Original articleTranslational science reviewGeographic Atrophy: Clinical Features and Potential Therapeutic Approaches
Section snippets
Epidemiology and Risk Factors
In the industrially developed world, AMD is the primary cause of blindness for adults >55 years of age. Patients in the early and intermediate stages of dry AMD generally do not lose central vision, but instead have other functional impairments, such as difficulty reading and limited vision at night or with reduced light.6 Risk factors for AMD include advanced age, race, smoking, and diet.
With aging, gradual and cumulative damage to the retina occurs through various factors, including oxidative
Pathophysiology of AMD
The pathology of AMD is characterized by degenerative changes in the outer portion of the retina, the photoreceptors, the RPE, Bruch's membrane, and the choriocapillaris, leading ultimately to visual loss (Figs 1 and 5). Early changes include basal laminar and basal linear deposits, thickening and accumulation of lipoidal material in Bruch's membrane, lipofuscin accumulation in the lysosomal compartment of the RPE, and drusen formation beneath the basal lamina of RPE as well as subretinal
Rationale for Therapeutic Strategy
The primary goal in treating AMD is to identify the underlying cause and prevent or slow disease progression and loss of vision (Table 1, available at www.aaojournal.org); however, suitable and reliable in vitro systems and/or animal models for testing the efficacy of new therapeutic agents are lacking. Although the main target for GA remains unknown, the pathways described offer some insight into potential therapeutic interventions. Although photoreceptor and RPE loss may be the initial event,
Clinical Implications
An appropriate short-term clinical endpoint for demonstrating efficacy of any pharmacologic intervention in GA remains to be identified. With neovascular (wet) AMD, VA loss is relatively rapid and a reduction in hyperpermeability and extracellular fluid may be observed soon after treatment with subsequent improvements in VA. In contrast, disease progression and vision loss in GA are gradual and relatively slow. Initially, GA may result in visual function deficits in reading, driving at night,
References (57)
- et al.
Beckman Initiative for Macular Research Classification Committee. Clinical classification of age-related macular degeneration
Ophthalmology
(2013) - et al.
Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Prog Retin Eye Res
(2010) - et al.
Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex
Mol Aspects Med
(2012) - et al.
Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the Multi-ethnic Study of Atherosclerosis
Ophthalmology
(2006) - et al.
Familial aggregation of age-related maculopathy
Am J Ophthalmol
(1997) - et al.
Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes
Ophthalmology
(2012) - et al.
AREDS Research Group. Retinal precursors and the development of geographic atrophy in age-related macular degeneration
Ophthalmology
(2008) - et al.
Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies
Surv Ophthalmol
(2003) - et al.
Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration
J Lipid Res
(2010) - et al.
DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88
Cell
(2012)
Age-related macular degeneration. The lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells
J Biol Chem
Histologic basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy
Ophthalmology
Embryonic stem cell trials for macular degeneration: a preliminary report
Lancet
Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11
Arch Ophthalmol
Age-related macular degeneration–emerging pathogenetic and therapeutic concepts
Ann Med
The epidemiology of progression of pure geographic atrophy: the Beaver Dam Eye Study
Am J Ophthalmol
Genetic Factors in AMD Study. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation
Br J Ophthalmol
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
Arch Ophthalmol
Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration
JAMA
Seven new loci associated with age-related macular degeneration
Nat Genet
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
Nat Genet
Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk
Proc Natl Acad Sci U S A
Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration
Nat Genet
Risk- and non-risk-associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency
Hum Mol Genet
Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)
Proc Natl Acad Sci U S A
Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration
Proc Natl Acad Sci U S A
Clinical characteristics, progression and risk factors of geographic atrophy [in German]
Ophthalmologe
Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26
Arch Ophthalmol
Cited by (324)
Pluripotent stem cell-derived models of retinal disease: Elucidating pathogenesis, evaluating novel treatments, and estimating toxicity
2024, Progress in Retinal and Eye ResearchMETformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial
2024, Ophthalmology ScienceDeep Learning Approaches for Detecting of Nascent Geographic Atrophy in Age-Related Macular Degeneration
2024, Ophthalmology ScienceNext generation therapeutics for retinal neurodegenerative diseases
2024, Journal of Controlled Release
Supplemental material is available at www.aaojournal.org.
The goal is to provide authoritative and cutting edge reviews of topical state-of-the-art basic research that is expected to have broad clinical impact in the next few years. This is primarily a “by invitation only” submission type, however, if you have suggestions for topics, please contact Jayakrishna Ambati ([email protected]) the Editor for this section.
Financial Disclosures: The authors have made the following disclosures:
Genentech, Inc, South San Francisco, CA provided support for this review.
Frank G. Holz: Consultant—Acucela, Alcon, Allergan, Bayer, Genentech, Heidelberg Engineering, Novartis, Optos, and Roche
Erich C. Strauss: Employee—Genentech, Inc.
Steffen Schmitz-Valckenberg: Consultant—Novartis; Research Funding—Alcon, Carl Zeiss Meditec, Genentech, Heidelberg Engineering, Novartis, and Optos.
Menno van Lookeren Campagne: Employee—Genentech, Inc.
Support for third-party writing and formatting assistance for this manuscript was provided by Linda Merkel, PhD, CMPP, and was funded by Genentech, Inc., South San Francisco, California.