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Visual Impairment in the Elderly
Bernard R. Hurley, MD, FRCSCAssistant Professor of Ophthalmology
University of Ottawa Eye Institute
Outline: Vision Loss in the Elderly
Introduction
The eye as an optical system»
Relevant anatomy
Disease of the aging eye
Cataract
Retinal vascular disease
Glaucoma
Age related macular degeneration»
Wet and Dry
Emphasize current and future treatments for each
Life is Beautiful to Look At
Life is Beautiful to Look At
My daughter Jenna shows us what it is like to suffer vision loss
Outline
Introduction
The eye as an optical system»
Relevant anatomy
Disease of the aging eye
Cataract
Retinal vascular disease
Glaucoma
Age related macular degeneration»
Wet and Dry
Emphasize current and future treatments for each
The Eye –
A Living Camera
The Eye –
A Living Camera
The Eye as an Optical System
Cornea
Lens
Retina
Optic Nerve
The Eye as an Optical System
Center of retina is macula
Affected in macular degeneration
Cornea
Lens
Retina
Cataract
Optic Nerve
Vascular Disease
Glaucoma
Outline
Introduction
The eye as an optical system»
Relevant anatomy
Disease of the aging eye
Cataract
Retinal vascular disease
Glaucoma
Age related macular degeneration»
Wet and Dry
Emphasize current and future treatments for each
The Eye as an Optical System
Lens
Retina
Cataract
Optic Nerve
Cataract
Aging change of lens
Loss of clarity
Major cause of blindness on global scale
Most common surgery performed in Canada
Replacing the Lens –
Cataract Surgery
Cornea
Focusing elements of eye
Most common surgery in Canada
Lens
Cataract Surgery Procedure
1.
Clear corneal incision
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
4.
Grooving
Surgeon’s View of Surgery
1.
Clear corneal incision 2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
4.
Grooving5.
Nuclear division6.
Emulsification and extraction
Surgeon’s View of Surgery
1.
Clear corneal incision 2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
4.
Grooving5.
Nuclear division6.
Emulsification and extraction
7.
Lens insertion
Surgeon’s View of Surgery
1.
Clear corneal incision
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
4.
Grooving
Surgeon’s View of Surgery
1.
Clear corneal incision2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
4.
Grooving
Surgeon’s View of Surgery
1.
Clear corneal incision 2.
Viscoelastic formation of the anterior chamber
3.
Capsular rhexis and hydro-dissection
4.
Grooving5.
Nuclear division6.
Emulsification and extraction
Real Life Operation
One More Time
What’s new: Choice of Lens
Previously
Limited to monofocal lens
Now
Technology allows custom lens»
Correct all ocular aberrations»
Multifocal
Distance and near correction
Requires
Bio-Imaging to measure optical aberrations of the eye
»
Correction beyond sphere and cylinder
Lens Selection
Oculus Pentacam
AMO/VISX Wavescan
The Eye as an Optical System –
Distant Objects
Take home message:
The eye is designed to place distance objects in focus on the retina
20mm
50 D
The Eye as an Optical System –
Near Objects
The eye NO LONGER strong enough
Focus is behind retina
Behind the retina
Requires Reading Glasses
The added power can not come from native lens
Must come from reading glasses
Multifocal IOL
Multifocal IOL
Simultaneously focuses near and distance objects»
Light intensity split between two images»
Result is decreased image quality but no need for reading glasses
Both images appear simultaneously on retina
Multifocal IOL
Older patient
Visual confusion in images
Less light intensity»
Lower contrast sensitivity»
Poorer image quality
Result: New IOL’s may not be best for elderly
Also expensive and not covered by OHIP
Outline
Introduction
The eye as an optical system»
Relevant anatomy
Disease of the aging eye
Cataract
Retinal vascular disease
Glaucoma
Age related macular degeneration»
Wet and Dry
Emphasize current and future treatments for each
Glaucoma
Cornea
Lens
Retina
Optic Nerve
Glaucoma
Glaucoma
A spectrum of disorders»
Pressure related damage to the optic nerve
Glaucoma
Glaucoma
A spectrum of disorders»
Pressure related damage to the optic nerve
↑
PRESSURE
Glaucoma
A spectrum of disorders»
Pressure related damage to the optic nerve
Glaucoma
Glaucoma
A spectrum of disorders»
Pressure related damage to the optic nerve
Glaucoma
Acute Angle Closure Glaucoma
Aqueous Outflow Intraocular Pressure 15 mmHg
60 mmHg
Intraocular Pressure
Acute Angle Closure Glaucoma
Mechanism60 mmHgIntraocular Pressure
Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure
Mechanism
Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure
Mechanism
Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure
Mechanism
Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure
Mechanism
Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure
Treatment
on
off
Acute Angle Closure Glaucoma60 mmHgIntraocular Pressure
Treatment
What’s New in Glaucoma
I stent –
micro valved implants to regulate IOP
Will everyone get one during cataract surgery?
Outline
Introduction
The eye as an optical system»
Relevant anatomy
Disease of the aging eye
Cataract
Retinal vascular disease
Glaucoma
Age related macular degeneration»
Wet and Dry
Emphasize current and future treatments for each
Vascular Disease
Cornea
Lens
Retina
Optic Nerve
Vascular Disease
Venous Occlusive Disease
Hypertensive changes in arteries
Retinal Vein Occlusion
Risk factors
Identified by the Eye Disease Case-Control Study
»
Age 60-69 most common»
Hypertension»
Cardiovascular disease»
Increased BMI at age 20»
Glaucoma»
Diabetes
Retinal Vein Occlusion
Visual Loss
Acute»
Macular hemorrhage»
Macular edema»
Capillary occlusion
With time»
Vascular remodeling/collateral formation may
Restore flow
Reduce edema and hemorrhage
Chronic»
Macular ischemia»
CME»
Macular pigmentary changes»
Epiretinal membrane formation»
Subretinal fibrosis
Retinal Vein Occlusion
Photocoagulation
Used to treat:»
Macular edema
Requires intact foveal perfusion
Macular edema»
Allow three months for improvement
»
Vision 20/40 or worse»
Light grid pattern of laser spots to involved sector of retina
»
Branch vein occlusion study
Treated eyes 2X more likely to gain 2 lines of vision
Branch Retinal Vein Occlusion
Vascular Remodeling
Collateral vessels
Help to reduce vascular congestion
Reduce edema
What’s New for Retina Vein Occlusion
Ozurdex implant
Biodegradable dexamethasone intravitreal implant
»
Polymer matrix»
Designed to last 6 months
OTHER OPTIONS?
Ozurdex implant
Biodegradable dexamethasone intravitreal implant
»
Polymer matrix»
Designed to last 6 months
Approved to treat macular edema from RVO
Effect does not last 6 months»
Three good months of control
NOT cheap
Ozurdex results
Ozurdex results: RVO (BRVO+CRVO)
Management
Intravitreal injection of Ozurdex OS
Management
Intravitreal injection of Ozurdex OS
Result
Excellent improvement in VA
Pre-Ozurdex: 20/200
One week Post-Ozurdex: 20/25
Surprising results
Surprising resultsOne week Post-Ozurdex: 20/25
Next visit –
implant in AC !
Outline
Introduction
The eye as an optical system»
Relevant anatomy
Disease of the aging eye
Cataract
Retinal vascular disease
Glaucoma
Age related macular degeneration»
Wet and Dry
Emphasize current and future treatments for each
Macular Degeneration (AMD)
Center of retina is macula
Affected in macular degeneration
Cornea
Lens
Retina
Optic Nerve
I love retina !
I love retina too!(not as much as pancakes)
AMD
Leading cause of severe central vision loss
i.e. legal blindness»
western world
people over 50 years old
Social/economic impact increasing
aging of population
AMD
Basic lesion is the druse
Thickening of inner aspect of Bruch’s membrane
AMD
Basic lesion is the druse
Thickening of inner aspect of Bruch’s membrane
»
Phospholipid vesicles»
Electron-dense granules
AMD –
Types
Dry
Most common, less severe
10% of population over 55
»
Degenerative changes only
Wet (exudative, neovascular, CNVM)
90% of pts with ≤20/200
10% of dry ARMD turns wet
»
New blood vessel formation
AMD –
Causes of severe vision loss
Neovascular (CNV)Neovascular (CNV)90%90%
DryDry10%10%
AMD -
Dry
Drusen
Phospholipid deposits
Geographic Atrophy
Loss of retinal cells
Responsible for vision loss
AMD -
Wet
Lipid (fat) deposits
Blood and fluid
AMD –
Wet End Stage
Scar tissue formation
“Diskaform scar”
Sub-retinal fibrosis
Treatment Options for Dry AMD
There is not cure
Life style modifications important
Quite smoking
Eat fresh fruits and vegetables
Maintain a healthy weight»
Exercise, Blood pressure control
? Reduce blue light/UV light exposure
Role of Nutrients in Dry AMD
therapy and prevention
Treatment of AMD -
DRY
AREDS
Age-Related Eye Disease Study
Multicenter, randomized trial
Up to 10 years follow-up
Assessed risk of:
Progression to wet AMD
Visual loss
AREDS -
Results
Vitamins reduce progression(CNV/visual loss)
25% at 5 years
Vitamins used
Vitamin C
Vitamin E
Beta-carotene
Zinc
Copper
Centrum Silver in addition is ok
What’s New for Dry AMD
AREDS II
Lower concentration of Zinc
Addition of new components
»
Lutein»
Zeaxanthin
»
Omega 3 fatty acids (fish oil)
Not available at the time of AREDS
Why Would These Vitamins Help?
The retina
One of the most metabolically activetissues in the body
This metabolism leads to the generation of “free radicals”
Highly reactive oxygen intermediates (ROIs)
ROIs:
Negatively charged molecules
Interfere with cellular function & damage retina layers
ROIs and antioxidants are balanced:
Antioxidants protect cells from potentially damaging effects of ROIs
What Is Oxidative Stress?
Disturbance in the ROI/antioxidant balance occurring because:
ROI production is increased, and/or
Availability of antioxidants is decreased
Believed to play major role in development of AMD
Factors Contributing To Oxidative Stress
Age
Low intake of antioxidants and minerals
Excessive exposure to blue light
Smoking
Pollution
Oxidative Stress & Cell Damage
ROIs damage Retinal Pigment Epithelium (RPE) & photoreceptors in two ways by:
Reacting with cell membranes & impairing normal cell function
Contributing to cellular waste products
Cells do not regenerate
Accumulating damage results in characteristic visual changes of AMD
Protection Against Oxidative Stress
1.
Blocking the formation of excess ROIs:
Lutein and zeaxanthin:»
Absorb harmful blue light
2.
Preventing the build-up of excess ROIs:
Antioxidants:»
Bind to and neutralize ROIs»
Renders ROIs harmless to cells in the RPE»
Prevents cell damage
Antioxidants
Two types of antioxidants:
Antioxidant nutrients:
Carotenoids –
lutein, zeaxanthin and beta-carotene
Vitamin C
Vitamin E
Antioxidant enzymes:
Zinc
Glutathione peroxidase
Catalase
Carotenoids
A subclass of xanthophylls
Yellow, oxygen-containing pigments found in plants
Dietary sources:
Spinach, collard greens, broccoli, carrots, corn, citrus fruit
Two major eye nutrients:
Lutein
Zeaxanthin
Lutein Supplementation
Lutein Supplementation
Increases macular pigment optical density (MPOD)
Filtersblue light
Provides protective effect
Clinical Studies on Beneficial Effects of Supplements
Dietary Intake Of Antioxidants & Risk Of Age- Related Macular Degeneration
•
van Leeuwen et al •
JAMA, December 28, 2005 –
Vol 294, No 24:
3101-3107
Study Overview
Objective:
To investigate whether regular dietary intake of antioxidants is associated with a lower risk of incident AMD
Design:
Dietary intake assessed»
Rotterdam Study (1990-1993) »
Divided into 3 intake groups
Study Population:
4170 adults >55 years of age
Mean follow-up of 8.0 years
van Leeuwen R et al, Dietary Intake of Antioxidants and Risk of Age-related Macular Degeneration. JAMA. 2005; 294: 3101-3107
Study Overview
Primary Outcome:Incident AMD
»
People who had no AMD at baseline»
Progression to incident AMD in at least one eye
van Leeuwen R et al, Dietary Intake of Antioxidants and Risk of Age-related Macular Degeneration. JAMA. 2005; 294: 3101-3107
1.20
1.00
0.65
0.00
0.20
0.40
0.60
0.80
1.00
1.20
Hazzard Ratio (Fully Adjusted)
Low Median HighCategory of Dietary Intake
Risk of AMD by Intake Group
Results
An above median intake of all 4 nutrients
beta carotene, vitamin C, vitamin E, and zinc
associated with a 35% reduced risk of AMD
35% risk reduction
Van Leeuwen*
Vitamin C 114 mg
Vitamin E 20 IU
Beta carotene 6,000 IU
Zinc 10 mg
minimum dose to be considered above-
median intake
Antioxidants Demonstrated Risk Reduction Of AMD
*total daily dose
van Leeuwen R et al, Dietary Intake of Antioxidants and Risk of Age-related Macular Degeneration. JAMA. 2005; 294: 3101-3107
Conclusions
1.
A larger risk reduction (35%) was observed for dietary intake for all 4 nutrients than for individual nutrients alone
2.
Dietary antioxidants may delay the development of early AMD and, possibly, of AMD in general
3.
Information may be useful to persons with signs of early AMD or to those with a family history of AMD
van Leeuwen R et al, Dietary Intake of Antioxidants and Risk of Age-related Macular Degeneration. JAMA. 2005; 294: 3101-3107
Antioxidants -
The Challenge
Antioxidant nutrients:
Cannot
be synthesized by the body
Must be supplied from dietary sources
Difficult and often impractical to obtain a sufficient amount of antioxidants from the diet alone
Treatments for Wet AMD
Established treatment
Laser therapy
Photodynamic therapy»
PDT
Modern Era
Intra-ocular injection»
The anti-VEGF revolution
Older treatments reduced the rate of visual loss but did not improve vision
Unequalled success
Now a treatable disease
Vision restored and protected
Life changing therapy
Wet AMD Therapy: Anti-VEFG Revolution
Before (20/400) After (20/40)
Profound impact
Driving
Reading
Independence
Life expectancy
Vascular Endothelial Growth Factor
What is VEGF?
Vascular Endothelial Growth Factor
Primary angiogenic factor
Endothelial cell»
Proliferation»
Migration»
Survival
Vascular permeability factor
78,000 times as potent as histamine
Four main isoforms of VEGF
VEGF165 most common isoform
Upregulated in angiogenesis
VEGF Isoforms: VEGF A
Dimer
165 121 110
165121110 189
189206
206
VEGFVEGF
VEGFVEGF86 -
89
VEGF Isoforms
Dimer
165 121 110
165121110 189
189206
206
VEGFVEGF
VEGFVEGF86 -
89
VEGF189
is sequestered in extracellular matrix
VEGF165
is most abundant and physiologically important isoform for normal angiogenesis
VEGF121
is highly diffusible
VEGF110
is a soluble and bioactive form that lacks the heparin binding domain; activated by plasmin
Endothelial Cell
VEGF receptor
Capillary formation (angiogenesis)
VEGF
VEGF
Anti VEGF Therapy
VEGF
Endothelial Cell
VEGF receptor
Lucentis binds VEGF in extracellular space
Endothelial cell Endothelial cell apoptosisapoptosis
H+H+
VEGF with Lucentis
Endothelial Cell
VEGF receptor
Prevents binding to endothelial cell
Anti-VEGF Treatment
Endothelial Cell
VEGF receptor
Antibodies against VEGF block
Embryonic development
Bone morphogenesis
Female reproductive cycling
Retinal and corneal angiogenesis
Growth of several tumor types in animal models
VEGF is required for embryonic development
Blocking VEGF is lethal
Even a 50% reduction of VEGF is lethal
VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1
Anti-VEGF(Avastin, Lucentis)
VEGF Receptor
Aptamer (Macugen)
Kinase Inhibitors
VEGF Trap
siRNA
Squalamine
Extracellular and CellularTargeting the VEGF Pathway
(Small interferening RNA)
What about other Anti-VEGF medications?
Macugen (Pegaptanib)
First FDA-approved anti-angiogenic agent for CNVM, Dec. 2004
Now clinically dead
Minimally Classic Occult (no classic)Predominantly Classic
Neovascularization
VEGF Macugen
Permeability
All CNVAll CNV
VEGF Isoforms
Dimer
165 121 110
165121110 189
189206
206
VEGFVEGF
VEGFVEGF86 -
89
Lucentis/Avastin Binds All VEGF Isoforms
*VEGF-189, -165, -121, and -110 have been tested.
165 121 110 1
1651211101
LucentisLucentis
LucentisLucentis
189
189206
Plasmin cleavage site
206
VEGFVEGF
VEGFVEGF86 - 89
Plasmin Cleaves VEGF165 to Produce Biologically Active VEGF110
Anti-VEGF Antibody (Lucentis, Avastin)
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102
Week
Visu
al A
cuity
(let
ters
)
2 Years Treatment (N=133;0.3 mg)Usual Care (N=107)
Treatment Effect Continues for 2 Years
45% Benefit,
P<0.01
Year One Year Two
Macugen (Aptamer)
VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1
Anti-VEGF(Avastin, Lucentis)
VEGF Receptor
Aptamer (Macugen)
Kinase Inhibitors
VEGF Trap
siRNA
Squalamine
Extracellular and CellularTargeting the VEGF Pathway
Study 2425: Occult CNV-
Group 1Day 140: 20/63 (+17 letters)Day 0: 20/125
457 µ 166
µ
FluoresceinAngiogram
OCT
Slide courtesy of Dr. P Rosenfeld, BPEI, Miami, FL
Anti-VEGF Antibody (Lucentis)
Lucentis = rhuFab V2 = ranibizumab
recombinantly produced
humanized
monoclonal Ab vs VEGF
Fab fragment
V2
–
Version 2 Affinity Matured
rhuMabMW 150 kD
rhuFabMW 48 kD
rhuFab V2MW 48 kD
Anti-VEGF Antibody (Lucentis)
Fab Retinal Penetration Following Intravitreal Injection
FabIgG
Fab (e.g. Lucentis)
MW 48 kD
IgG (e.g. Avastin™)MW 150 kD
Fab penetrates through all
retinal layers while IgG only penetrates superficially.
Toxicologic Pathology. 27(5):536-44, 1999 Sep-Oct.
Inner retina
Outer retina
Anti-VEGF Antibody (Lucentis, Avastin)
Lucentis/Avastin Binds All VEGF A Isoforms
*VEGF-189, -165, -121, and -110 have been tested.
165 121 110 1
1651211101
LucentisLucentis
LucentisLucentis
189
189206
Plasmin cleavage site
VEGF-receptor binding site
206
VEGFVEGF
VEGFVEGF86 - 89
Plasmin Cleaves VEGF165 to Produce Biologically Active VEGF110
Anti-VEGF Antibody (Lucentis, Avastin)
Lucentis™: Phase I/II (FVF2128g) Mean Change in VA (3 and 6 Months)Mean change in visual acuity to day 210
12.8
–5.1
8.1
15.012.6
–10
–5
0
5
10
15
20
ETD
RS
lette
rs
Usual care0.3 mg0.5 mg
n = 22
n = 20
n = 19
n = 21
Baseline
N = 11
Day 210Day 98
Anti-VEGF Antibody (Lucentis)
First therapy to improve vision
Avastin (Bevacizumab)
Recombinant humanized monoclonal IgG1 antibody
Full length antibody
Binds and inhibits human VEGF (all isoforms)
FDA approved for
Metastatic colorectal cancer
Colorectal cancer
Renal cell carcinoma
Glioblastoma
Non-small cell lung cancer
Intravenous avastin for neovascular AMD showed promising results in small series1
Intravitreal avastin for neovascular AMD effective in anecdotal reports2
1Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab therapy for neovascular age-related macular degeneration. Ophthalmology 2005;112:1035-47.2Rosenfeld PJ, Moshfeghi AA, Puliafito CA. OCT findings after an intravitreal injection of bevacizumab for neovascular age-
related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-335.
Intravitreal Avastin
Advantages
400-fold less drug required compared to intravenous dose
Higher safety margin
Lower cost $50 per dose
Disadvantages
No efficacy or safety data
Systemic side effects: »
hypertension, hemorrhage, GI perforation, arterial thromboembolic events (stroke, MI), proteinuria, CHF
No protocol for dosing or frequency of injection
Limited retinal penetration (in theory)
VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1
Anti-VEGF(Avastin, Lucentis)
VEGF Receptor
Kinase Inhibitors
VEGF Trap
siRNA
Squalamine
Extracellular and CellularTargeting the VEGF Pathway
Direct acting anti-angiogenic small molecule
Rapid systemic clearance
Long intracellular half-life and effects
Excellent safety profile with intravenous use
Inhibits VEGF and othergrowth factors
O H
NH H
O
OH
NHNH2
S OO
Squalam ineSqualamine
Squalamine lactate (investigational)
Given by intravenous
injection
Growth factors (VEGF, bFGF, etc.)
Endothelial Cell
Growth factor enhanced uptakeof squalamine aborts intracellular signaling
Squalamine
calmodulin
Intracellular Effects of Squalamine: Mechanism Of Action Model
Capillary formation (angiogenesis) F-Actin Filaments
Endothelial cell Endothelial cell apoptosisapoptosis
H+H+
Squalamine chaperonescalmodulin
Blockade of VEGF signaling, Blockade of VEGF signaling, decreased motility &decreased motility &integrin expressionintegrin expression
Squalamine lactate (investigational)
VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1
Anti-VEGF(Avastin, Lucentis)
VEGF Receptor
Kinase Inhibitors
VEGF Trap
siRNA
Squalamine
Extracellular and CellularTargeting the VEGF Pathway
VEGF Trap (New Kid on the Block)
Soluble “decoy”
receptor
Fusion protein
Smaller than antibody
“Mops-up”
VEFG in extracellular space
Binds VEFG more tightly than native receptors, antibodies (Lucentis, Avastin) or aptamers (Macugen)
Blocks VEGF in mammalian species (VEGF A, VEFG B and Placental Growth Factor)
VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1
Anti-VEGF(Avastin, Lucentis)
VEGF Receptor
Kinase Inhibitors
VEGF Trap
siRNA
Extracellular and CellularTargeting the VEGF Pathway
Double stranded RNA silences gene expression specifically and potently
siRNA (investigational)
How does siRNA work?Once activated the RISC complex destroys targeted mRNA in
a multiple turnover kinetic fashion.
ActivatedActivatedRISCRISC
V
V
V
V
V
V
RISC RISC SurveillanceSurveillance
ModeMode
No VEGF
siRNA (investigational)
What activates the RISC?
Small interfering RNA (siRNA) 21 Nucleotide double stranded RNA
siRNA is the key that activates the RISC
siRNA (investigational)
siRNA (investigational)
Inhibits VEGF in vitro and in vivo
Intravitreal injection inhibits laser induced CNV in mouse and monkey
VEGFVEGFAnti-VEGFR-2Anti-VEGFR-1
Anti-VEGF(Avastin, Lucentis)
VEGF Receptor
Kinase Inhibitors
VEGF Trap
siRNA
Extracellular and CellularTargeting the VEGF Pathway
The Big ThreeRanibizumab (Lucentis)Bevacizumab (Avastin)Aflibercept (VEFG Trap, Eylea)
May be differentiated by:Pharmacology EffectivenessSafety profile
Summary of Choices
Avastin
Never designed for the eye »
Label specifically states not for intra-ocular use»
No clinical trial support»
Vast world wide experience (60 million doses)
Cheap: $60/dose
Duration: 6 weeks
? Systemic side effects
Lucentis
Specifically designed and manufactured for the eye
Expensive: $1600/dose
Duration: 1 month
Eylea
New kid on the block
Still expensive
Duration: 2 months
Unequalled success
Practical limitations to achieving this
Physician factors
Patient/family factors
Societal factors
Wet AMD Therapy: Anti-VEFG Revolution
The Future: Long Acting Implants
The Ultimate Perhaps
Topical therapy
Summary
Major disease of the aging eye
Cataract»
Good surgical treatment available
New lenses for “super vision”
May not be good choices in elderly
Retinal vascular disease»
Age, Diabetes, Hypertension»
Long acting steroid implants
Glaucoma»
Medical and Surgical treatments»
Micro-valve implants
Age related macular degeneration»
Most common cause of age related blindness»
New exciting treatments»
Need longer acting formulations
Thanks for listening to my Dad
Thanks for listening to my Dad
Thanks for listening to my Dad
Thank-you