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Review Retina Advances in Age-related Macular Degeneration Understanding and Therapy Joan W Miller, Saghar Bagheri, and Demetrios G Vavvas Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, US W hile the development of anti-vascular endothelial growth factor (anti-VEGF) as a therapy for neovascular age-related macular degeneration (AMD) was a great success, the pathologic processes underlying dry AMD that eventually leads to photoreceptor dysfunction, death, and vision loss remain elusive to date, with a lack of effective therapies and increasing prevalence of the disease. There is an overwhelming need to improve the classification system of AMD, to increase our understanding of cell death mechanisms involved in both neovascular and non-neovascular AMD, and to develop better biomarkers and clinical endpoints to eventually be able to identify better therapeutic targets—especially early in the disease process. There is no doubt that it is a matter of time before progress will be made and better therapies will be developed for non-neovascular AMD. Keywords Age-related macular degeneration (AMD), neuroprotection, biomarkers, anti-vascular endothelial growth factor (VEGF), complement inhibition, statin Disclosure: Joan W Miller has provided consulting for Alcon (serving on the Alcon Research Institute committee), Amgen, Inc., KalVista Pharmaceuticals, Ltd., Maculogix, Inc., and ONL Therapeutics within the last 12 months. She is a named inventor on patents/patent applications on methods and compositions for preserving photoreceptor viability (assigned to Massachusetts Eye and Ear; licensed to ONL Therapeutics) and receives a share of the financial remuneration related to the proprietary interest of Massachusetts Eye and Ear in photodynamic therapy for conditions involving unwanted ocular neovascularization (licensed to Valeant Pharmaceuticals); however, Joan W Miller has nothing to declare in relation to this article. Saghar Bagheri and Demetrios G Vavvas have nothing to declare in relation to this article. Acknowledgements: This work was supported by: NEI R21EY023079-01A1, R01- EY025362-01 (DGV); the Yeatts Family Foundation (DGV, JWM); the Loefflers Family Fund (DGV, JWM); the 2013 Macula Society Research Grant award (DGV); a Physician Scientist Award from Research to Prevent Blindness (DGV), the Alcon Research Institute Young Investigator Award (DGV), an unrestricted grant from Research to Prevent Blindness (JWM), and the Champalimaud Vision Award (JWM). None of the aforementioned funding organizations had any role in publication of this article. The authors would also like to thank Christina Kaiser Marko for editorial assistance and support. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: September 28, 2017 Accepted: October 16, 2017 Citation: US Ophthalmic Review, 2017;10(2):119–30 Corresponding Author: Joan W Miller, Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Ste. 800, Boston, MA 02114, US. E: TOU CH MED ICA L MEDIA Age-related macular degeneration (AMD) is the third leading cause of blindness worldwide and the primary leading cause of vision loss in the Western world. Its prevalence is expected to increase as a consequence of an aging population, such that it is estimated that close to 288 million people will be affected by AMD by 2040. 1 AMD presents in two major forms: the non-neovascular, non-exudative “dry” form affecting 85–90% of patients and the neovascular, exudative “wet” form affecting 10–15% of patients. Up until the late 1990s, treatment for AMD was limited to destructive thermal laser therapy for the neovascular form. In the last two decades, we have experienced a renaissance with more targeted approaches for the treatment of neovascular AMD. Liposomal verteporfin- based photodynamic therapy (Visudyne ® ) was used to selectively close choroidal neovascularizations (CNV)—it is the first pharmacotherapy for AMD that is able to reduce and slow vision loss. 2 Further work to understand the biological process of new vessel development, and demonstration of the key role of vascular endothelial growth factor (VEGF) led to extremely effective therapies, revolutionizing the treatment of neovascular AMD and preserving sight for millions of people. 3 Subsequently, anti-VEGF therapy was applied to other diseases with abnormal angiogenesis and vascular leakage, including diabetic retinopathy, retinal vein occlusions, and pathologic myopic neovascularization, among others. However, the pathologic processes underlying dry AMD remain elusive to date, with a lack of effective therapies. Non-exudative AMD is characterized by accumulation of deposits under the retinal pigment epithelium (RPE) and neurosensory retina, as well as degeneration of the RPE, photoreceptors, and even the choroidal vasculature. All of these ultimately lead to photoreceptor dysfunction, death, and vision loss. Although epidemiological and genetic studies have identified several candidates for the formation and progression of dry AMD, they also point to involvement of multiple biological pathways, including: lipid metabolism and transport regulation, inflammation (especially the complement system), extracellular matrix remodeling, cell adhesion, cellular toxicity, cell death, and angiogenesis. However, there is a lack of a unifying hypothesis that can explain how the disease starts and progresses—the causes of RPE and photoreceptor degeneration and loss remain obscure. The failure in truly understanding 119