1. Foresight: The Promise of Clinical Trials
Moving RD Treatments From the Laboratory Bench to the Patient Bedside
LGerald J. Chader, Ph.D., M.D.hc
Department of Ophthalmology
Keck School of Medicine
University of Southern California
Los Angeles, CA USA
os Angeles, CA
University atlo
October 22, 2009

2. Q.: WHAT ARE WE DOING TO FIND NEW RD TREATMENTS?

3. Great Basic Science Progress
We know more than half of the genetic mutations that lead to the different types of retinal degenerations.
We also know the biochemical pathway called “apoptosis” that leads to photoreceptor cell death and we know several agents called neuron-survival factors that slow apoptosis by protecting photoreceptors.
Animal models for many of the RD diseases are known. These are invaluable since approval for human clinical trials is much easier if efficacy and safety can first be demonstrated in an animal model.
Now, building on this basic information, I want to summarize 6 research areas that have or can lead to clinical trials and finally to treatments for the RDs.

4. First though, let’s take a quick look specifically at AMD
Wet AMD is a special case in that the main problem is growth and leakage of new, abnormal blood vessels near the retina. This can be fairly well controlled though through the use of drugs such as anti-VEGF agents that are designed to stop new vessel growth.
For dry AMD, antioxidants can slow disease progression as with the AREDS agents. Otherwise, dry AMD is similar to RP and, in the main, the six therapy areas I will cover pertain to dry AMD as well as RP and the rare, allied diseases.

5. 1) Photoreceptor Transplantation
If photoreceptor cells are dead, why not just transplant normal photoreceptor cells into the RD retina from a normal donor retina?
Unfortunately, this has shown only limited success in many previous animal studies.
Dr. Norman Radtke in the USA had government approval to treat several human RP patients by transplantation of embryonic photoreceptor cells in a clinical trial. He reported good safety but only very limited efficacy.
So, is there anything new?

6. YES! Recent Modifications of Old Transplant Strategies Seem to Work -
Dr. Robin Ali et al. used transplantation of young photoreceptor cells to improve vision in a mouse model of RD. These cells are past the embryo stage used in most previous studies but are not yet well developed photoreceptors. After transplantation, visual signals are projected to the brain with resulting light-driven changes in behavior of the animal.
Dr. Tom Reh showed that small numbers of adult rod photoreceptor cells can integrate into the mature RD mouse retina and restore some functional vision.

7. .
Dr. Ali et al. now have shown repair of degenerate retinas by photoreceptor transplantation in 6 different mouse RD models. He reported “robust integration” of the cells into the damaged retina even in late stage disease.
Bottom Line: In photoreceptor cell transplantation, there are new ideas that could lead to clinical trials and sight restoration.
One of the most important is the use of stem cell transplantation.

8. Stem Cell Transplantation
Stem cells are primitive multi-potential cells that have the ability to develop into all different adult cell types – such as photoreceptor cells.
So, stem cells transplanted into the sick retina might replenish the supply of photoreceptor cells that died due to degeneration.

9. Where are stem cells found?
Stem cells are, of course, present in embryonic (fetal) tissue. However, small numbers have been found in many adult tissues.
For example, Dr. Derek Van der Kooy first reported stem cells close to the retina in the eye of the adult mouse. These stem cells can be harvested and appear to function as true retinal stem cells.
Also, some adult cells such as skin cells can be reprogrammed to revert back into a primitive stem cell and then induced to differentiate into another mature cell type such as a photoreceptor cell.

10. There are examples of sight rescue in RP animal models using stem cells:
Dr. Tom Reh developed a special type of retinal cell from human embryonic stem cells.
When these cells are injected into the eyes of mice that have a form of LCA, they migrate into the retina and settle in the photoreceptor layer. There, they begin to express rod and cone photoreceptor biochemical markers.
Importantly, light responses are restored in the treated animals.
A clinical trial is being planned.

11. Ocata is conducting a clinical trial injecting undifferentiated embryonic stem cells behind the retina to supply fresh cells in Stargardt Disease and dry AMD. A group at RIKEN in Japan is conducting a clinical trial on wet AMD using stem cells. Other groups are working on cell replacement in AMD using established cell lines of human ESCs. Preclinical results have been good. Applications to RP are obvious.
Clinical Trials?
1) Ocata
2) London Project to Cure Blindness
3) California Project to Cure Blindness
4) RIKEN (Japan)
Also, Dr. Henry Klassen in the US is starting a clinical trial with 16 RP subjects. He hopes to not only supply new photoreceptors but to help save remaining cone cells that are yet alive.

12. Foresight: Future Treatment?
Direct Photoreceptor cell transplantation?: Not yet!
Stem Cell conversion to photoreceptor cells?: research is continuing and good progress is being made.
Photoreceptor repopulation from other cell types?: good progress is being made in basic, preclinical research.
And, there are many opportunities for use of stem cells that are not obtained from new human embryos.
Clinical trials are here!
Foresight: Future Treatment?

13. 2) Artificial Vision
Uses an electronic prosthetic device to replace the function of dead photoreceptors. This includes a small “patch” usually implanted on the retinal surface. Depending on design, the “patch” could contain light-sensitive diodes or tiny electrodes that react to a visual stimulus. Either way, it substitutes for the dead photoreceptor cells, replacing their function.

14. There Are Many Groups Around the World Working on Artificial Vision
Retina Implant AG in Germany is an outstanding leader in this field. RI has a device, the Alpha AMS, that is now available for implantation in Europe.
Second Sight Medical Products has its Argus II device implanted in over 200 recipients.
Other academic groups and companies are doing excellent work on other types of retinal devices that should lead to commercial products in the next few years. Groups in Japan, Korea, Australia, Ireland, USA.

15. Implants are now available from two companies:
The Alpha AMS from Retina Implant is available at 6 sites in Germany with more centers to be established in France, England and Spain.
The Argus II is now available at several hospitals in the USA and Europe. There are 17 cities in North America where the Argus II is available for implant. In Europe, the Argus II is available in England, France, Germany, The Netherlands and soon at a site in Australia.

16. In Summary -
Results from use of the Argus II and Alpha AMS prosthetic devices have been very good.
The medical and social needs are great.
- the financial reward is also great in savings in both
patient medical costs and government assistance.
Safety issues seem to be satisfied – up to 10 yrs now.
Improvements should greatly improve Quality of Life.
Restoration of reading ability and face recognition
will allow for performing almost normal household
tasks and ability in the workplace.
No other treatments are available or as widely applicable
to as many severely impaired RD patients.

17. Where Are We Today?
Clinical trials on RP have been successfully concluded but testing continues.
The Alpha AMS system is available in Europe.
The ARGUS II system is available for general implantation in advanced RP in Europe and the USA. Studies on dry AMD have begun.
Technologies are being improved to allow for face recognition and reading ability as well as color vision.

18. Brain Prostheses Groups have been working on brain cortical prosthetic
devices that could bypass
the eye completely.
In the past, the group of Dr. William Dobelle prematurely did human implants with poor results.
More recently, SSMP is developing a cortical prosthetic device called Orion 1 that will bypass the eye completely.

19. 3) Optogenetics (Photoswitches)
Many animal and plant cells have proteins that react to light and produce an electrical signal.
For example………..
Molecular engineering can be used to insert channelrhodopsin molecules into remaining retinal cells, e.g., ganglion cells, in RD animals to make them light sensitive.
The light signals can be passed on to the brain which can then distinguish at least a “lights on” or “lights off” situation.
Chlamydomonas is a tiny one celled algae that contains a light-sensitive protein called channel rhodopsin

20. Different types of photoswitches can be inserted into different types of remaining cells in RD retinas.
Dr. Roska has shown that photoswitches can be inserted into retinal bipolar cells to restore visual function in an RD mouse model.
Dr. Tamai used a photoswitch called Channel Rhodopsin2 targeted to ganglion cells in an RD mouse retina to “restore effective vision”
Dr. Roska showed that another photoswitch called halorhodopsin can be used in surviving cone cells to substitute for the native defective phototransduction proteins and restore light sensitivity in a mouse RP model.

21. Optogenetics Companies
Several companies have formed or are forming to bring Optogenetics to clinical trial. For example, GenSight Biologics is a newly formed gene therapy company in France.
It is testing a therapy developed by Dr. Sahel in Paris. He uses gene therapy to deliver a gene expressing the light-sensitive protein “halorhodopsin” to remaining retinal cells in RP animal models. The halorhodopsin picks up the light energy and gives a visual signal.

22. Foresight: Future Treatments?
Basic work on Photoswitches is yet in development.
Some photoswitches only work at very high and dangerous light intensities or at damaging light wavelengths. Some react to light too slowly to be useful in human vision. Others, though, work well.
Excellent work by several investigators on insertion of specific photoswitches into remaining retinal cells in RP animal models gives hope for restoration of functional vision in the future using optogenetics.

23. 4) Neuroprotection
Is the use of neuron-survival agents to delay photoreceptor death. This has been proven in several RP animal models.
In 1990, Dr. LaVail and his group first showed that a natural growth factor (bFGF) could delay photoreceptor cell degeneration when injected into the eye of an animal model of RP. Since then, many natural factors in brain, retina and other tissues like CNTF have been found that inhibit photoreceptor cell death.
Collectively, these are now called “Neurotrophic Factors” or “Neuron-Survival Agents”

24. Clinical Trials?
Neurotech is in clinical trials with CNTF on RP and dry AMD subjects.
Using a technique called Encapsulated Cell Technology, they deliver the neuron-survival protein CNTF to the sick retina.
In ECT, a small capsule is surgically placed inside the eye of the patient. Within the capsule are special living cells that are bioengineered to produce CNTF.
The CNTF leaves the capsule and enters the retina where it helps to protect the sick photoreceptor cells.

25. Many Neuron-Survival Agents are Available for Testing:
For example, Dr. Sahel et al. have shown the Rod-derived Cone Viability Factor (RdCVF) is a potent agent that promotes cone cell viability. Cone cells are the most important type of photoreceptor cell since they are used in central, sharp and color vision.
Dr. LaVail and others have identified over 30 natural and man-made factors that can act as neuron-survival agents, protecting retinal photoreceptor cells and prolonging vision.

26. Electrical stimulation is another way to prolong photoreceptor cell life and increase visual function
The idea of using electrical current therapeutically is quite old but it has been updated. A clinical trial has been conducted testing Transcorneal Electrical Stimulation (TES) to test its effect on the RP retina. The TES device is placed in front of the eye and electrical stimulation is applied to the retina through the cornea.
Electrical stimulation of the retina might increase secretion of neurotrophic agents, thus protecting the retinal cells.
Okuvision’s TES has CE Mark approval in Europe.

27. Foresight: Future Treatments?
The current Neurotech clinical trial should soon be completed.
It could produce the first effective and generally available treatment for many forms of RP, allied diseases and dry AMD.
BUT - there are many agents to test yet! Drugs, Natural Factors. Alone or in combination.
Foresight: Future Treatments?

28. 5) Antioxidants It is clear that antioxidants can slow disease
progression in some patients with mid-stage dry
AMD. This was proven in the AREDS clinical trials.
The AREDS formulation is generally available for use.
In Retinitis Pigmentosa, two research groups - Van Veen and Campochiaro have
demonstrated that anti oxidants slow the course of retinal degeneration in RP animal models. This is specifically photoreceptor cell death through apoptosis.

29. Antioxidant Trial Together, these agents are called RetinaComplex.
Dr. van Veen fed animals with retinal degeneration a special combination of antioxidants and slowed the degeneration process.
Together, these agents are called RetinaComplex.
Based on this preclinical work, a small clinical trial in Spain has finished on RP and dry AMD patients. Initial reports of the results were good but we are waiting for a final report.
More extensive trials must be planned.
Ingredients:
Lutein, zeaxanthin, alpha-lipoic acid, L-glutathione, extract of lycium barbarum (wolfberry)

30. Foresight: Future Treatments?
For dry AMD, antioxidants work at least at mid-stage disease.
For RP, clinical trials such as on RetinaComplex must be completed.
In the future, there are many types of antioxidants that can be tested in RP and AMD animal models and then in the human.
For now, take your mother’s advice: Eat your Fruits and Vegetables!
Foresight: Future Treatments?

31. Gene Therapy replaces defective mutated genes in living cells with new, normal copies of the gene.
The new gene acts as a blueprint, synthesizing a normal protein that restores function in the cell.
Different types of Gene Therapy are available. These are suited for all genetic types of RP – recessive, dominant and X-linked.
Importantly, long-term, positive effects of Gene Therapy in RP animal models have been shown even if treatment is done fairly late in the disease process after significant photoreceptor loss.
6) Gene Therapy

32. In 2001, Dr. Gus Aguirre and coworkers reported remarkable restoration of visual function in Briard dogs, a model for Leber’s disease. (RPE65 mutation)
It is now about 15 years later and the treated dogs saw better for their lifetime.
More recently, many other dogs have been treated and the results appear to be excellent. Even in older dogs with few photoreceptor cells remaining.
Gene Therapy
Lancelot

33. Gene Therapy Clinical Trials
The newer and exciting news is that Gene Therapy will restore some visual function in the human.
About 5 years ago, Dr. Robin Ali et al. started the first gene therapy clinical trial supplying a normal copy of the RPE65 gene to specific patients with LCA. Other groups (e.g., Drs. Bennett, Jacobson) soon started similar trials and most treated patients seem to be doing well with some restored vision.
The focus now is on early treatment, i.e., children.
This success can now be used as a model for treatment of many other retinal degenerative diseases.

34. Future Treatments? Clinical trials are ongoing/planned for:
Forms of dominant, recessive and X-linked RP: MERTK – Abboud –S.A.
Forms of LCA: LCA 1 (GUCY2D) – UF; LCA 5 – Lebercillin consortium
Stargardt’s Disease - ProgStar
Retinoschisis –AGTC, NEI
Forms of Usher Syndrome – Ushstat
Choroideremia – MacLaren –UK
Gene Therapy also can be tested in combination with other therapies such as neurotrophic or anti-oxidant agents.

35. So, looking into the future….
I hope you agree that we are finally passing out of the time of scientific darkness and into the era of enlightened clinical trials.
Over 25 years of hard work at the laboratory bench has led to many clinical trials that are testing meaningful and sight-saving therapies. This will lead to new treatments that will save and restore vision in all RD patients.
So, looking into the future….

36. I leave you with one last piece of good news --
At the recent meeting of the RI Scientific & Medical Advisory Board in Seattle WA, we reached a significant milestone.
At past meeting, we usually had about 15 short reports on basic RD research and progress towards clinical trials.
This year, all talks reported on clinical trials with no time for any news on basic studies.
We believe that this is tremendous progress, again pointing to oncoming treatments for all retinal degenerative diseases.

37. THANK YOU FOR YOUR ATTENTION!
Any Questions?