Transcript Retinal Genetics and Prosthetics:Where are we in 2013?

Retinal Genetics and
Prosthetics:
Where are we in 2013?
VRS Retinal Update 2013
D. Wilkin Parke III, M.D.
Objectives
• Describe the clinical value of current genetic
testing for AMD
• Describe some currently available retinal
prostheses and clinical scenarios in which they
might be beneficial
Other subjects in retina have better photos
Scenario 1
• You’re on a flight out of town and
the guy next to you recognizes you
as his mother’s doctor
• Mom has AMD and son desperately
wants to know whether the whole
family should get genetic testing
• You blame the ad for an AMD gene
test that you see in the in-flight
magazine
• Your smart phone is turned off and
it’s a three-hour flight
• What do you say?
Genetic testing for AMD
#1: What role do genes play in development of
AMD and advanced AMD?
#2: Which genes look like the big players?
#3: Can we risk stratify patients yet?
– Is this any better than a good exam?
#4: Can we target therapy to genotype?
AMD in the U.S.
2012
• 2.2 million with AMD
• 300,000 with wet AMD
2020
• 3 million with AMD
• 400,000 with wet AMD
• Not only is it a leading cause of blindness, but 50% of all new
registered blindness!
• 30% greater than 75 will have it
Risk Factors
Modifiable:
• Smoking
• Hypertension
• Hyperlipidemia
• Obesity
• Sunlight exposure
Not modifiable:
• Genetics
• Age
Genetic testing for AMD
#1: What role do genes play in development of
AMD and advanced AMD?
#2: Which genes look like the big players?
#3: Can we risk stratify patients yet?
– Is this any better than a good exam?
#4: Can we target therapy to genotype?
How important are genes in AMD?
• FH: First degree relative is at 6-12x higher risk
than the general population
• Genetic variants are responsible for 60-70% of
the risk
(Seddon et al 2009, Spencer et al 2011)
AMD Gene Consortium
• Confirmed 12 and identified 6 more loci of
AMD “susceptibility” in a meta-analysis of
7600 cases
• Asian and European gene markers appear
different in prevalence and significance
(Holliday et al 2013)
Genetic testing for AMD
#1: What role do genes play in development of
AMD and advanced AMD?
#2: Which genes look like the big players?
#3: Can we risk stratify patients yet?
– Is this any better than a good exam?
#4: Can we target therapy to genotype?
Genes in AMD
• Complement factor H
(CFH)
– Chrom 1q31
– The first one for AMD, 2005
– Alternate complement pathway
• ARMS2/HTRA1
– Chrom 10q26
– Age-related maculopathy
susceptibility factor 2
– Extracellular matrix and basement
membrane formation
Others:
• Chromosome 6
• Complement component 2 (C2) and
complement factor B (CFB)
• Nearby genes for VEGF-A and
Col10A
• Chromosome 9
• Nearby genes for Col15A1, TGFBR1,
ABCA1
• Weaker associations on chromosomes 2,
3, 4, 5, 8, 12, 15, 17, 18, 21
Rare variants
• CFH mutation (CFHR1*B)
associated with hemolytic uremic
syndrome,
– found in some individuals with
nonsyndromic AMD
• PRPH2 gene mutation is
associated with a CACD-like
macular atrophy
• ABCA gene polymorphisms have
been associated with severe AMD
Rare variants (cont’d)
• Elastin mutations identified in
Japanese with AMD
– Leads some to think that IPCV may be a
subtype of AMD expressed in certain
genetic variations
• Case control studies are not
possible with these conditions—
they’re too rare
• Distinguishing atypical AMD from
other macular diseases can be
difficult
Genes to remember
• ARMS2
• Chromosome 10
• CFH
• Chromosome 1
• What role do genes play in development of
AMD and advanced AMD?
• Probably a large one, but there are too many
contributing genes and too much
environmental modification for us to
categorize it as predominantly inherited
• Which genes look like the big players?
• CFH and ARMS2 on chromosomes 1 and 10.
Genetic testing for AMD
#1: What role do genes play in development of
AMD and advanced AMD?
#2: Which genes look like the big players?
#3: Can we risk stratify patients yet?
– Is this any better than a good exam?
#4: Can we target therapy to genotype?
Talking about odds ratios
• Characteristic 1q31 and 10q26 variants
have the strongest association with
development of advanced AMD
• But even for these, odds ratios are
difficult to define
– Ratios vary based on the study
– Different populations
– Different phenotypic characteristics
– Almost all are case control studies—
not true measurements of relative
risk
18
Odds ratios for high risk genotypes
• CFH (Y402H variant)
– Odds ratio of 2-2.5 in Europeans
• ARMS2
– Odds ratio of 6-10 for highest risk genotype
• C2/CFB
– Protective alleles may reduce risk by 45-53%
• CFH and ARMS2 – highest risk genotypes for both
– Odds ratio of 62
• Smoking – 10-15% current population,
– Odds ratio of 2.5-6
• But these are compared to “normal” age-matched controls!
• This is not from prospective monitoring of a population as it ages
What we know
• Those with the highest concentration of high
risk alleles have a higher risk than those with
the lowest concentration of high risk alleles
• Most patients are in the middle ground
• Most authors agree current tests lack “the
level of sensitivity and specificity that one
would normally demand of a clinical test”
(Jakobsdottir et al 2009)
20
So how can we assess risk without
genetic testing?
Clinical severity score
In each eye:
• 1 point for presence of large drusen
• 1 point for presence of pigment epithelial abnormality
Score
5-yr risk of late stage AMD
0
0.5%
1
3%
2
12%
3
25%
4
50%
Ferris FL et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18.
Arch Ophthalmol 2005; 123(11):1570-4.
Clinical severity score
Further modification by age, smoking status, family history
www.ohsucasey.com/amdcalculator
Score
5-yr risk of late
stage AMD
70-yr-old
nonsmoker
70-yr-old smoker
0
0.5%
1
1
1
3%
5
9
2
12%
11
19
3
25%
25
40
4
50%
34
52
Ferris FL et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18.
Arch Ophthalmol 2005; 123(11):1570-4.
Clinical severity score
Factoring in the CFH and ARMS2 variants changes the score,
but not by much
Score
5-yr risk of late
stage AMD
70-yr-old smoker
70-yr-old smoker,
high risk CFH and
ARMS2 variants
0
0.5%
1
2
1
3%
9
13
2
12%
19
26
3
25%
40
52
4
50%
52
66
Ferris FL et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18.
Arch Ophthalmol 2005; 123(11):1570-4.
So is this any better than a good
exam?
• Probably not, at
least right now
Genetic testing for AMD
#1: What role do genes play in development of
AMD and advanced AMD?
#2: Which genes look like the big players?
#3: Can we risk stratify patients yet?
– Is this any better than a good exam?
#4: Can we target therapy to genotype?
The only things to reduce risk
•
•
•
•
•
•
Stop smoking
Low glycemic index diet
Lutein and zeaxanthin
Vitamin D (only to avoid deficiency)
Beta-carotene, zinc
UV protection
27
Vitamins and genotype
• Antioxidants, lutein, zeaxanthin, and zinc
might reduce impact of high risk genotypes (Ho et
al 2011, Klein et al 2008)
Anti-VEGF therapy and genotype
• One homozygous CFH genotype
and one VEGFA gene variant may
be predictive of improved
response to anti-VEGF
(Chen et al 2012, Abedi F et al
2013)
• No consistent evidence yet of
association between at-risk alleles
on chromosomes 1 and 10 and
either positive or negative
responders to therapy
(Orlin et al 2012)
Alternative Screening
• Home-based monitoring
in the near future
– iPhone app
– Foresee Home device
• Can we tailor the
intensity of home
screening to genetic
risk?
www.foreseehome.com
www.digisight.com
Patient motivation
• Testing early might motivate higher risk
individuals to address risk factors more
aggressively
• But this could disadvantage lower risk
patients. It might produce surprise and
disillusionment if they still get advanced AMD
• Genetic testing is rarely straightforward
31
Genetic testing:
The holy grail
• In the future we may find
the risk-benefit balance
for each age, clarify the
pharmacogenetic
associations, and develop
specific monitoring and
therapy.
32
• “Avoid routine genetic
testing for genetically
complex disorders like agerelated macular
degeneration and lateonset primary open angle
glaucoma until specific
treatment or surveillance
strategies have been shown
in 1 or more published
clinical trials to be of
benefit to individuals with
specific disease-associated
genotypes” (Stone et al 2012)
33
Scenario 2
• You had a great vacation and you’re on
the flight home
• The flight attendant overhears what
you do
• Her son has RP and she’s saving up to
send him to Italy for a retinal
prosthesis
• She’s happy to take your drink order if
you’ll only tell her whether the
prosthesis is worth it
• Your smart phone is turned off and it’s
still a three-hour flight
• What do you say?
Retinal prosthetics
#1: How do they work?
#2: What types are available, and when are
these being used right now?
#3: With which patients do we have this
discussion?
Retinal prosthetics
#1: How do they work?
#2: What types are available, and when are
these being used right now?
#3: With which patients do we have this
discussion?
Retinal prosthetics:
The rationale
• Outer retinal disorders
• Postmortem analyses indicate that after total
photoreceptor loss in RP, that up to 90% of inner
retinal neurons can remain histologically intact.
• The visual pathway downstream to the
photoreceptors remains theoretically viable
Retinal prosthetics
• Electronic implants
• Non-electronic implants
Retinal prosthetics
• Electronic implants
• Non-electronic implants
The parts
• Encoder – converts light
into electrical energy
(retina’s data)
• Transducer implant
– Formulates stimulation
pattern
– Triggers electrodes
– Electrodes fire in close
proximity to target cells
(usually ganglion cells)
– Target cells activated by
proximal electrical charge
Weiland et al, 2011
Retinal prosthetics
#1: How do they work?
#2: What types are available, and when are
these being used right now?
#3: With which patients do we have this
discussion?
Epiretinal Prosthesis
Epiretinal implant/electrode array
Extraocular receiver
Wireless transmitter
Camera in glass frame
Humayun, et al (2003)
Epiretinal Prosthesis
4x4 platinum
electrode array
Humayun, et al (2003)
Epiretinal Prosthesis
• Yanai (2007):
– Visual performance tested via simple visual tasks:
•
•
•
•
Locate and count objects
Differentiate three objects
Determine orientation of a capital L
Differentiate four directions of a moving object
– Performance was significantly better than chance in 83%
of the tests
Subretinal Prosthesis
Chow, et al (2004)
Subretinal Prosthesis
• Chow AY, Pollack JS et al (2004):
– Silicon-based subretinal microchip
• 5000 microelectrode-tipped microphotodiodes
powered by incident light
– Implanted subretinally in 6 patients
– Subjective visual improvement seen in all patients
Problems and limitations with
electronic prostheses
• Power:
– Large heat dissipation per electrode
– Implants can’t heat tissue more than 1 degree Celsius.
– Limits electrode number
• Cochlear implants do well with only 16
electrodes, but vision requires more resolution
• Triggering the appropriate “on” and “off” neurons
• The inner retinal layers show some architectural
and functional change with the photoreceptor
degeneration, so the downstream system may
not be “normal”
47
Retinal Prostheses and RP
No. of
Subjects/
Centers Best Result
Trial
Optobionics (phases I and
II)
SSMP Argus I
IMI
Retina Implant Subretinal
Device
SSMP Argus II
Retina Implant Alpha
Study
6/1
7/1
Expanded visual field,
improved ETDRS scores
Motion detection, VA
20/250
Some form discrimination
12/1
Letter reading, VA 20/100
30/10
Letter reading, VA 20/125
Object localization, letter
reading
30/4
5/1
Modified from Weiland, et al, 2011
Collective experience
• Since 2002, published series with retinal
prostheses have come out of the US, Italy,
France, Germany, the UK, and Japan.
• The first clinically approved Argus II was
performed 10/2011 in Italy.
• The Argus II received FDA approval for adult
advanced RP on February 13, 2013.
• Over 70 patients with end-stage RP have
received one.
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Retinal prosthetics
#1: How do they work?
#2: What types are available, and when are these
being used right now?
#3: With which patients do we have this
discussion?
Candidates
• After implantation, training and calibration
take time and effort
• This requires a very compliant and aware
patient
• Surgical complications have been uncommon
but routine follow-up is required
51
Candidates
• Only patients with history
of functional vision loss
who are now LP due to
photoreceptor
degeneration are
candidates for prosthetics
• All prosthetics aim to
bypass the PR cell and
stimulate the bipolar or
ganglion cell
52
Where are we going
• Increased stimulator resolution (more
electrodes, more transducers)
• Smaller units
• More complex neural code incorporation
• Determination of best location for the
transducer (subretinal, epiretinal, etc.)
• Cortical and optic nerve prostheses also in
development, but no current human trials
Retinal prosthetics
• Electronic implants
• Non-electronic implants
– Cell/tissue transfer
– Gene transfer
• Optogenetics
• Other gene transfer
Retinal tissue implantation
• Fetal retina/RPE
implantation
– Surgically transplanted
sheets of fetal neural
retina and RPE
Retinal tissue implantation
• Radtke (2008):
– 10 patients (6 RP, 4
AMD)
– Vision 20/200 or worse
– 7 patients (3 RP, 4 AMD)
had improved ETDRS
visual acuity
– 2 RP patients had
decreased vision
– No clinical rejection of
implanted tissue
Optogenetics
• Fusing optics and genetics
• Concept:
– Expression of photosensitive
molecules from bacteria or
algae in human cells
(photoreceptors, ganglion
cells, other neurons)
– Host cells are conferred with
optical activity (via gene
delivery) and can be
manipulated by light.
57
Optogenetics
• Research into use throughout
body, but eye lends itself to
optogenetic technology because
it is light accessible
• Unlike electronic prostheses, this
offers potential to control gain or
loss of function, not just
stimulation.
Optogenetics:
What can we do right now?
• Mostly using a channel
rhodopsin (ChR2), a
membrane transport ion
channel
• Transfection into neural cells
via viral vector
• Virus vector, transfected gene,
and expressed protein have
been shown to be safe
• Light production by the cells is
safe (no phototoxicity
reported)
Credit: Viviana Gradinaru, Murtaza Mogri,
and Karl Deisseroth, Stanford University via
Science Daily
59
Optogenetics:
Current limitations
• Indiscriminate stimulation
– Unable to target specific cells or groups of cells
– No discrimination between “on” and “off” cell
types
• Response intensity is insufficient
60
Other gene therapy
• Retina is an early clinical adapter because
small volumes are needed, there is less risk of
systemic toxicity, and there is a contralateral
control
• Not necessarily just for genetic defects
• Turning off unwanted gene expression
(neovascularization, autoimmune processes, etc.)
• Inducing expression of therapeutic molecules (anti-VEGF
agents, corticosteroids)
61
Gene therapy:
Vectors
• Adeno-associated virus, lentivirus,
and adenovirus have been studied
in the eye
• AAV has the best safety record and
transduces cells efficiently
• Nonviral vectors being investigated
include lipid or nanoparticles
Gene therapy:
Delivery
• Currently vitrectomy and subretinal injection to access the
photoreceptor layer
• Suprachoroidal catheterization to target RPE or choroid
• Vector penetration through the retina may allow for
intravitreal injection.
Gene therapy:
Trials
• LCA Trial: Gene transfer with AAV
vector is safe
Current trials:
• 9 for inherited dystrophies
– Promising early results for Stargardt,
Usher, and choroideremia
•
20-30 for AMD
Stem Cell Companies
• Advanced Cell Technology (ACT) – RPE cells for dry AMD and
Stargardt
• AstraZeneca – diabetic retinopathy
• Janssen R&D – RPE cells for AMD
• Cell Cure Neurosciences – RPE cells for dry AMD
• Mesoblast – VEGF producing cells for wet AMD
• Neostem inc – vessel growth for AMD
• Neurotech – RPE cells for AMD, Usher, RP
• Pfizer – RPE cells for AMD; stem cells for DR, ROP, RP
• Stemedica,
• Stem Cells Inc
Conclusions
• Genetic testing is appropriately an area of active research in AMD
• At this time clinical genetic testing for AMD outside of research does not
have a clearly defined role and is not generally recommended
• An old fashioned clinical exam and history are remarkably predictive of
risk for advanced AMD
• Electronic retinal prosthetics are currently available for select patients
with very poor vision due to outer retinal degenerations
• Several implant designs have achieved remarkable results in previously
blind eyes
• Optogenetics = optics + genetics = very newsworthy right now
• Gene therapy trials in the posterior segment will continue to proliferate
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