, a Phase II study (for rheumatoid arthritis, but certainly with potential applications to neovascular age-related macular degeneration and to diabetic retinopathy) of an anti-VEGF tyrosine kinase inhibitor is under way,19 and a similar drug for neovascular age-related macular degeneration is in a Phase I trial.20 Another approach is to use “small inhibitory RNAs” (siRNAs). These are short strands of modified RNA that target the mRNA for a particular protein (in this case, one of the VEGF receptors) following introduction into the eye.21

3.STEROIDS AND STEROID-LIKE MOLECULES

A variety of other pharmacologic approaches have been attempted, or are currently being attempted, or are in the planning stages for the treatment of more advanced diabetic retinopathy. Corticosteroids were reported some years ago to have anti-angiogenic properties.22 More recently, intravitreal injections of triamcinolone, a steroid molecule that is available in a form suitable for parenteral administration, has been reported to reduce retinal thickness, as measured by optical coherence tomography (OCT), and to improve visual acuity in patients with macular edema from diabetes or other

causes.23-25 Some years earlier, the Early Treatment Diabetic Retinopathy Study (ETDRS) had demonstrated that focal argon laser treatment of the macula could reduce macular edema and stabilize visual acuity, but that laser treatment rarely produced improvement in vision that had already been lost.26 A therapy that can actually improve visual acuity in eyes that have suffered diminished vision due to diabetes or other causes would be of substantial benefit.

Following the publication of the reports cited above, controlled clinical trials of intravitreal triamcinolone for macular edema due to diabetic retinopathy, or to branch or central retinal vein occlusions, were planned by the National Eye Institute (the “SCORE” study for vein occlusions) and the Diabetic Retinopathy Clinical Research Network, and are now in progress. Oculex Pharmaceuticals has also begun trials to treat these disorders by injection of intravitreal dexamethasone through a special new device.27 Anecortave acetate, a steroid-like molecule that is anti-angiogenic but lacks many of the other properties of glucocorticoids, has been tested in neovascular age-related macular degeneration via a novel periocular injection device.28

4.PROTEIN KINASE C INHIBITORS

Several other approaches have been considered. Protein kinase C (PKC) refers to a large family of enzymes, present in many tissues in the body, that transfer a terminal phosphate from ATP to an effector molecule, usually an enzyme, an ion channel, or a cell membrane receptor. PKCs require a magnesium ion for activation, but they also require a second activator. Among these possible activators is diacylglycerol, whose systemic levels are increased by the hyperglycemia of diabetes.29

PKC is thought to upregulate VEGF, but it may also be reciprocally upregulated by the binding of VEGF to the vascular endothelial cell plasma membrane via the appropriate receptor. PKC inhibition is thus a plausible mechanism to block the VEGF-related pathways leading to advanced diabetic retinopathy. However, because the PKC isoforms are so ubiquitous, a generalized PKC inhibitor is likely to have substantial toxicity. This was the case with PKC412 (staurosporin), a relatively general inhibitor of PKC that also had some other inhibitory activities.30 In a three-month clinical trial in patients with diabetic macular edema, PKC412 did reduce edema, as demonstrated by optical coherence tomography, and it also produced a moderate increase in visual acuity in some patients, but its toxicity prevented its being adopted for clinical use.

years ago, to the hypothesis that hypoxia is a major effector of retinal neovascularization.8,9 A stimulus to the theory that VEGF is critical for neovascularization in the retina has been the finding that this growth factor is upregulated by hypoxia.7,38 As clearly demonstrated over 20 years ago by the Diabetic Retinopathy Study (DRS), “pan-retinal” or “scatter” laser photocoagulation, in which up to several thousand large laser burns are placed in the mid-peripheral retina, is highly effective in reducing progression to blindness from proliferative diabetic retinopathy, even though the neovascular formations themselves (for example, when they arise on the optic nerve head) are often not directly treated.39 A leading hypothesis for the efficacy of this mode of treatment is that it destroys regions of hypoxic retina, thereby eliminating a major stimulus of neovascularization.40,41 More recently, in a brief duration clinical trial, Campochiaro and colleagues had diabetic patients with macular edema breathe high oxygen mixtures for prolonged periods.42 These investigators found that this procedure, although somewhat cumbersome, did appear to ameliorate the macular edema as measured by optical coherence tomography, at least over a short period.

8.PIGMENT EPITHELIUM-DERIVED FACTOR (PEDF)

PEDF, which is discussed in more detail elsewhere in this volume, has the interesting dual properties of enhancing the differentiated state of neurons and inhibiting neovascularization.43,44 Although its major site of synthesis in the eye is the retinal pigment epithelium (RPE), it is also produced by other cells of the retina.45 The RPE also produces substantial amounts of VEGF. This cellular layer secretes VEGF primarily from its basal surface,46 opposite the richly vascular and anatomically highly polarized choriocapillary layer, while it secretes its PEDF primarily from its apical surface,47 opposite the highly differentiated neural layers of the outer retina, which are normally avascular. Major sites of secretion of VEGF and PEDF in the retina and RPE are shown in Figure 1. There is evidence that PEDF and VEGF behave in a “yin-yang” fashion, such that upregulation of VEGF in ischemic retinopathies like diabetic retinopathy leads to downregulation of PEDF.49 Upregulation of PEDF in the retinas of experimental animals with retinal or choroidal neovascularization leads to diminution of the abnormal vessels.50 In an ongoing Phase I clinical trial investigators are attempting to upregulate PEDF in the retinas of human subjects with choroidal neovascularization due to age-related macular degeneration by a “gene therapy” approach, in which a non-replicating adenoviral vector containing the gene for human PEDF is injected intravitreally.51 If the virus can insert the PEDF gene into retinal

cells, thereby increasing production of this protein, this mechanism can be a long-lasting therapy for choroidal neovascularization and also, perhaps, for retinal neovascularizing diseases like diabetic retinopathy.

Figure 21-1. Retinal Anatomy and Mechanisms of Diabetic Retinopathy. A normal retina is shown in Panel A, and a retina from a patient with proliferative diabetic retinopathy is shown in Panel B. Several polypeptide growth factors and their cell-membrane receptors have possible relevance to the pathogenesis of diabetic retinopathy, but vascular endothelial growth factor (VEGF) and its receptors, VEGFR-1 and VEGFR-2, and pigment epithelium–derived factor (PEDF), are currently undergoing the most intensive investigation. These two growth factors are both produced in the retinal pigment epithelium, where their constitutive secretion appears to be highly polarized. Retinal neovascularization in diabetic retinopathy and other proliferative retinal vascular diseases nearly always occurs away from the retinal pigment epithelium and toward the vitreous space. There is evidence that both VEGF and PEDF are produced in retinal neurons and in glial cells, such as the cells of Müller. In the normal retina, VEGFR-1 is the predominant VEGF receptor on the surface of retinal vascular endothelial cells, but in diabetes, VEGFR-2 appears on the endothelial cell plasma membrane.

9.CONCLUSIONS AND CAVEATS

To date, laser photocoagulation and, for more advanced cases, vitrectomy,

are the only proven therapies for proliferative diabetic retinopathy and for diabetic macular edema.26,39,52 It has been estimated that, if applied early

enough, photocoagulation can prevent blindness and visual impairment by as much as 95%.53 However, because large studies of representative populations before and after the widespread use of laser treatment have not been carried out, and because of a lack of optimal blood glucose control in

both type 1 and type 2 diabetes, the recommendation of which followed from the outcomes of two large controlled clinical trials,54,55 we will never be able

to quantify the effects of these therapies for the prevention of visual impairment and blindness from diabetes. Every clinician who sees many diabetic patients knows that these problems exist, and as a result, new therapies are under intense investigation.

Our knowledge of the pathogenesis of diabetic retinopathy is still incomplete. Although a great deal of effort has been expended on developing treatments directed against a single molecule, VEGF, it is entirely likely that VEGF is only one among several agents that produce neovascularization and breakdown of the blood-retina barrier with resultant macular edema. Thus, for example, various anti-VEGF strategies have inhibited retinal neovascularization in a widely used animal model by less than 50%.12-14

What might be necessary to cause regression of the remaining new vessels? Growth factors other than VEGF, for example, connective tissue growth factor,56 hepatocyte growth factor,57 or other molecules, may share the responsibility for retinal neovascularization. The ultimate treatments for vision-threatening diabetic retinopathy may require multiple modalities or at least multiple drug therapies. The possibility that the more severe forms of diabetic retinopathy may in part have a genetic basis,58 such that the identification of genes conferring increased risk might identify more susceptible individuals for special preventive measures or early therapeutic intervention, requires additional research emphasis. Despite substantial advances in our understanding and in our ability to treat diabetic retinopathy, this common, potentially blinding disease remains a perplexing problem.

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