Beyond VEGF-The Weisenfeld Lecture

Abstract

Purpose: To review advances made in the treatment of age-related macular degeneration (AMD) and share perspectives on the future of AMD treatment.

Methods: Review of published clinical and experimental studies.

Results: Inhibitors of vascular endothelial growth factor (VEGF) truly revolutionized the treatment of AMD. However, available results from longer-term studies suggest that a degenerative process is unveiled, and continues to occur, even when neovascularization is controlled. Furthermore, anti-VEGF therapy may play a role in the development of atrophic changes. We have proposed using neuroprotection to prevent atrophy, and multiple models of retinal degeneration have shown that it is necessary to block both apoptotic and necrotic cell death pathways. Despite the success of anti-VEGF therapy and the promise of neuroprotection, neither addresses the underlying cause of AMD. It has been postulated that in early AMD, the retention and abnormal accumulation of lipids in Bruch's membrane and below the retinal pigmented epithelium (RPE) lead to drusen. Thus, it is conceivable to target the retained lipoproteins and seek to remove them. In a case study and pilot multicenter clinical trial, we observed significant regression of drusen and an improvement in visual acuity in patients taking high-dose statin therapy. These results, though preliminary, warrant further investigation.

Conclusion: Future treatment of AMD should be based on biology, which will require continued elucidation of the pathogenic mechanisms of AMD development. Neuroprotection represents a potential therapeutic approach, and other promising targets include immune pathways (e.g., inflammation, complement, and inflammasomes) and lipid/lipoprotein accumulation. Finally, due to the heterogeneity of AMD, future progress in therapy will benefit from improved phenotyping and classification.

Figure 1

Top left: normal macula. Top center: macula with intermediate AMD showing intermediate (>63 μm, black arrow), large (>125 μm, green arrow), and very large (>250 μm, white arrow) drusen. Top right: hyperpigmentation (black arrows) and focal atrophy in an eye with intermediate AMD. Bottom left: geographic atrophy; bottom middle: neovascular AMD; and bottom right: disciform scar. Reprinted with permission from Miller JW. Age-related macular degeneration revisited--piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am J Ophthalmol. 2013;155:1–35.e13. Copyright 2013 Elsevier, Inc.

Figure 2

Upper right: loss of cones over drusen. Lower right: The retinal pigment epithelium (RPE) and rods are lost in geographic atrophy. Reprinted with permission from Milam AH. The Human Retina in Health and Disease [CD-ROM]. Philadelphia: Scheie Eye Institute, University of Pennsylvania. Copyright by Scheie Eye Institute, University of Pennsylvania.

Figure 3

Upper: The retinal pigment epithelium (RPE) is intact over the choroidal neovascularization (CNV), indicated by the asterisk, but photoreceptor degeneration is occurring. Lower: Photoreceptor degeneration is more pronounced and accompanied by loss of the RPE. Reprinted with permission from Green WR. Histopathology of age-related macular degeneration. Mol Vis. 1999;5:27; originally published in Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology. 1993;100(10):1519–1535. Copyright 1993 American Academy of Ophthalmology, Inc.

Figure 4

Top: loss of choriocapillaris with growth of choroidal neovascularization (CNV). Bottom: (A) Loss of choriocapillaris adjacent to a region of CNV (right). Reprinted with permission from McLeod DS, Taomoto M, Otsuji T, Green WR, Sunness JS, Lutty GA. Quantifying changes in RPE and choroidal vasculature in eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2002;43:1986–1993. Copyright 2002 the Association for Research in Vision and Ophthalmology.

Figure 5

Early AMD pathogenesis. In the outer retina, Bruch's membrane (BrM) consists of a layer of elastin (EL) sandwiched between two layers of collagen and basal lamina (BL), and underlies the retinal pigment epithelium (RPE). The neural retina (not shown) is above the RPE. (A) Development of the lipid wall, leading to basal linear deposits (BlinD), basal laminar deposits (BlamD), and drusen. (B) Complement activation. See text for details. Adapted from Miller JW. Age-related macular degeneration revisited--piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am J Ophthalmol. 2013;155:1–35.e13. Copyright 2013 Elsevier, Inc.

Figure 6

Progression to advanced age-related macular degeneration (AMD). (A) Dissolution of Bruch's membrane (BrM), disruption of the extracellular matrix, and angiogenesis (advanced neovascular AMD). (B) Injury of the retinal pigment epithelium (RPE) and subsequent death of the RPE and photoreceptors in geographic atrophy (advanced atrophic AMD). Adapted from Miller JW. Age-related macular degeneration revisited--piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am J Ophthalmol. 2013;155:1–35.e13. Copyright 2013 Elsevier, Inc.

Figure 7

Regression of drusen in a patient receiving high-dose oral atorvastatin. (A) An otherwise healthy patient with age-related macular degeneration (AMD) with bilateral, large, soft, confluent macular drusenoid pigment epithelial detachments and pigmentary alterations on color fundus photography (upper figure parts), and decreasing visual acuity with significant distortion. (B) Spectral-domain optical coherence tomography (SD-OCT) showing the significant extent of these deposits and the overlying retinal pigment epithelium (RPE) and photoreceptor architectural distortion (upper figure parts). The patient was started on atorvastatin 10 mg and escalated to 80 mg over 9 months. Six months after 80 mg atorvastatin, visual acuity improved by 12 letters to 20/20. Fundus photographs and SD-OCT revealed complete disappearance of the drusen without accompanying atrophy of the retinal pigment epithelium (lower figure parts). Reprinted with permission from Vavvas DG, Daniels AB, Kapsala ZG, et al. Regression of some high-risk features of age-related macular degeneration (AMD) in patients receiving intensive statin treatment. EBioMedicine. 2016;5:198–203. Copyright 2016 by Vavvas DG, Daniels AB, Kapsala ZG, et al.