Therapeutic targets in age-related macular disease

Abstract

Age-related macular disease (AMD) accounts for more than 50% of blind registration in Western society. Patients with AMD are classified as having early disease, in which visual function is well preserved, or late disease, in which central vision is lost. Until recently, there was no therapy available by which the course of the disorder could be modified. Now, the most common form of late-stage AMD - choroidal neovascularization - responds to treatment with anti-VEGF therapies; although visual loss is modified in a portion of these cases, no therapeutic approach exists that alters the evolution from early to late disease. However, as discussed in this Review, research over the last few years has demonstrated several features of AMD that are likely to be amenable to treatment. Potential targets for treatment are described, and possible therapeutic approaches are discussed.

Figure 1. Ocular anatomy relevant to AMD.

(A) Cross-section of an eye showing the retina lining the inside of the eye. (B) Cross-section of the retina showing the neural retina and, external to it, the RPE and choroid. INL, inner nuclear layer; ONL, outer nuclear layer. (C and D) Diagram (C) and light microscopic view (D) of retinal tissues involved in AMD. The apical microvilli of the RPE interdigitate with the distal portions of the photoreceptor outer segments. External to the RPE is the choroid, with Bruch membrane interposed between them.

Figure 2. Exudative lesions in AMD.

(A and B) In CNV, blood vessels grow inward toward the choroid and may proliferate within Bruch membrane (A) or transgress the RPE to grow in the subretinal space (B). (C) In RPE detachment, lipid accumulates in Bruch membrane, rendering it hydrophobic. The RPE moves water outward toward choroid (arrows); as it fails to pass freely outward, the water induces detachment of the RPE from Bruch membrane.

Figure 3. Scanning electron images of the inner surface of choroidal casts.

(A) In a young donor, the choriocapillaris is a dense sinusoidal network, with no view of the larger vessels of the outer choroid. (B) In an 87-year-old subject, the capillaries are tubular, with large gaps between the capillaries. Figure reproduced courtesy of J. Olver.

Figure 4. Lipid stained in frozen sections of the eye.

Light micrographs of cross-sections of frozen retinas from 16-year-old (A), 44-year-old (B), and 84-year-old (C) donors stained with Oil Red O, demonstrating that lipid quantities in Bruch membrane increase with age.

Figure 5. Putative disease pathways in AMD, from the initiators of the process through the intermediate disease processes to the final event.

The initiating events are considered to be generated by known as well as unknown genetic and environmental factors that may affect the Bruch membrane/choroid (BM/C), RPE, or photoreceptor cells (PRCs). The metabolic interdependence of the tissues is such that changes in any one would inevitably influence the others, giving rise to a complex of intermediate disease mechanisms of which little is known. The final events of GA, CNV, and PED are partially understood. It is likely that effective therapeutic intervention at any stage of the disease evolution would be of benefit and that successful treatment directed at one tissue would have a beneficial effect on other tissues.