Present and Future Treatments for Retinal Degenerative Diseases: An Overview Gerald J. Chader Doheny Retina Institute USC Medical School Los Angeles, CA

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 suipplements might help some. Similarly, no effective treatment other than nutritional supplements 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 Treatments All treatments will not benefit all RP or AMD patients. Thus, 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 First, let’s consider three possible treatments where the patient yet has viable photoreceptor cells in their retina. These are: 1) Gene Therapy 2) Pharmaceutical Therapy 3) Nutritional Therapy

1) Gene Replacement Therapy Gene Therapy is the replacement of a defective (mutated) gene such that an important protein (e.g., enzyme) is present again in the cell. With this, the photoreceptors function better and live longer. In Gene Therapy, a modified viral vehicle (called a “vector”) is used to bring a normal, replacement gene into the cell. Since it is estimated that about half of the RD gene mutations are known for humans, we have the theoretical possibility of replacing many of these genes in the future and helping many 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, 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 in LCA have begun in London and Philadelphia. Other trials are planned around the world. No results on safety or efficacy have yet been reported but the initial results seem to be good.

2 ) Pharmaceutical Therapy Pharmaceutical 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 natural 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.

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 R.I. for updates! Neurotech Clinical Trial

3) Nutrition: For RP The 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 oral use of vitamin A has been the only treatment available to date to RP patients. BUT – due to the small effect in only some patients, some Ophthalmologists do not recommend the treatment.

Another Trial for Vitamins A & E To better test the possible helpful effects of Vitamin A on RP and to determine whatever vitamin E does (good or bad), another trial was started. It is now complete although the results have not been announced. The trial tested vitamins A and E alone or in combination to assess their effects on the progression of RP. Keep in touch with R.I. for news!

Antioxidants slow photoreceptor cell death in RP Recently, Prof. Theo van Veen reported that the use of antioxidants was very effective in slowing the disease course in a rodent model of RP. Using sophisticated techniques, he showed that severe oxidative damage occurred in the retinal photoreceptor cells preceding cell death in the model of RP. BUT, supplementation with a specific cocktail of antioxidants greatly reduced the oxidative damage and slowed photoreceptor cell death – both rods and cones. Importantly, the supplements were given by mouth to the animals. No injection is needed.

Upcoming Nutritional 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. BUT, 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”.