1. Gerald J. Chader, Ph.D., M.D.hc Doheny Retina Institute
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

2. WHAT ARE WE DOING TO FIND NEW AMD TREATMENTS?

3. 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.

4. 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, Bruch’s 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?

5. 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…..

6. 1) The Immune Connection: AMD 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.

7. 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.

8. 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.

9. Oxidative stress is a general component in neurodegeneration
ANTI-OX
PRO-OX
SOD
GSH
Vit C, E
Carotenoid
O-2
OH
 NO
H2O2
An imbalance between the prooxidants and the antioxidants of the organism, in favour of the former lead to disease (Sies 1985).

10. 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

11. 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.

12. 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!

13. 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?

14. Gene therapy restores vision in a canine model of childhood blindness
Gene therapy restores vision in a canine model of childhood blindness. Nature Genetics 2001 May;28(1):92-5.

15. 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.

16. Pharmaceutical Therapy: 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!

17. 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.

18. 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.
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.

19. 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?

20. 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.

21. This is NOT Vision of Terminator or Geordi from Star Trek

22. Prototype Human Retinal Prosthesis

23. 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.

24. 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.

25. 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.

26. Treatments – Wet AMD
Lucentis – Genentech’s 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.

27. 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.

28. 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.

29. 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.

30. 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?