Present and Future Treatments for Retinal Degenerative Diseases: An

Overview

Gerald J. ChaderDoheny Retina Institute

USC Medical SchoolLos Angeles, CA

WHAT ARE WE DOING TO FIND NEW TREATMENTS?

The Needs:Treatment Availability

• No generally effective treatment is yet available for Retinitis Pigmentosa or allied diseases such as Usher Syndrome (deaf-blindness). Vitamin A supplements might help some.

• Similarly, no effective treatment other than nutritional supplementation is available for the millions with dry AMD.

• Treatment is available for wet AMD but it is expensive and often must be repeated.

Current and Future TreatmentsAll treatments will not benefit all RP or AMD patients.• Thus, RP treatments must be divided into 2

categories: 1) treatments used when some photoreceptors

remain alive and functional. These treatments prolong the life of the photoreceptor cell.

2) treatments used when photoreceptors are dead and need to be replaced.

Luckily, we have good clinical techniques like OCT to distinguish between these 2 conditions.

Current and Upcoming RP Clinical Trials

There are three major possible treatments where the patient yet has viable photoreceptor cells in their retina.

These are: 1) Gene Therapy 2) Pharmaceutical Therapy

3) Nutritional TherapyWithout photoreceptors, these will not work.

First, let’s look at some of the progress in RD Genetics

For Retinitis Pigmentosa:In 1990, the first RP gene mutation was found.

This was for the rhodopsin gene in work by Drs. Humphries, Dryja and their groups.

Now: Over 100 gene mutations have been found for the forms of RP and other rare diseases. About 50 % known???

These are compiled on the Internet at a site called “Retnet”.

What about AMD Genes?

• In 2000, no genes were identified whose mutations were known to cause or predispose to AMD.

• This has been difficult since AMD is a “complex disease” where both genes and environment (e.g., smoking) lead to or speed up the disease process.

• Now, at about 10 genes are known whose mutations cause or are associated with about 70% of AMD cases. Several more are yet to be identified.

Progress in Cell BiologyQ.: How do photoreceptor cells actually die?A.: No matter what the initial mutational insult,

the common final pathway to death is by Apoptosis (Programmed Cell Death). This process is now well studied.

So, with all this basic science information on RD genetics and cell biology, certain possible routes to therapy are clear:– replace defective genes– prolong the life of photoreceptor cells– replace dead photoreceptor cells

1) Gene Replacement Therapy

• Gene Therapy is the replacement of a defective (mutated) gene such that an important protein (e.g., enzyme) is again synthesized and present in the cell. With this, the photoreceptors function better and live longer.

• What is a gene anyway?A gene is a small segment of the long DNA strand in the nucleus of our cells that acts as a blueprint for synthesizing a specific protein within the cell.A mutated gene is a defective gene that produces a disabled protein or none at all. If that protein serves an important function in the cell, the cell will not function properly and possibly will die.

Gene Therapy

• In Gene Therapy, a modified virus called a “vector” is used as a truck/vehicle to bring the normal, replacement gene into the cell to produce a normal protein product.

• The virus is modified such that it cannot reproduce but it can yet penetrate a target cell efficiently with its cargo – the normal gene.

Since it is estimated that about half of the RP gene mutations are known for humans, we have the theoretical possibility of replacing many of these genes in the future and treating many RP patients.

Gene Replacement Therapy

Starting in the ’90, several groups showed that they could replace defective genes in animal models affected by RP and partially restore visual function. For example:

• In 2001, a group of scientists reported good restoration of visual function in a dog model for Leber’s disease.

• Even now, almost 8 years later, the dogs first treated are still seeing very well. Other dogs have more recently been treated and the results are excellent.

• Older dogs with relatively advanced disease have been treated with good results. This demonstrates that there is hope even for some patients with advanced RP.

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

Gene Therapy Clinical Trials• Based on the excellent preclinical animal studies,

Clinical Trials for Gene Replacement Therapy in patients with Leber Congenital Amaurosis (LCA) have begun. One in London and two in Philadelphia. Other trials are planned around the world.

• These trials replace the mutated RPE65 gene in RPE cells of LCA patients. The RPE65 protein is critical in the visual cycle. Retinal dysfunction and ultimately degeneration is the result if the protein does not function properly.

• No final results on safety or efficacy have yet been reported but the initial results are good.

2) Pharmaceutical TherapyPharmaceutical Therapy is the use of an agent that

will prolong the life and function of a photoreceptor cell. • Some agents available are natural proteins found in the

body that are called “neuron-survival agents”. Some other agents are man-made drugs that function similarly.

• In 1990, it was shown that the natural growth factor, bFGF, could delay photoreceptor cell degeneration in an animal RP model.

• Since then, many factors found in small amounts in brain, retina and other tissues have been shown to slow photoreceptor cell death when delivered to the retinas of RD animal models.

Pharmaceutical Therapy:Clinical Trials

• There are currently two Pharmaceutical Clinical Trials underway. One in RP patients and one in dry AMD patients. These Trials are testing a neuron-survival agent called CNTF.

• The company Neurotech has a special 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 RP and dry AMD patients. (Maybe next year?)

• The Neurotech device with CNTF was well tested in an animal model of RP and found to be very effective in slowing the degeneration.

• The safety results of Phase 1 of Neurotech’s Clinical Trial are excellent. In 3 of 10 RP patients tested, even some improvement in vision was noted.

• Based on these results, there are high expectations for positive efficacy results from the Phase 2 and 3 parts of the Trials.

• Keep in touch with FFB for updates!

Neurotech Clinical Trial

3) Nutrition: For RPThe use of nutrition as a therapy in RP is

controversial but now must be taken seriously in prevention or at least slowing down the degenerative process.

• In 1993, Dr. Eliot Berson found that vitamin A supplementation slows RP to a small extent in some patients. On the other hand, Vitamin E was found to be harmful.

• Thus, the use of vitamin A has been the only treatment available to RP patients.

• BUT – due to the small effect in only some patients and the fact that vitamin A can be toxic to some patients, many Ophthalmologists do not recommend the treatment.

Antioxidants slow photoreceptor cell death in RP

• Recently, two noted investigators (Profs. Theo van Veen and Peter Campochiaro) reported that the use of antioxidants was very effective in slowing the disease course in rodent models of RP.

• Using sophisticated techniques, they showed that severe oxidative damage occurred in the retinal photoreceptor cells preceding cell death in the models of RP.

• BUT, supplementation with a specific cocktail of antioxidants greatly reduced the oxidative damage and slowed photoreceptor cell death.

• Importantly, the supplements were given by mouth to the animals. No injection is needed.

The RetinaComplex Supplements

In his studies, Prof. van Veen fed the RD animals a combination of 4 antioxidants that are individually well known to have high antioxidant properties.

• Lutein and Zeaxanthin– natural plant pigments known to be concentrated in the human retina and probably function there as antioxidants

• L-Glutathione – a natural antioxidant found in the body and concentrated in the eye.

• Alpha-Lipoic Acid – a general, potent antioxidant.

Q. What about Safety and Efficacy of the Antioxidants?

Safety?• High doses of the antioxidants were used but no

toxicity to the animals was observed. No toxicity for these antioxidants has been reported in the scientific literature for humans.

• The supplements are taken by mouth and so need no invasive procedures as in gene therapy or ECT.

Efficacy?• The supplements were effective in RP animal

models with very rapid photoreceptor degeneration and so are probably effective on even aggressive forms of RD in the human much less those with a slower time course.

RetinaComplex Clinical Trial

A clinical trial has now begun to test the effectiveness of the antioxidant agents in humans.

• This trial is in Spain sponsored by Dr. F.J. Romero and will probably take 2 years or more to complete. Good results at 1 year.

The supplement is already available for purchase over the internet – it is called RetinaComplex.

• It is probably safe since the supplement ingredients are classified by the US FDA as safe “nutrients” rather than untested “drugs”.

A Clinical Trial for AMD

• A Trial with lutein is underway in AMD patients at the NEI. Lutein/Zeaxanthin are carotenoids in fruits and vegetables that are concentrated in the retina (particularly macula) and may act as antioxidants.

• So far, lutein has not shown any protective effect in RP patients (Jacobson et al., 2002).

• However, a small experiment is now being conducted on human RP patients that could lead to a larger Trial to determine if there is any efficacy in dietary supplements of lutein alone for RP.

Current and Upcoming Clinical Trials

Now, let’s consider 2 treatments where very few or no photoreceptor cells remain alive.

Possible treatments here would include:• Donor Photoreceptor Cell and Stem Cell

Transplantation• The use of Electronic Prosthetic Devices

4) Photoreceptor Cell Transplantation Clinical Trial

• The idea of replacing dead photoreceptor cells with new, donor photoreceptors by transplantation has long been worked on.

• There is a small human Clinical Trial on transplantation of photoreceptor cells being conducted by Dr. Norman Radtke in the USA.

• It has proven the relatively safety of the technique. BUT, unfortunately, there has not been much good news from the study as to improvement in vision in the patients.

Thus, with only very modest positive results from both animal and human studies, it is difficult to see how this will be a viable treatment in the future.

Transplantation: Stem Cells

But, an exciting new area of research is in the study of Stem Cell transplantation.

• Stem cells are cells that have the potential of multiplying and developing into almost any type of cell in the body.

• Thus, theoretically, stem cells could be transplanted into the retinal space where photoreceptor cells have died and could develop and replace them.

• However, proper and complex biological signals have to be given to the stem cells such that they develop into mature, functional photoreceptor cells – instead of other cell types.

Stem Cell Definition • Stem cells are primitive, multipotential cells

that are most often associated with early embryonic tissues that have not yet matured into a specific cell and tissue type.

• Stem cell have two major characteristics:- they can multiple greatly in number and…,- with a proper set of signals, they can stop

multiplying and develop into one of many different adult cell types – such as photoreceptor cells.

Stem Cells - Quo Vadis?• Stem cell research is at a very early

stage of study. Few photoreceptor characteristics yet can be induced to develop in the cells.

• Safety issues are also very important but poorly studied to date.

• Thus, although the potential is great, much work yet needs to be done on stem cells before they can be used to replace dead photoreceptor cells in the retina.

Stem Cell Treatment in Humans• To date, no positive stem cell Clinical Trials have been

conducted on any form of retinal degeneration.• In spite of this, stem cell treatments are being given in many

countries to patients with many conditions including blindness. These cannot be considered to be safe and the effectiveness is highly questionable.

• Encouragement though comes from a press release a few days ago from the company StemCells Inc. They have used human stem cells in a rodent model of RP and found “preservation of the photoreceptors and stabilization of visual function” in the transplanted animals.

• Bottom Line: Great potential but more work needs to be done!

5) Electronic Prosthetic Devices for Sight Restoration

These fall into 2 categories:1)Brain (cortical) electronic implants2)Retinal implants – within the eye but

either in front or behind the retinaFor the retinal implants, there are many

different designs and surgical approaches from groups around the world.

Brain Prosthetic Devices

Three main groups of investigators have worked or are working on brain prosthetic devices that will have the potential to bypass the eye completely.

• One group has prematurely done human implants with poor results.

• A second group continues to do mainly basic lab work.

• The third group is doing excellent work in monkey and is planning a human clinical trial.

Cortical Implant

How Does the Retinal Prosthesis Work?

• The device uses electrical signals to bypass defective or dead photoreceptors and stimulate remaining viable, non-photoreceptor cells of the retina.

• Images come from an external video camera worn behind the patient’s glasses.

• The images are transmitted through a computer to electrodes (called an array) attached to the retina to reproduce the visual image in the brain.

Visual Prosthetic Devices

The Retinal Chip The Retinal Chip Electrode

Retinal Prosthesis Trials

Groups in many countries are developing retinal prostheses.

There are 4 groups around the world that have implanted human subjects with retinal prosthetic devices of different design.

• Optobionics Co. (Chicago, IL) – poor design such that it does not function well or at all.

• 2 excellent German companies – early stages of human testing – e.g., Retina Implant AG.

• Second Sight (Sylmar, CA) – with Dr. Mark Humayun, has already implanted 6 subjects in a Phase 1 study and now over 15 subjects in a Phase 2 Clinical Trial that recently started.

Phase 1 Patient UpdateChronic studies on human implants have been done

on an early electrode device with 16 electrodes -- from February 2002.

Six patients were implanted. There were NO device failures.

All subjects saw discrete visual images (called phosphenes) and could again perform visual spatial and motion tasks.

Mobility (walking and navigation) has been improved.

The remaining 5 patients use the device at home.

Retinal Prostheses – The Future

• Clinical trials continue. If successful, commercial models should soon become available for implant.

• Designs are improving to increase the number of electrodes touching the retina.

• Theoretically, a design with about 1,000 electrodes is needed to give reading ability and face recognition.

• The prosthetic device may be the best hope for restoring sight to severely affected RP and dry AMD patients.

This is NOT Vision of Terminator orGeordi from Star Trek !

In Conclusion for RP….Several Clinical Trials are in progress. Proof

of Principle for several other types of therapies has been established.

• For example, Gene Therapy work on a dog model of RP-LCA shows not only sight restoration but a long term, positive effect.

• Other basic work in the fields of gene therapy, stem cell research, pharmaceutical therapy, nutrition and electronic implants shows promise in current and for starting future Clinical Trials.

What Clinical Trials Can We Expect for RD in the Future?

Groups of investigators are now working on several of the Rare Diseases to move to Trials.

1) Leber Disease: Three groups have started Clinical Trials on Gene Replacement Therapy for a form of LCA. At least one other group also is planning an LCA Trial but with replacement of another gene whose mutation leads to a form of LCA.

Future Clinical Trials

2) Stargardt Disease: Dr. Rando Allikmets and coworkers are working on Gene Replacement Therapy of the mutated gene in a rodent model of Stargardt Disease. So far, the results are preliminary but good and, if finally positive for safety and efficacy, a Clinical Trial is planned.Other research groups are working on other types of therapy for Stargardt Disease.

Future Clinical Trials

3) Usher Disease: Research groups are working on both Usher 1 and Usher 3 to replace the mutated genes in the two conditions through Gene Therapy.

• Producing good animal models in both conditions has been a problem that is currently being worked on.

• Even Gene Therapy on the cochlea of the ear is being assessed as to possible restoration of hearing.

Future Clinical Trials

4) Choroideremia: Scientists are close to producing a good rodent model for Choroideremia. They will then use Gene Therapy to replace the mutated gene in the model. If successful, a human Clinical Trial can be planned.

5) Similar Gene Replacement is planned for some of the other Rare Diseases such as Retinoschisis.

What about AMD?CURRENT AMD TREATMENTS

Dry AMD – nutrition therapy. The antioxidants studied in the AREDS clinical trial of the NEI are available.

Wet AMD – several drugs now have been approved by government agencies in many countries to slow the growth of new, abnormal blood vessels. The best known is Lucentis.

Nutrition and AMD

AREDS Antioxidant TreatmentA Clinical Trial for antioxidants in treating AMD has

been completed by the National Eye Institute. It was called the Age-Related Eye Disease Study (AREDS).

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 only slow the course of the disease at a specific (mid) stage of AMD.

The antioxidants are available for sale although a physician should be consulted before using them.

Clinical Treatments – Wet AMD

• Lucentis – Genentech has an agent, “Lucentis” for wet AMD. Lucentis is an antibody that works against VEGF, a small protein that calls in the new, abnormal blood vessels. Lucentis actually improves vision.

• One of the problems with Lucentis though is that it must be injected into the eye.

• Also, there usually have to be repeat injections.• Another problem is the high cost but a similar

agent, Avastin, is available at much lower cost.

Wet AMD Clinical Trials –Gene Therapy Trial

• 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 and the safety results are very good.

• PEDF is a natural protein that has both antineovascular and neuron-survival properties. Thus, it could be used for both AMD and RP.

• If the results on wet AMD are positive, GenVec could then move on to the use of PEDF in RP and in dry AMD along with wet AMD.

AMD Clinical Trials - Nutrition• As I mentioned before, a Nutrition Trial

called AREDS2 with lutein is underway in AMD patients at the NEI in the USA.

• Lutein/Zeaxanthin are carotenoids, the colored pigments in fruits and vegetables, that are concentrated in the human retina – especially the macula. It is thought that they act as antioxidants and thus protect photoreceptor cells from oxidative damage.

• This Trial will take several years though to complete. Until then, take your mother’s advice and “Eat your fruits and vegetables!”

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, positive effect. Is this a “cure”?

• Other basic work in the fields of gene therapy, stem cell research, pharmaceutical therapy, nutrition and electronic implants shows promise with several Clinical Trials in progress.

• The retinal prosthetic device could be the best hope for sight restoration for patients with advanced retinal degeneration.

A Final Thought…..

• We can treat and, in some cases, maybe even cure diseases in many animal models of retinal degeneration.

• Many human Clinical Trials are starting such that treatments are coming soon.

• These are expensive and time consuming….. but who can put a price on restoring sight?