AGE RELATED MACULAR  DEGENERATION –   THE RECENT ADVANCES   IN BASIC RESEARCH   AND CLINICAL CARE    Edited by Gui‐Shuang Ying                      Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care Edited by Gui-Shuang Ying Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work Any republication, referencing or personal use of the work must explicitly identify the original source As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher No responsibility is accepted for the accuracy of information contained in the published chapters The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book Publishing Process Manager Iva Simcic Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published January, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care, Edited by Gui-Shuang Ying p cm ISBN 978-953-307-864-9 free online editions of InTech Books and Journals can be found at www.intechopen.com     Contents   Preface IX Part Basic and Translational Research Chapter Wet Age Related Macular Degeneration Fardad Afshari, Chris Jacobs, James Fawcett and Keith Martin Chapter Pathogenic Roles of Sterile Inflammation in Etiology of Age-Related Macular Degeneration Suofu Qin 25 Chapter Bruch’s Membrane: The Critical Boundary in Macular Degeneration 49 Robert F Mullins and Elliott H Sohn Chapter Non-Enzymatic Post-Translational Modifications in the Development of Age-Related Macular Degeneration Yuichi Kaji, Tetsuro Oshika and Noriko Fujii Chapter Chapter Part Experimental Treatments for Neovascular Age-Related Macular Degeneration C V Regatieri, J L Dreyfuss and H B Nader 73 83 Basic Research and Clinical Application of Drug Delivery Systems for the Treatment of Age-Related Macular Degeneration 99 Giuseppe Lo Giudice and Alessandro Galan Clinical Research 121 Chapter Treatment of Neovascular Age Related Macular Degeneration 123 Ratimir Lazić and Nikica Gabrić Chapter Re-Treatment Strategies for Neovascular AMD: When to Treat? When to Stop? 143 Sengul Ozdek and Mehmet Cuneyt Ozmen VI Contents Chapter Combined Therapies to Treat CNV in AMD: PDT + Anti-VEGF 161 Jorge Mataix, M Carmen Desco, Elena Palacios and Amparo Navea Chapter 10 Nutritional Supplement Use and Age-Related Macular Degeneration 185 Amy C Y Lo and Ian Y Wong Chapter 11 Two-Photon Excitation Photodynamic Therapy: Working Toward a New Treatment for Wet Age-Related Macular Degeneration 213 Ira Probodh and David Thomas Cramb Chapter 12 Clinical Application of Drug Delivery Systems for Treating AMD 227 Noriyuki Kuno and Shinobu Fujii Chapter 13 Use of OCT Imaging in the Diagnosis and Monitoring of Age Related Macular Degeneration 253 Simona-Delia Ţălu and Ştefan Ţălu Chapter 14 Treatments of Dry AMD 273 George C Y Chiou Chapter 15 Promising Treatment Strategies for Neovascular AMD: Anti-VEGF Therapy Young Gun Park, Hyun Wook Ryu, Seungbum Kang and Young Jung Roh 289       Preface   In the past decade, great progress has been made in understanding the pathobiology  and genetics of Age‐Related Macular Degeneration (AMD), and the effective therapies  for this blinding disease have become available. These advancements have lead to the  substantial change in the management of AMD patients. The online book Age Related  Macular Degeneration – The Recent Advances in Basic Research and Clinical Care presents  the  most  recent  advances  in  basic  research  and  clinical  care  of  AMD.  Different  from  other  AMD  books,  this  book  aims  to  cover  the  new  findings  from  basic  and  translational research on the biological and genetic mechanism of AMD, and the new  interventions to prevent and treat this disease.  The book has a total of 15 chapters, grouped into two sections. Section one includes six  chapters  covering  the  basic  and  translational  research  of  AMD.  Section  two  includes  nine chapters describing the clinical research and management of AMD. Each chapter  has been contributed to by outstanding researchers or clinicians in the area of AMD.  They present a very detailed review of new research and findings in the topic‐specific  AMD  area,  and  also  provide  direction  for  future  research.  The  book  is  targeted  at  researchers  and  clinicians  who  are  interested  in  learning  about  new  advances  in  the  understanding and treatment of AMD, and insights into future research of AMD.  We  hope  that  this  AMD  book  will  provide  the  latest  information  to  its  readers.  The  large  amount  of  information  presented  in  this  book  will  help  clinicians  to  take  best  care  of  their  AMD  patients.  Additionally,  it  will  assist  researchers  in  conducting  further  AMD  research  and,  eventually,  achieve  the  goal  of  finding  effective  and  safe  ways to prevent or treat AMD.    Gui‐Shuang Ying, PhD  Assistant Professor of Ophthalmology  University of Pennsylvania, Perelman School of Medicine  Philadelphia, PA  USA    286 Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care Kohri, T., Moriwaki, M., Nakajima, M., Tabuchi, H., Shiraki, K Reduction of experimental laser-induced choroidal neovascularization by orally administered BPHA, a selective metalloproteinase inhibitor [J] Graefes Arch Clin Exp Ophthalmol, 2003;241(11):943-952 Kokame, G.T NEI VFG-25, useful tool for determining patients vision-related function Retina Today Nov/ Dec 2008:27-29 Leibowitz, H.M., Krueger, D.A., Maunder, R.A An ophthalmological study of cataract, glaucoma, diabetic retinopathy, macular degeneration and visual acuity in a general population of 2631 adults 1973-1975 Surv Ophthalmol 1980; 24 (Suppl):335610 Li, Z., Clarke, M.P., Barker, M.D., McKie, N TIMP3 mutation in Sorsby’s fundus dystrophy: molecular insights Expert Rev Mol Med, 2005; 31;7(24): 1-15 Lin, B.Q., 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Non-invasive recording and response characteristics of the rat dC-ERG Vis Nerosc, 2002;19:693-701 Treatments of Dry AMD 287 Radu RA, Han Y, Bui TV, et al Reductions in serum vitamin A arrest accumulation of toxic retinal flurophores: a potential therapy for treatment of lipofuscin based retinal diseases Invest Ophthalmol Vis Sci 2005;46:4393-4401 Rasmussen, H., Chu, K.W., Campochiaro, P., Gehlbach, P.L., Haller, J.A., Handa, J.T., Nguyen, Q.D., Sung, J.U Clinical protocol An open-label, phase I, single administration, dose-escalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD) [J] Hum Gene Ther, 2001;12(16):2029-2032 Raz-Prag, D., Ayyagari, R., Fariss, R.N., Mandal, M.N.A, Vasireddy, V., Majchrzak, S., Webber, A.L., Bush, R.A., Salem, N Jr, Petrukhin, K., Sieving, P.A Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elov14 knockout mouse model of STGD3 disease Invest Ophthalmol Vis Sci, 2006; 47(8): 3603-3611 Rechtman, E., Danis, R.P., Pratt, L.M., Harris, A Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularization in age-related macular degeneration [J] Br J Ophthalmol, 2004; 88:344-347 Richer, S., Stiles, W., Statkute, L., Pulido, J., Frankowski, J., Rudy, D., Pei, K., Tsipursky, M., Nyland, J Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST Study (Lutein Antioxidant Supplementation Trial) [J] Optometry, 2004; 75(4):216-230 Rudolf, M., Winkler, B., Aherrahou, Z., Doehring, L.C., Kaczmarek, P., Schmidt-Erfurth, U Increased expression of vascular endothelial growth factor associated with accumulation of lipids in Bruch’s membrane of LDL receptor knockout mice Br J Ophthalmol, 2005; 89:1627-1630 Schachat, AP Safety issues related to the long-term use of VEGF inhibitors DSN SuperSite June, 2007 Shen, Y., Zhang W.Y., Chiou G.C.Y Effects of naringenin on NaIO3-induced retinal pigment epithelium degeneration and laser-induced choroidal neovascularization in rats International J Ophthalmol, 2010a; 10:1-4 Shen, Y., Zhuang, P., Zhang, W.Y., Chiou, G.C.Y Effects of guanabenz on rat AMD models and rabbit choroidal blood flow The Open Ophthalmol J., 2011; 5:27-31 Shen, Y., Zhuang, P., Zhang, W.Y., Chiou, G.C.Y Effects of tetramethylpyrazine on RPE degeneration, choroidal blood flow and oxidative stress of RPE cells International J Ophthalmol, 2010b; 10:1843-1847 Study of Fenretinide in the treatment of geographic atrophy associated with age-related macular degeneration ClinicalTrials.gov Website http://www.clinicaltrials.gov/ct/show/NCT00429936?order=1 Accessed on October 3, 2007 Suñer, I.J., Espinosa-Heidmann, D.G., Marin-Castaño, M.E., Hernandez, E.P., Pereira-Simon, S., Cousins, S.W Nicotine increases size and severity of experimental choroidal neovascularization Invest Ophthalmol Vis Sci, 2004;45 (1) :311-317 Tanito M, Li F, Elliott WH, et al Protective effect of TEMPOL derivatives against lightinduced retinal damage in rats Invest Ophthalmol Vis Sci 2007,48:1900-1905 Wang, T.Y, Loon, S-C, Saw, S-M The epidemiology of age related eye diseases in Asia Brit J Ophthalmol, 2006; 90:506-511 288 Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care Xu, W, Grunwald JE, Metelitsina TI, DuPont JC, Ying GS, Martin ER, Dunaief JL and Brucker AJ Association of risk factors for choroidal neovascularization in agerelated macular degeneration with decreased foveolar choroidal circulation Amer J Ophthalmol 2010, 150:40-47 Xu, X.R Zhou, Y.H., Chiou, G.C.Y The effect of D-timolol and L-timolol on rat experimental choroidal neovascularization (CNV) in vivo and endothelial cells culture in vitro International J Ophthalmol, 2005; 5:831-835 Yehoshua Z, Wang F, Rosenfield PJ, Penha FM, Feuer WJ and Gregori, G Natural history of drusen morphology in age-related macular 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Therap 2006; 22:425-430 Zou, Y.H., Chiou, G.C.Y Pharmacological therapy in AMD International J Ophthalmol, 2005; 5:8-18 Zou, Y.H., Jiang, W., Chiou, G.C.Y Affect of tetramethylpyrazine on rat experimental choroidal neovascularization in vivo and endothelial cell culture in vitro Current Eye Res, 2007; 32:71-75 Zou, Y.H., Xu X.R., Chiou, G.C.Y Effort of interleukin-1 blockers, CK112 and CK116 on rat experimental choroidal neovascularization (CNV) in vivo and endothelial cells culture in vitro J Ocular Pharmacol Therap 2006; 22:19-25 15 Promising Treatment Strategies for Neovascular AMD: Anti-VEGF Therapy Young Gun Park, Hyun Wook Ryu, Seungbum Kang and Young Jung Roh Department of Ophthalmology, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Introduction Age-related macular degeneration (AMD) is one of the leading causes of substantial and irreversible vision loss The prevalence of AMD can be expected to increase along with life expectancy, which has risen steadily [1, 2] Without treatment, the neovascular form of AMD leads to severe quality-of-life loss within a short time period and considerable economic burden Vascular endothelial growth factor (VEGF) is a key mediator involved in the control of angiogenesis and vascular permeability and has been shown to be induced by hypoxia in cultured human retinal pigment epithelium (RPE) [3] VEGF-A is the most potent promoter of angiogenesis and vascular permeability within the VEGF family and its role in the pathogenesis of neovascular AMD is well recognized [4, 5] The advent of intravitreous VEGF inhibitors has revolutionized the management of neovascular AMD Yet, frequently, indefinite injections of VEGF blocking agents introduce a significant treatment burden for patients with neovascular AMD, and may potentially put patients in the risk of developing ocular and systemic adverse effects from injections Many studies on modified treatment regimens have been performed in an attempt to mitigate this burden without compromise to visual acuity outcomes Meanwhile, various randomized clinical trials on combination therapies and efforts to develop new pharmacologic agents are ongoing Therapeutic monoclonal antibodies and fragments 2.1 Intravitreal ranibizumab and bevacizumab monotherapy 2.1.1 Vascular endothelial growth factor VEGF plays an important role in a variety of in vitro processes, including angiogenesis, microvascular permeability, and endothelial cell survival On the other hand, these activities are all essential to survival, VEGF has been linked to a number of pathogenic conditions, including neovascular AMD, diabetic retinopathy, and cancer Three VEGF therapies are currently used for the treatment of patients with neovascular AMD: pegaptanib (Macugen, OSI Pharmaceuticals, USA), ranibizumab (Lucentis, Genentech, USA), and bevacizumab (Avastin, Genentech, USA) 290 Age Related Macular Degeneration – The Recent Advances in Basic Research and Clinical Care Pegaptanib is an oligonucleotide aptamer and was the first VEGF antagonist to be approved by the US Food and Drug Administration (FDA) for use in wet AMD However, wet AMD patients treated with pegaptanib still experience visual decline [2, 6] The first monoclonal antibody developed to target VEGF was bevacizumab, a humanized murine monoclonal antibody Bevacizumab was initially developed for applications in oncology, and received approval as a first-line therapy for widespread colorectal cancer from the US FDA in 2004 Bevacizumab has subsequently been approved for use in non-small cell lung cancer and breast cancer The successful development of VEGF as an oncology target led to interest in the potential of anti-VEGF treatment for other therapeutic indications, including ocular neovascular disorders VEGF-A has been identified as the primary angiogenesis mediator in the eye It is implicated in ocular neovascularization through its promotion of blood vessel formation and permeability A role for VEGF-A in neovascular AMD is suggested by immunohistochemistry localization in human choroidal neovascular (CNV) lesions and extrapolation from other disease models [5, 7-9] New blood vessel formation and leakage play important roles in the development of the neovascular form of AMD, and clinical trials of agents that block VEGF-A activity have produced more evidence that VEGF-A is important in development of this disease Ranibizumab is a humanized antibody fragment against VEGF which was specifically designed for intraocular use as a smaller antibody fragment to penetrate through the retina better The Food and Drug Administration (FDA) approved ranibizumab for treatment of subfoveal neovascular AMD in June, 2006 It was the first drug for AMD treatment shown to improve visual acuity in a substantial percentage of patients Bevacizumab is a recombinant humanized monoclonal immunoglobulin antibody that inhibits the activity of VEGF It has a similar action and is related to the ranibizumab compound with respect to its structure Bevacizumab was approved by the FDA for the treatment of metastatic colorectal cancer in 2004, but it has not been licensed for the treatment of wet AMD or any other ocular conditions However, it is recently used off-label worldwide not only for wet AMD but also for other ocular disease entities associated with macular edema and abnormal vessel growth Intraocular pharmacokinetic data derived from studies in monkeys demonstrated that through intravitreal administration, ranibizumab distributed rapidly to the retina and had a vitreous half-life of days Studies in rabbits have demonstrated that ranibizumab can rapidly penetrate through the retina to reach the choroid, just hr after intravitreal admidistration [10] In primates, serum ranibizumab levels were found to be more than 1000-fold lower than in the vitreous and aquous humor following a single intravitreal injection [11] These were negligible and tissue concentrations were undetectable 2.1.2 Safety Systemic VEGF inhibition is suspected to be associated with an increased risk of hypertension and arterial thromboembolic events Given the average age of patients requiring treatment for AMD, it is important that their treatment does not significantly increase the risk of these events The rate of arterial thromboembolic events and Promising Treatment Strategies for Neovascular AMD: Anti-VEGF Therapy 291 hypertension was low Over the 24 months trial period, the rates in the ranibizumab 0.5 mg treatment group of the ANCHOR, MARINA, and PIER trials was 5.0 %, 4.6 %, and %, respectively, compared with 4.2 %, 3.8 %, and % in the control group 2.1.3 Efficacy The pivotal phase III Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) [12] and the Anti-VEGF Antibody for the Treatment of Predominantly Classic CNV in AMD (ANCHOR) trial [13, 14] demonstrated best-corrected visual acuity (BCVA) outcomes were far superior to any previously published study in the treatment of this disease At the end of 24 months in the MARINA trial, significantly more ranibizumab-treated patients had maintained [lost