Retinal Degeneration: Proof of Principal, Medical Therapy
Transcript Retinal Degeneration: Proof of Principal, Medical Therapy
Gerald J. Chader, Ph.D., M.D.hc
Doheny Retina Institute
USC Medical School
Los Angeles, CA
Presented at the AMD Alliance International Annual General Meeting and
Presentations held in Toronto, May 2008
WHAT ARE WE DOING TO FIND NEW AMD TREATMENTS?
Remembering that the Retinal Degenerations
are a family of diseases that result in
degeneration and ultimate death of the
photoreceptor cells of the retina.
• These diseases are all inherited or at least
have a genetic component.
The RDs fall into 2 main branches:
The Retinitis Pigmentosa branch
The Macular Degeneration branch
New Assessment: What we know about one
might be applied to the other. There are
several similar mechanisms involved in
all/most of the diseases.
AMD is a “complex disease” with both genetic
and environmental factors. True but…
• Having a gene mutation may not necessarily
mean that you get AMD. How can this be
translated into a treatment?
AMD is a disease of cone cells. True but….
• It is a disease of the full retina, RPE, Bruch’s
Membrane, rod cells and choroid - not just
AMD starts with cone dysfunction. Actually,…
• The disease may start with RPE or rod cells.
Can this give us an earlier start on a
AMD: Major Contributors and
Research Areas for Future Study
Genes – gene mutations have been implicated in
over 70% of AMD cases.
So, knowing that a gene mutation is at the root of
the disease process, what subsequent
biochemical mechanism(s) occur over time
(aging) that results in the disease process we
know as AMD?
1) Immunology/inflammation problems
2) Oxidative Damage
3) Injury/Wound healing response
These are not mutually exclusive…..
1) The Immune Connection:
Genetic variation in the protein Complement
Factor H (CFH) accounts for about 50% of
risk of all AMD cases.
• CFH is an important regulator of the immune
system inhibiting the “alternative
• Variations in Factor B and Complement
Component (C2) account for 24% of risk.
Altogether, we know the gene mutations that
account for 3/4 of risk in AMD patients.
Assessment: A huge immune involvement.
AMD Gene Progress
• In 2000, no genes were identified
whose mutations lead to AMD.
• This has been difficult since AMD is a
“complex disease” where both gene
mutations and environment (e.g.,
smoking) lead to or speed up the
• Now, about a dozen genes are known
whose mutations cause or are
associated with ¾ of AMD cases.
Assessment: Good work but several
more genes are yet to be identified.
2) AMD: An Oxidative-Damage
Crabb et al. subjected isolated drusen to analysis
and found many oxidative protein modifications.
• Lipid oxidative products were also found. These
were probably generated from DHA, a highly
unsaturated fatty acid which is in high
concentration in photoreceptor outer segments.
They suggest that oxidative damage is a major
contributing factor in AMD pathogenesis.
Assessment: Oxidative damage could play a
significant role in at least some AMD processes.
Oxidative stress is a general component in
Vit C, E
An imbalance between the prooxidants and the antioxidants of the
organism, in favour of the former lead to disease (Sies 1985).
3) Injury/Wound Healing
• A tissue responds to an insult or injury
by trying to correct or counteract the
• Sometimes, this can itself result in
pathology and making things worse.
• In wet AMD, the new, abnormal blood
vessels may be an example of the retina
trying to heal itself.
• Assessment: This “normal” response
could trigger neovascularization
Current and Future Treatments:
Treatments must fall into 2 general categories:
1) Treatments when some photoreceptor cells
yet remain and can be made to function
better. Three such treatments are Gene
Therapy, Pharmaceutical Therapy and
2) Treatments when all or most photoreceptor
cells are dead. Two such treatments are
Photoreceptor and Stem Cell Transplantation
and the use of Electronic Prosthetic Devices.
Clinical Trials are currently underway or
planned in all these areas for either AMD or
similar pathologies in RP.
1) Gene Replacement Therapy
In Gene Replacement Therapy a new, normal
gene is supplied to a target cell in which
there is a defective (mutated) gene. The new
gene will code for the synthesis of an
important protein (e.g., enzyme) that is
defective or lacking in the cell because of
the gene mutation.
• With this new expression, the photoreceptors
may function better and longer.
Assessment: Since many of the AMD gene
mutations are known for humans, we have
the theoretical possibility of replacing many
of these genes in the future.
“Spinach vision” may also be possible!
Example Clinical Trial:
Gene Replacement Therapy
In 2001, a group of scientists reported good
restoration of visual function in a blind Briard
dog, a model for Leber’s (RP) disease. Even
now, about 7 years later, the dogs first
treated are still seeing very well. Other dogs
have more recently been treated and the
results are excellent.
• Clinical Trials for Gene Replacement Therapy
on LCA have begun in London and
Philadelphia. Several more trials are planned
around the world.
Assessment: Great results! After 7 years, could
this be a “cure”, not just a “treatment”? The
clinical trials will give us the answer. But,
can this be applied to AMD?
Gene therapy restores vision in a canine
model of childhood blindness. Nature
Genetics 2001 May;28(1):92-5.
2) Pharmaceutical Therapy
Pharmaceutical Therapy can be defined as the
use of an agent that will prolong the life and
function of a photoreceptor cell.
• Some agents available are natural agents
found in the body that are called “neuronsurvival agents”. Some other agents are manmade drugs that function similarly.
• We now know many natural factors found in
small amounts in brain, retina and other
tissues can inhibit photoreceptor cell death
(apoptosis) to some degree when delivered
pharmacologically to the retina.
Assessment: Photoreceptors die from
apoptosis in both RP and AMD. Many
inhibitors of apoptosis are available.
Example Clinical Trial
• There are currently Clinical Trials underway
in both dry AMD and RP patients using a
neuron-survival agent called CNTF.
• Neurotech has a tiny capsule that can be
implanted within the eye that produces the
CNTF. The CNTF then diffuses to the retina
where it helps remaining photoreceptor cells
to survive and even function better.
• If the trials are successful, this will probably
be the first treatment generally available to
both RP and dry AMD patients.
Assessment: Great news but it is a treatment
not a cure!
3) Nutrition and AMD
A Clinical Trial for antioxidants in treating AMD
has been completed by the National Eye
Institute, the Age-Related Eye Disease Study.
• It found that some nutritional supplements
helped in AMD. The antioxidant nutrients
studied were B-carotene and vitamins C and
E along with the mineral zinc.
• The antioxidants are available for sale
although a physician should be consulted.
Assessment: The antioxidants really work but
only slow the course of the disease at a
specific (mid) stage of AMD.
Antioxidants work in RP as well. An AMD/RP
Clinical Trial has started in Spain.
NEI AREDS2 Trial.: (Phase 3)
• Lutein/Zeaxanthin are carotenoids that are
concentrated in the retina – especially the
macula. It is thought that they act as
antioxidants and thus protect photoreceptor
cells. Testing is also with Omega-3 LCPUFAs.
Othera’s Omega Study: (Phase 2)
• Eye drops to treat Geographic Atrophy
• The agent (OT-551) is thought to be an
antioxidant. No reported results yet.
4) Transplantation: Stem Cells
Theoretically, stem cells could be transplanted
into the retinal space where the
photoreceptor cells have died and could
develop and replace them.
• Stem cells are primitive, embryonic cells that
have the potential of developing into almost
any type of cell in the body – such as a
• Work to replace sick/dead RPE cells also
progresses both with stem cells and with
transplantation of adult donor cells.
Assessment: Great potential! But a rumored
clinical trial with stem cell transplantation in
RP patients is said to have failed. Applicable
5) Electronic Prosthetic Devices
for Sight Restoration
When photoreceptor cells are dead, an
electronic prosthetic device might be used to
take the place of the photoreceptors.
For the retina implants, there are many
different designs and surgical approaches
from groups around the world.
Clinical trials on RP patients are in progress.
This is NOT Vision of Terminator or
Geordi from Star Trek
Prototype Human Retinal
Argus 1 Clinical Trial :
A First Generation Device
The Argus 1 has only 16 electrodes in the
array touching the retina.
A Phase 1 Trial on 6 blind RP patients with
implants has been done -- from 2/02 and
yet continuing with functional testing.
All subjects had light perception restored
and can see discrete visual images
(phosphenes). They can perform simple
visual spatial and motion tasks.
Mobility (walking and navigation) has been
One device had to be removed for
unrelated health reasons.
The remaining 5 patients use the device at
A 2nd generation Retinal Prosthesis:
The Argus® II System
A Phase 2 Clinical Trial using the ARGUS II system
• The new device has 60 electrodes – not only 16.
This should allow for much finer detail in the
• So far, good safety profile but no efficacy data
yet since “sight restoration” is a slow, learning
Assessment: The real goal is use in AMD patients.
What are Current Treatments
for WET AMD?
• Antioxidants – old and new
• Antineovascular agents –
Several drugs now have been approved
by government agencies to slow
neovascularization. Best known is
Lucentis. Others like Visudyne and
Macugen are also available but work
poorly and are little used.
Treatments – Wet AMD
Lucentis – Genentech’s agent Lucentis is an
antibody that works against the growth
• It actually improves vision. One of the
problems with Lucentis though is that it must
be injected into the eye – often repeatedly.
• Cost too! Avastin work continues.
Oxigene – has an agent, Combretastatin, that
they have used as an antineovascular agent
• It is now in a Clinical Trial for wet AMD. This
drug can be delivered through the blood so is
• GenVec is conducting a Gene Therapy
Clinical Trial for wet AMD. It delivers the
PEDF gene into the eye. Phase 1 of the Trial
is completed - good safety results.
• PEDF is a natural protein that has both
antineovascular and neuron-survival
properties. Thus, it could be help stop the
formation of new blood vessels and also
protect photoreceptor cells.
Assessment: This could be the first real
success of Gene Therapy for a major disease.
Unfortunately, treatment is not longterm due
to poor choice of vector. Other gene
therapies (siRNAs) are yet being assessed.
Wet AMD Clinical trials RPE Cell Transplantation
Early degeneration of RPE cells is a
hallmark of AMD.
• Some researchers think that defects in
RPE cells could precede other damage.
Boltzman Institute Trial:
• To test if RPE cell transplantation helps
at the time of surgical extraction of
submacular neovascular membranes in
wet AMD. Good preliminary results.
Several Clinical Trials are planned or are
already in progress for different types
of RD therapies.
• For example, Gene Therapy work in RP
animal models shows not only sight
restoration but a long term effect.
• Other basic work in the fields of gene
therapy, transplantation, stem cell
research, pharmaceutical therapy,
nutrition and electronic implants
shows promise for future Clinical
A Final Thought…..
• We can treat and, in some cases,
maybe even cure diseases in many
animal models of retinal degeneration.
• We already have at least one effective
treatment for wet AMD although this is
NOT a cure. Similarly, the AREDS
antioxidants are good but only slow
the disease process.
• Other Clinical Trials are starting such
that more treatments are coming soon.
Assessment: These are expensive and
time consuming….. but who can put a
price on restoring sight?