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Macular Degeneration Clinical Trials
Research on Dry Macular Degeneration:
- The Age-Related Eye Disease Study (AREDS)
The large, multicenter national collaborative study, directed at the Wilmer Institute by principal investigator, Dr. Susan Bressler has been ongoing since 1991. AREDS, sponsored by the National Eye Institute, includes a clinical trial that is complete and a natural history study that is continuing until 2006. The clinical trial was designed to determine if people at risk for the development of the advanced stages of age-related macular degeneration (AMD) could lower their risk for progression and associated vision loss by ingesting high dose, micronutrient supplements. The supplements studied included vitamins C, E, beta-carotene, zinc and copper. The AREDS demonstrated that individuals with intermediate levels of AMD or unilateral advanced disease had a 25% risk reduction in progression to advanced AMD and 19% risk reduction in rates of moderate vision loss over 5 years. Participants with early AMD did not derive benefit from using supplements over an average period of 6 years.
AREDS continues to follow the same individuals that participated in the clinical trial at least through 2006. The long-term safety of these antioxidants and minerals as well as further information on the natural history and progression of AMD will be collected during this phase of the study.
The Geographic Atrophy Study
Dr. Janet Sunness is investigating the natural history of geographic atrophy using scanning laser ophthalmoscopy, a sensitive technique in which retinal sensitivity can be mapped.
- The CAPT Study
Early signs of AMD, particularly drusen (deposits under the retina that appear as yellow spots), may be present on ocular examination prior to visual loss. Therefore, it is possible to identify individuals who are at risk of vision loss from advanced forms of AMD, but currently this does not help us, because there is no proven method of preventing vision loss in patients with dry AMD. Recently, it has been demonstrated that light laser photocoagulation can make drusen disappear, but it is not known if this helps to preserve vision. The Complications of Age-related Macular Degeneration Prevention Trial (CAPT) is a multicenter collaborative trial designed to determine if laser treatment in patients with high risk drusen results in better vision over the long term than observation.
Research on Wet Macular Degeneration (neovascular AMD):
There are several treatments aimed at destroying abnormal blood vessels once they occur and several aimed at neutralizing the stimuli for abnormal blood vessel growth with drugs.
- Laser photocoagulation
Laser photocoagulation involves brief exposures to tiny spots of intense laser light to the area occupied by abnormal blood vessels. The light energy is absorbed by pigment in RPE cells and converted to heat energy that cauterizes and destroys the abnormal blood vessels. However the adjacent RPE and retina are also destroyed resulting in a blind spot or "scotoma" in the area of the laser treatment. If the center of the macula, the fovea, is not involved, good vision can be maintained. The beneficial effect of laser was demonstrated in the Macular Photocoagulation Study (MPS), a large multicenter trial that was directed by physicians at the Wilmer Institute. Drs. Neil Bressler and Susan Bressler have continued to study the data obtained in the MPS and are providing many new insights concerning diagnosis, natural history, and management of patients with AMD.
- Photodynamic Therapy
In the past, only about 10% of patients with neovscular AMD qualified for conventional laser because often the abnormal blood vessels could not be localized or are located beneath the center of the macula and therefore treatment with laser would destroy the overlying retina and result in loss of central vision. A new option will at least double the number of treatable patients as well as increase the chance of avoiding visual loss.
Photodynamic therapy involves intravenous injection of a photosensitive dye, Visudyne, followed by irradiation of the macula with low intensity laser to activate the drug. The dye is concentrated in CNV and it is postulated that it absorbs the laser light and releases reactive oxygen intermediates that selectively damage the abnormal blood vessels while sparing the overlying retina. Because of encouraging results in animal models, a large multicenter clinical trial, the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP), was conducted under the direction of Dr. Neil Bressler. It demonstrated that photodynamic therapy decreases the likelihood of moderate levels of vision loss compared to placebo treatment. The TAP results were published in the October 1999 issue of Archives of Ophthalmology. This data formed the basis for the FDA approval of Visudyne in April, 2000. Another investigation, the Verteporfin in Photodynamic Therapy Trial (VIP) also directed by Dr. Neil Bressler, is underway to assess the effects of this treatment in patients with earlier forms of wet AMD. The Wilmer Photograph Reading Center, under the direction of Dr. Susan Bressler, has pioneered new methods of interpreting fluorescein angiograms in patients with wet AMD receiving photodynamic therapy. You may schedule a consultation relating to this treatment online or by phone at 410-955-3518.
- The Submacular Surgery Trial
An alternative to destroying abnormal blood vessels with laser or photodynamic therapy is surgical removal through a small opening in the retina. Pilot studies demonstrated that this approach is feasible. Therefore, since August 1997, the National Eye Institute (NEI) agreed to fund several multicenter, randomized clinical trials to evaluate the potential benefits and risks of submacular surgery for abnormal blood vessels, including cases caused by age-related macular degeneration. There are twenty-one clinical centers across the country that are currently enrolling and following patients including a center at Wilmer at Johns Hopkins.
Dr. Neil Bressler is the SST Chairman who directs the activities of the clinical centers, Dr. Barbara Hawkins directs the SST Coordinating Center that receives and analyzes data received from all of the participating centers, Dr. Susan Bressler directs the Photograph Reading Center that receives the retinal photographs taken of all SST patients.
- Limited Retinal Translocation
Another approach to dealing with patients who have CNV beneath the center of the macula is to move the retina with respect to the underlying CNV so that the CNV can be treated with laser without destroying the fovea. Original procedures to achieve this were difficult and fraught with complications. A simplified approach, Limited Retinal Translocation was developed by Dr. Eugene de Juan at the Wilmer Institute and initial results have been encouraging.
- Drug treatments to inhibit abnormal blood vessel growth
All of the treatments discussed above are aimed at eliminating abnormal blood vessels, but do not address the underlying stimuli for blood vessel growth. As a result, even when the blood vessels are successfully eliminated, they frequently come back and cause severe loss of vision. Therefore, there is strong motivation to develop drug treatments that inhibit the stimuli for blood vessel growth. This requires an understanding of the molecular signals involved which provide the targets for drug treatment (see above). One of the molecular signals involved is vascular endothelial growth factor (VEGF) which is a potent stimulator of blood vessel growth. There are several approaches to neutralize VEGF that are being explored; one is to use anti-sense oligonucleotides which decrease VEGF mRNA levels and thereby decrease VEGF levels. Dr. Julia Haller is principal investigator at the Wilmer Institute for a multicenter phase one study sponsored by Nexstar Pharmaceuticals which is investigating the safety of intravitreous injection of VEGF anti-sense oligonucleotides in patients with advanced neovascular AMD.
Angiostatic steroids are agents consisting of a glucocorticoid (anti-inflammatory steroid) coupled to heparin. They inhibit abnormal blood vessel growth primarily through inhibition of matrix metalloproteinases.
There are currently several additional drug studies that are in the planning phase and they should begin sometime over the next year - stay tuned.