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134.A.H. Tu, R. Equi, S.-I. Arai, S. Sadda, S. Varner, N. Rao, and E. de Juan Jr., Subretinal delivery of triamcinolone in a laser-induced primate model of choroidal neovascularization: Angiographic and histopathological study, Annual Meeting of the Association for Research in Vision and Ophthalmology, Abstract No. 5055 (2004).

135.N.R.F. Beeley, S.E. Varner, J.V. Rossi, M. Mahmoud, P.A.A. Mello-Filho, G.Y. Fujii, and E. de Juan Jr., Subretinal drug delivery using polymeric matrix loaded filaments,

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Chapter 23

NOVEL THERAPEUTIC STRATEGIES FOR POSTERIOR SEGMENT NEOVASCULARIZATION

David P. Bingaman,1 DVM, PhD, DACVO, Xiaolin Gu,1 MD, PhD, Adrian M. Timmers,1 PhD, and Alberta Davis,2 PhD

1Retina Drug Discovery and 2Retina Clinical Development, Alcon Research Ltd., Forth Worth, Texas

1.INTRODUCTION

The era of anti-angiogenic therapy became a reality in human medicine during 2004, when novel molecules were approved in the United States for both oncology (Avastin®, Genentech) and ophthalmology (Macugen®, Eyetech/Pfizer). The successful clinical results generated with these agents validated the concept that inhibition of pathological new blood vessel growth could provide therapeutic benefit in man. The scientific concept ratified by their FDA approvals was originally introduced by Dr. Judah Folkman decades earlier, when he suggested that angiogenesis-dependent diseases, such as solid tumor growth, could potentially be treated using inhibitors acting directly on the abnormal endothelial cells.1

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Effective and safe therapies for the treatment of retinal and choroidal angiogenesis are arguably the greatest unmet needs in ophthalmology. As thoroughly described in the preceding chapters, exudative age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR) are the major causes of acquired blindness in developed countries and are characterized by pathological posterior segment neovascularization (PSNV). The PSNV found in exudative AMD is characterized by choroidal NV, whereas PDR exhibits preretinal NV. PSNV, similar to angiogenesis in other tissues, occurs as a cascade of events that progress from an initiating stimulus to the formation of abnormal, leaky new capillaries (Figure 1).

Figure 23-1. Basic description of the major steps in the angiogenic cascade. GF: growth factor, ECM: extracellular matrix, VEC: vascular endothelial cell, MMP: matrix metalloproteinase.

The inciting cause(s) in both exudative AMD and PDR is still unknown; however, the elaboration of various pro-angiogenic growth factors appears to be a common stimulus. Elevated levels of soluble growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF or FGF-2), insulin-like growth factor 1 (IGF-1), angiopoetins, etc., have been found in ocular tissues and

fluids removed from patients with pathological ocular angiogenesis. Following initiation of the angiogenic cascade, the capillary basement membrane and extracellular matrix are degraded, and capillary endothelial cell proliferation and migration occur. Recent evidence from animal models indicates that endothelial cells at sites of NV are produced not only by mitosis, but also by an influx of endothelial precursor cells (EPCs) derived from the bone marrow. Endothelial sprouts anastomose to form tubes with subsequent patent lumen formation. The new capillaries commonly have increased vascular permeability or leakiness due to immature barrier function, which can lead to tissue edema. Differentiation into a mature capillary is indicated by the presence of a continuous basement membrane, influx of pericytes, and formation of normal endothelial-endothelial and endothelial-pericyte junctions. Unfortunately, the differentiation process is often impaired in pathological conditions. The complex cascade of events described above represents a variety of potential targets against which treatment modalities could be designed.

Historically, treatment strategies for pathological PSNV have been few and palliative at best. Regarding the exudative form of AMD, previously approved treatments included laser photocoagulation and photodynamic therapy with Visudyne® (QLT/Novartis). Both therapies involve laserinduced occlusion of the affected vasculature and can be associated with localized laser-induced damage to the overlying retina (“by-stander” tissue damage). More recently, Macugen® (Eyetech/OSI), an intravitreally injected anti-VEGF aptamer, and Lucentis® (Genentech), an intravitreally injected anti-VEGF antibody fragment, have been approved for this indication. The approval of Lucentis® was likely the biggest breakthrough in the history of the treatment of exudative AMD, primarily because a substantial number of patients actually exhibit improvement in vision. Nonetheless, a variety of different compounds that target a wide range of mechanisms and/or routes of administration are currently being clinically evaluated as pharmacological treatments for exudative AMD (Figure 2). Based upon their specific mechanism(s) of action, many of these agents may also be useful in the treatment of PDR.

Diabetic retinopathy (DR) is a retinal microvascular disease found in patients with diabetes mellitus that is manifested clinically as a progression of stages with increasing levels of severity and, thereby, a worsening prognosis for vision. DR is broadly classified into 2 major clinical stages: nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), where the term “proliferative” refers to the presence of preretinal NV as previously stated. PDR is the major cause of acquired blindness in working-aged people in the United States, whereas diabetic macular edema (DME) is the major cause of vision loss in diabetic patients