Dry age-related macular degeneration: A currently unmet clinical need.

Age-related macular degeneration (AMD) is a leading cause of severe visual impairment and disability in older people worldwide. Although considerable advances in the management of the neovascular form of AMD have been made in the last decade, no therapy is yet available for the advanced dry form of AMD (geographic atrophy). This review focuses on current trends in the development of new therapies targeting specific pathophysiological pathways of dry AMD. Increased understanding of the complex mechanisms that underlie dry AMD will help to address this largely unmet clinical need.

[1]  J. Monés,et al.  Update on Geographic Atrophy in Age-Related Macular Degeneration , 2011, Optometry and vision science : official publication of the American Academy of Optometry.

[2]  Masaru Miyagi,et al.  Drusen proteome analysis: An approach to the etiology of age-related macular degeneration , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Marco A Zarbin,et al.  Current concepts in the pathogenesis of age-related macular degeneration. , 2004, Archives of ophthalmology.

[4]  R. Klein,et al.  Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. , 2002, Ophthalmology.

[5]  R. T. Smith,et al.  Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration , 2006, Nature Genetics.

[6]  J. Xu,et al.  What determines the switch between atrophic and neovascular forms of age related macular degeneration? - the role of BMP4 induced senescence , 2009, Aging.

[7]  Eric N Brown,et al.  Complement, age-related macular degeneration and a vision of the future. , 2010, Archives of ophthalmology.

[8]  F. Colotta,et al.  Targeting C5a: recent advances in drug discovery. , 2005, Current medicinal chemistry.

[9]  P. Mitchell,et al.  The prevalence of age-related macular degeneration in Asians: a systematic review and meta-analysis. , 2010, Ophthalmology.

[10]  Weng Tao,et al.  Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Ferris,et al.  Treatment of geographic atrophy by the topical administration of OT-551: results of a phase II clinical trial. , 2010, Investigative ophthalmology & visual science.

[12]  R. Klein,et al.  Early age-related maculopathy in the cardiovascular health study. , 2003, Ophthalmology.

[13]  Benita J. O’Colmain,et al.  Prevalence of age-related macular degeneration in the United States. , 2004, Archives of ophthalmology.

[14]  T. Léveillard,et al.  Identification and characterization of rod-derived cone viability factor , 2004, Nature Genetics.

[15]  F. Hallböök,et al.  The growth factor response in ischemic rat retina and superior colliculus after brimonidine pre-treatment , 2006, Brain Research Bulletin.

[16]  G. Peyman,et al.  A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring. , 1991, Ophthalmic surgery.

[17]  K. Palczewski,et al.  Retinopathy in Mice Induced by Disrupted All-trans-retinal Clearance* , 2008, Journal of Biological Chemistry.

[18]  T. Léveillard,et al.  Rod–Cone Interactions: Developmental and Clinical Significance , 2001, Progress in Retinal and Eye Research.

[19]  J. Ott,et al.  Complement Factor H Polymorphism in Age-Related Macular Degeneration , 2005, Science.

[20]  P. Bernstein Nutritional Interventions against Age-Related Macular Degeneration. , 2009, Acta horticulturae.

[21]  Marco A Zarbin,et al.  PATHWAY-BASED THERAPIES FOR AGE-RELATED MACULAR DEGENERATION: An Integrated Survey of Emerging Treatment Alternatives , 2010, Retina.

[22]  B. Roska,et al.  Optogenetic therapy for retinitis pigmentosa , 2011, Gene Therapy.

[23]  Stephen S Lane,et al.  Implantable miniature telescope for the treatment of visual acuity loss resulting from end-stage age-related macular degeneration: 1-year results. , 2006, Ophthalmology.

[24]  D. Birch,et al.  SAFETY AND EFFECT ON ROD FUNCTION OF ACU-4429, A NOVEL SMALL-MOLECULE VISUAL CYCLE MODULATOR , 2012, Retina.

[25]  Gislin Dagnelie,et al.  Visual perception in a blind subject with a chronic microelectronic retinal prosthesis , 2003, Vision Research.

[26]  S. Sehgal Sirolimus: its discovery, biological properties, and mechanism of action. , 2003, Transplantation proceedings.

[27]  G. Parmigiani,et al.  Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. , 2008, The New England journal of medicine.

[28]  D. Weeks,et al.  Susceptibility genes for age-related maculopathy on chromosome 10q26. , 2005, American journal of human genetics.

[29]  B S Hawkins,et al.  Epidemiology of age-related macular degeneration. , 1999, Molecular vision.

[30]  R.V. Shannon,et al.  A model of safe levels for electrical stimulation , 1992, IEEE Transactions on Biomedical Engineering.

[31]  D. Clayton,et al.  Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. , 2006, Investigative ophthalmology & visual science.

[32]  George A. Williams,et al.  Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration , 2011, Proceedings of the National Academy of Sciences.

[33]  L. Hjelmeland Dark matters in AMD genetics: epigenetics and stochasticity. , 2011, Investigative ophthalmology & visual science.

[34]  K. Palczewski,et al.  Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Jennifer I. Lim,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. , 2001, Archives of ophthalmology.

[36]  R. Birngruber,et al.  Selective retina therapy (SRT) in patients with geographic atrophy due to age-related macular degeneration , 2007, Graefe's Archive for Clinical and Experimental Ophthalmology.

[37]  Ronald Klein,et al.  The epidemiology of age-related macular degeneration. , 2004, American journal of ophthalmology.

[38]  G. Ying,et al.  DNA methylation is associated with altered gene expression in AMD. , 2012, Investigative ophthalmology & visual science.

[39]  山城 健児 Age-Related Eye Disease Study 2 (特集 臨床において必要なサプリメントの知識) , 2012 .

[40]  P. Bernstein,et al.  HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration , 2007, Cell cycle.

[41]  A. Adamis,et al.  Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. , 2009, Archives of ophthalmology.

[42]  Jennifer I. Lim,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. , 2001, Archives of ophthalmology.

[43]  C. Romano,et al.  Agonists at the serotonin receptor (5-HT(1A)) protect the retina from severe photo-oxidative stress. , 2011, Investigative ophthalmology & visual science.

[44]  P. Sieving,et al.  CNTF and retina , 2012, Progress in Retinal and Eye Research.

[45]  R. Glynn,et al.  Body mass index and the incidence of visually significant age-related maculopathy in men. , 2001, Archives of ophthalmology.

[46]  Frederick L Ferris,et al.  Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. , 2009, Archives of ophthalmology.

[47]  Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. , 2000, Ophthalmology.

[48]  P. Jong Prevalence of age-related macular degeneration in the United States. , 2004 .

[49]  José-Alain Sahel,et al.  Rod-Derived Cone Viability Factor for Treating Blinding Diseases: From Clinic to Redox Signaling , 2010, Science Translational Medicine.

[50]  G. Omenn,et al.  Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. , 1996, The New England journal of medicine.

[51]  Chi-Chao Chan,et al.  Molecular pathology of age-related macular degeneration , 2009, Progress in Retinal and Eye Research.

[52]  Johanna M Seddon,et al.  The genetics of age-related macular degeneration: a review of progress to date. , 2006, Survey of ophthalmology.

[53]  A. Caramoy Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study , 2011 .

[54]  R. Braun,et al.  DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration , 2011, Nature.

[55]  R. Rosen,et al.  Qualitative spectral OCT/SLO analysis of drusen change in dry age-related macular degeneration patients treated with Copaxone. , 2011, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[56]  A. Hofman,et al.  Alcohol consumption and risk of aging macula disorder in a general population: the Rotterdam Study. , 2008, Archives of ophthalmology.

[57]  T. Wong,et al.  Prevalence of and risk factors for age-related macular degeneration in a multiethnic Asian cohort. , 2012, Archives of ophthalmology.

[58]  Glen Jeffery,et al.  Viewing Ageing Eyes: Diverse Sites of Amyloid Beta Accumulation in the Ageing Mouse Retina and the Up-Regulation of Macrophages , 2010, PloS one.

[59]  W. Drexler,et al.  Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study , 2010, British Journal of Ophthalmology.

[60]  B. Stanzel,et al.  Transplantation of the RPE in AMD , 2007, Progress in Retinal and Eye Research.

[61]  Usha Chakravarthy,et al.  Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). , 2006, Archives of ophthalmology.

[62]  R. T. Smith,et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[63]  S. Biswal,et al.  Chronic Cigarette Smoke Causes Oxidative Damage and Apoptosis to Retinal Pigmented Epithelial Cells in Mice , 2008, PloS one.

[64]  P. Mitchell,et al.  Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. , 2002, Archives of ophthalmology.

[65]  J. Lambris,et al.  Suppression of drusen formation by compstatin, a peptide inhibitor of complement C3 activation, on cynomolgus monkey with early-onset macular degeneration. , 2010, Advances in experimental medicine and biology.

[66]  K. Palczewski,et al.  Effects of Potent Inhibitors of the Retinoid Cycle on Visual Function and Photoreceptor Protection from Light Damage in Mice , 2006, Molecular Pharmacology.

[67]  Robert F Mullins,et al.  A role for local inflammation in the formation of drusen in the aging eye. , 2002, American journal of ophthalmology.

[68]  J. Gilbert,et al.  Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration , 2005, Science.

[69]  Lawrence A. Yannuzzi,et al.  Dietary Carotenoids, Vitamins A, C, and E, and Advanced Age-Related Macular Degeneration , 1994 .

[70]  Stuart Richer,et al.  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). , 2004, Optometry.

[71]  A. Bird,et al.  Towards an understanding of age-related macular disease , 2003, Eye.

[72]  R Hiller,et al.  Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. , 1994, JAMA.

[73]  B. Sagdullaev,et al.  Transsynaptic virus tracing from host brain to subretinal transplants , 2005, The European journal of neuroscience.

[74]  Dean P. Jones,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. , 2001, Archives of ophthalmology.

[75]  B. Rohrer,et al.  Systemic human CR2-targeted complement alternative pathway inhibitor ameliorates mouse laser-induced choroidal neovascularization. , 2012, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[76]  A. Edwards,et al.  Complement Factor H Polymorphism and Age-Related Macular Degeneration , 2005, Science.

[77]  N. Camp,et al.  A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration , 2006, Science.

[78]  S. Fisher,et al.  Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk , 2005 .

[79]  John D Lambris,et al.  Synthetic small-molecule complement inhibitors. , 2004, Current opinion in investigational drugs.

[80]  D. Emerich,et al.  NT-501: an ophthalmic implant of polymer-encapsulated ciliary neurotrophic factor-producing cells. , 2008, Current opinion in molecular therapeutics.

[81]  D. Clegg,et al.  Protective Effects of Human iPS-Derived Retinal Pigment Epithelium Cell Transplantation in the Retinal Dystrophic Rat , 2009, PloS one.

[82]  Robert F. Mullins,et al.  An Integrated Hypothesis That Considers Drusen as Biomarkers of Immune-Mediated Processes at the RPE-Bruch's Membrane Interface in Aging and Age-Related Macular Degeneration , 2001, Progress in Retinal and Eye Research.

[83]  Margaret A. Pericak-Vance,et al.  Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration , 2010, Proceedings of the National Academy of Sciences.