AMD Update

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AMD Update

• 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
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WHAT ARE WE DOING TO FIND NEW
AMD TREATMENTS?
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Think Big

• 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.

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AMD Pathology New Thinking

• 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, Bruchs
  Membrane, rod cells and choroid - not just cone
  photoreceptors.
• AMD starts with cone dysfunction. Actually,
• The disease may start with RPE or rod cells. Can
  this give us an earlier start on a treatment?

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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..

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1) The Immune ConnectionAMD Genes

• 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 complement
  pathway.
• 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.

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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 disease process.
• 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.

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2) AMD An Oxidative-Damage Pathology?

• 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.

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Oxidative stress is a general component in
neurodegeneration
An imbalance between the prooxidants and the
antioxidants of the organism, in favour of the
former lead to disease (Sies 1985).
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3) Injury/Wound Healing Response

• A tissue responds to an insult or injury by
  trying to correct or counteract the problem.
• 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

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Current and Future Treatments Dry AMD

• 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 Nutritional Therapy.
• 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.

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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!

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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 Lebers (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?

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Gene therapy restores vision in a canine model of
childhood blindness. Nature Genetics 2001
May28(1)92-5.
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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 neuron-survival
  agents. Some other agents are man-made 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.

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Pharmaceutical TherapyExample 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!

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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.

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Other Nutrition/Antioxidant Trials

• 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 LC-PUFAs.
• Otheras Omega Study (Phase 2)
• Eye drops to treat Geographic Atrophy
• The agent (OT-551) is thought to be an
  antioxidant. No reported results yet.

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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
  photoreceptor cell.
• 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 to
  AMD?

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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.

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This is NOT Vision of Terminator orGeordi from
Star Trek
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Prototype Human Retinal Prosthesis
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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
  improved
• One device had to be removed for unrelated health
  reasons.
• The remaining 5 patients use the device at home.

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A 2nd generation Retinal Prosthesis The Argus
II System

• A Phase 2 Clinical Trial using the ARGUS II
  system has begun.
• The new device has 60 electrodes not only 16.
  This should allow for much finer detail in the
  visual image.
• So far, good safety profile but no efficacy data
  yet since sight restoration is a slow, learning
  process.
• Assessment The real goal is use in AMD patients.

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What are Current Treatmentsfor 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.

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Treatments Wet AMD

• Lucentis Genentechs agent Lucentis is an
  antibody that works against the growth factor
  VEGF.
• 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 in cancer.
• It is now in a Clinical Trial for wet AMD. This
  drug can be delivered through the blood so is
  fairly safe.

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Gene Therapy

• 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.

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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.

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In Conclusion.

• 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 Trials.

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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?