Therapeutic targets in age-related macular disease

Bird, Alan C.

doi:10.1172/jci42437

Cited by 156 publications

(156 citation statements)

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“…Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye A major feature of the aging retina is the deposition of proteins (1) and lipids (2) external to the retinal pigment epithelium (RPE), leading to the formation of sub-RPE deposits that can be focal (drusen) or diffuse (basal linear and basal laminar deposits) (3,4). Sub-RPE deposits increase in number and size with age, and are believed to impair metabolic exchange between the choroidal blood circulation and the retina (5).…”

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confidence: 99%

“…This blockage of nutrient and waste flow to and from the highly active photoreceptors is widely suspected of inducing degeneration of the sensory retina, particularly in the macula, eventually leading to age-related macular degeneration (AMD). Due to this correlation between AMD and sub-RPE deposit formation, substantial effort has been devoted to determining the composition and origin of sub-RPE deposits, with a view to developing better diagnosis, prevention, and treatment for AMD (4). Although AMD does not necessarily follow the same course in all patients (6), it is acknowledged that progression of sub-RPE deposit formation is a major factor in a large proportion of cases.…”

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confidence: 99%

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Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Thompson

Reffatto

Bundy³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5–20 μm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch’s membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch’s membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.

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confidence: 99%

mentioning

confidence: 99%

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Thompson

Reffatto

Bundy³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

113

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“…These systems include the alternative complement pathway, the innate immune response pathway, the chromosome 10q26 locus, extracellular matrix/cell adhesion complex genes, lipid metabolism/transport/signaling-related genes, the mitochondrial genome, vitamin D pathway genes, angiogenesis-related genes, iron metabolism genes, and cellular stress and toxicity genes. Reviews over the past decade have also addressed concepts of pathogenic mechanisms in the context of the human genome (Ambati et al 2003;Haddad et al 2006;Hageman et al 2008;Bird 2010). Initially, family-based and GWA studies applied an empirical (data-driven) approach to identify and characterize mechanisms involved in AMD pathogenesis; hypothesis-driven research is now the mainstay, guided by or supported with evidence from model systems, epidemiologic studies, and clinical observations.…”

Section: Key Discoveries In Amd Genetics: Pathogenesis and Pathophysimentioning

confidence: 99%

Clinical Applications of Age-Related Macular Degeneration Genetics

SanGiovanni

Chew

2014

Cold Spring Harbor Perspectives in Medicine

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Understanding genetic causes of age-related macular degeneration (AMD) will eventually yield effective discoveries and improvements in predictive/prognostic methods. These include, but are not limited to, reliable disease prediction (screening for increased discrimination of clinical risk), differential classification of AMD subtypes with biomarkers (development of risk-linked molecular taxonomies), selection of optimal preventive and therapeutic interventions (guided by a biologically meaningful understanding of treatment response), and drug dosing. In this review, we discuss clinical applications informed by key findings in AMD genetics, and provide commentary on leveraging extant and forthcoming evidence to improve AMD risk prediction, AMD classification, and knowledge on the genetic basis of drug activity and toxicity. Advances in translating AMD genetics findings for AMD risk prediction require development of a genetics-based causality for AMD incidence and progression. Molecular subtyping of AMD phenotypes requires a set of dynamic biomarkers presenting prognostic value; although these have yet to be identified, the formation of multidisciplinary teams and their participation in large-scale consortia may yield promising results. Drugs targeting complement and vascular endothelial growth factor (VEGF) systems are under evaluation, and forthcoming work on rare variants and noncoding DNA in AMD pathogenesis will likely reveal biochemical pathways enriched with AMD-associated genetic variants. Pharmacologic targets in these pathways may inform a rational and effective therapeutic approach to preventing and treating this sight-threatening disease.A ge-related macular degeneration (AMD) is a complex sight-threatening disease of public health significance . Knowledge on the nature of AMD phenotypes and related pathogenic processes (as well as on constraints in approaches to investigation) has influenced our ability to make inferences on a geneticsbased causality of this disease. Such inferences are necessary in the development of feasible clinic-based approaches for effective AMD prevention, prognosis, and treatment (Gorin 2012). In this review we discuss clinical applications informed by key findings in AMD genetics, and provide commentary on leveraging extant and forthcoming evidence to improve AMD risk prediction, classification, and knowledge on the genetic basis of drug activity and toxicity. We start with a definition of AMD phenotypes and follow with an overview of what research in AMD genetics has told us about the nature and

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“…The accumulation of this undegraded material, known as drusen in the RPE leads to production of inflammatory mediators that cause photoreceptor degeneration in the central retina, or macula (42). The center of the macula, named fovea, mediates high acuity vision; hence its degeneration causes severe vision loss.…”

Section: Age-related Macular Degeneration (Amd)mentioning

confidence: 99%