in Wet AMD · 2014-09-11 · 1 3 6 7 4 ANGIOGENESIS VASCULOGENESIS VEGF-C VEGF-D VEGF VEGFR-3...
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Macula Improvement in vision Treatment over time Continued treatment is important ENDOTHELIAL CELL: The vascular endothelial growth factor (VEGF) family (A-D) binds to receptors VEGFR-1, VEGFR-2, VEGFR-3, activating signal transduction to promote angiogenesis, vasculogenesis, and lymphangiogenesis. Aflibercept Ranibizumab Bevacizumab VEGF Anti-VEGF treatment VEGF Receptor The neovascular form of age-related macular degeneration (wet AMD) is characterized by excessive proliferation of abnormal, leaky blood vessels (angiogenesis) growing from the choroidal layer through Bruch’s membrane and into the retinal layers. If left untreated, the proliferating vessels will eventually cause a subretinal fibrotic scar and permanent vision loss. Angiogenesis in Wet AMD Treatments for wet AMD neutralize VEGF, the primary angiogenesis-stimulating factor. Antiangiogenic Treatments Optic nerve Lens Iris Cornea Light Area seen above Retinal blood vessels Macula Endothelial progenitor cell (EPC) from bone marrow Inflammatory cytokines Choroid blood vessel MMPs dissolve tissue matrix Fluid accumulation beneath the retina Sprouting 2 Displaced photoreceptors While wet AMD accounts for only about 10-15% of all AMD cases, this form is responsible for up to 90% of severe vision loss or legal blindness from the disease. 5 The three major anti-VEGF therapies, Ranibizumab, Bevacizumab, and Aflibercept, are administered intravitreally (injected directly into the eye), usually at monthly or less frequent intervals. 6 Inhibiting excessive VEGF in the eye causes regression and maturation of abnormal, leaky capillaries, and reduces fluid accumulation. Many patients experience an improvement in vision very soon after treatment. 7 With prolonged VEGF blockade, the accumulation of fluid beneath the retina resolves and the photoreceptors reattach to the underlying retinal pigment epithelium. Wet AMD is a chronic, progressive condition, so patients must receive regular, long-term anti-VEGF therapy in order to maintain vision and slow the advance of the disease. Anti-VEGF treatments bind VEGF-A, inhibiting angiogenesis by preventing this ligand from binding to its receptors. Some therapies can specifically bind to related ligands, such as VEGF-B and PlGF. Choroid Photoreceptors Bruch’s membrane Thickening of Bruch’s membrane Retinal pigment epithelium (RPE) Fluid accumulation within retinal layers New blood vessels penetrate Bruch’s membrane Retina Retinal blood vessels Macula Area of enlargement Fluid leakage from immature vessels Leaky blood vessels 1 3 6 7 4 ANGIOGENESIS VASCULOGENESIS VEGF-D VEGF VEGF-C VEGFR-3 (Flt-4) VEGFR-1 (Flt-1) VEGFR-2 (Flk-1) VEGF-A VEGF-B PIGF 1,2 Ras Raf MEK ERK p38MAPK PI3K Akt mTOR eNOS Caspase-9 LYMPHANGIOGENESIS HIF-1α VEGF Expression VEGF Hypoxia PROLIFERATION MIGRATION CELL ACTIVATION SURVIVAL Excess fluid drains from region Blood vessels stop growing through Bruch’s membrane and nascent capillaries regress Photoreceptors realign with RPE, vision can be partially restored Inflammatory cell Overexpression of VEGF Normal vision Wet Age-Related Macular Degeneration 5 1 Oxidative stress such as UV light exposure, aging, and smoking, as well as genetic predisposition, leads to inflammation in blood vessels. With age, Bruch’s membrane can thicken, causing hypoxia in the retina and RPE. 2 In response to inflammation, inflammatory cells are recruited to the retina. These recruited cells, as well as the RPE, secrete angiogenic growth factors such as VEGF and inflammatory cytokines. 3 The growth factors stimulate the growth of blood vessels in the choroid layer. These vessels then penetrate the Bruch’s membrane, and fluid begins to accumulate within and below the retinal layer. 4 The new blood vessels are disorganized and leaky. The leaked fluid lifts the retina away from the RPE and Bruch’s membrane. www.scienceofamd.org This resource was independently developed with grants from Bayer Pharma AG, Genentech, and Regeneron. © 2014 by The Angiogenesis Foundation. All Rights Reserved. www.scienceofamd.org
Transcript of in Wet AMD · 2014-09-11 · 1 3 6 7 4 ANGIOGENESIS VASCULOGENESIS VEGF-C VEGF-D VEGF VEGFR-3...
Macula
Imp
rove
men
t in
vis
ion
Treatment over time
Continued treatment is important
ENDOTHELIAL CELL: The vascular endothelial growth factor (VEGF) family (A-D) binds to receptors VEGFR-1, VEGFR-2, VEGFR-3, activating signal transduction to promote angiogenesis, vasculogenesis, and lymphangiogenesis.
Aflibercept
Ranibizumab
Bevacizumab
VEGF Anti-VEGF treatment
VEGF Receptor
The neovascular form of age-related macular degeneration (wet AMD) is characterized by excessive proliferation of abnormal, leaky blood vessels (angiogenesis) growing from the choroidal layer through Bruch’s membrane and into the retinal layers. If left untreated, the proliferating vessels will eventually cause a subretinal fibrotic scar and permanent vision loss.
Angiogenesis in Wet AMD
Treatments for wet AMD neutralize VEGF, the primary angiogenesis-stimulating factor.
AntiangiogenicTreatments
Optic nerve
Lens
Iris
Cornea
Light
Areaseen above
Retinal bloodvessels
Macula
Endothelial progenitor
cell (EPC) from bone
marrow
Inflammatorycytokines
Choroidblood vessel
MMPs dissolvetissue matrix
Fluid accumulationbeneath the retina
Sprouting
2
Displaced photoreceptors
While wet AMD accounts for only about 10-15% of all AMD cases, this form is responsible for up to 90% of severe vision loss or legal blindness from the disease.
5 The three major anti-VEGF therapies, Ranibizumab, Bevacizumab, and Aflibercept, are administered intravitreally (injected directly into the eye), usually at monthly or less frequent intervals.
6 Inhibiting excessive VEGF in the eye causes regression and maturation of abnormal, leaky capillaries, and reduces fluid accumulation. Many patients experience an improvement in vision very soon after treatment.
7 With prolonged VEGF blockade, the accumulation of fluid beneath the retina resolves and the photoreceptors reattach to the underlying retinal pigment epithelium.
Wet AMD is a chronic, progressive condition, so patients must receive regular, long-term anti-VEGF therapy in order to maintain vision and slow the advance of the disease.
Anti-VEGF treatments bind VEGF-A, inhibiting angiogenesis by preventing this ligand from binding to its receptors. Some therapies can specifically bind to related ligands, such as VEGF-B and PlGF.
Choroid
Photoreceptors
Bruch’smembrane
Thickening of Bruch’s membrane
Retinal pigmentepithelium (RPE)
Fluid accumulationwithin retinal layers
New blood vesselspenetrateBruch’s membrane
RetinaRetinal blood
vessels MaculaArea of
enlargement Fluid leakage fromimmature vessels
Leaky blood vessels
13
6
7
4
ANGIOGENESISVASCULOGENESIS
VEGF-D VEGFVEGF-C
VEGFR-3(Flt-4)
VEGFR-1(Flt-1)
VEGFR-2(Flk-1)
VEGF-A
VEGF-B
PIGF 1,2
Ras
Raf
MEK
ERKp38MAPK
PI3K
Akt
mTOR
eNOS
Caspase-9
LYMPHANGIOGENESIS
HIF-1αVEGF
Expression VEGF
Hypoxia
PROLIFERATIONMIGRATION
CELL ACTIVATIONSURVIVAL
Excess fluiddrains from region
Blood vessels stop growing through Bruch’s membrane and nascent capillaries regress
Photoreceptors realign with RPE, vision can be partially
restored
Inflammatorycell
Overexpressionof VEGF
Normal vision Wet Age-Related Macular Degeneration
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1 Oxidative stress such as UV light exposure, aging, and smoking, as well as genetic predisposition, leads to inflammation in blood vessels. With age, Bruch’s membrane can thicken, causing hypoxia in the retina and RPE.
2 In response to inflammation, inflammatory cells are recruited to the retina. These recruited cells, as well as the RPE, secrete angiogenic growth factors such as VEGF and inflammatory cytokines.
3 The growth factors stimulate the growth of blood vessels in the choroid layer. These vessels then penetrate the Bruch’s membrane, and fluid begins to accumulate within and below the retinal layer.
4 The new blood vessels are disorganized and leaky. The leaked fluid lifts the retina away from the RPE and Bruch’s membrane.
www.scienceofamd.org
This resource was independently developed with grants from Bayer Pharma AG, Genentech, and Regeneron.
© 2014 by The Angiogenesis Foundation. All Rights Reserved.
www.scienceofamd.org
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