Aptamers: Remember the Name
BY LEO SEMES, OD, FAAO
First of all, what are aptamers? They are DNA or RNA molecules (proteins) that bind selectively to other molecules. The "active" molecules (those selected on the basis of their ability to bind specific nucleic acids tightly), have many potential therapeutic uses.
The term "aptamers" has its origin in the Latin aptus, which means fitted, fastened, connected. Because of their ability to bind tightly to a vast array of molecular targets such as proteins, lipids, carbohydrates, or even viruses, aptamers represent a powerful tool in drug development. We can use them to alter abnormal membrane-bound proteins in disorders as diverse as cocaine addiction and epilepsy. In fact, experts have established an aptamer database at the Ellington Lab at the University of Texas (www.ellingtonlab.org).
Studying the Possibilities
So what does all of this have to do with the eye? As long ago as 1996, aptamers were shown to have potentially antagonistic effects on vascular endothelial growth factor (VEGF). This was the birth of anti-angiogenesis research for age-related macular degeneration (AMD) and diabetic retinopathy. The initial targets were vascular tumors investigated in mice.
Currently, the National Eye Institute is conducting clinical trials (Phase II and Phase III) to establish the safety and efficacy of intravitreal injections of aptamers in human patients who have exudative (neovascular) AMD. Injections are frequent: Every six weeks for 54 weeks. But, nearly immediate improvement in visual acuity establishes compliance for re-treatments. You can find study details, including eligibility requirements, at www.clinicaltrials.gov.
By 2030, the population over age 65 is estimated to reach 88 million. As the population ages and lifespans increase, as many as 6.3 million cases of vision loss from neovascular AMD will be among those. It becomes clear that while the neovascular form of AMD affects only about 10 percent of those who have AMD, it's responsible for up to 90 percent of severe vision loss attributable to AMD. Therefore, efforts to prevent increasing incidence of blindness are important.
Treatment options for the neovascular form of AMD were limited to photocoagulation until the advent of verteporfin (Visudyne, Novartis) in April 2000. This breakthrough allowed potential for treatment of subfoveal and other untreatable choroidal neovascular membranes.
Currently there is considerable interest in two aptamers for application to vascular proliferation in the eye:
1. Pegaptanib sodium (Macugen, EyeTech Pharmaceuticals)
2. Ranibizumab, rhuFab V2, (Lucentis, Genentech).
Each is a powerful VEGF inhibitor, which prevents the uptake of VEGF by endothelial cells, thus allowing maintenance of vascular integrity. Preliminary human data are promising.
Under the umbrella of anti-angiogenesis agents, angiostatic steroids, anecortave acetate (Retaane, Alcon), and the dexamethasone intravitreal insert (Posurdex, Oculex Pharmaceuticals) demonstrate a positive impact on diabetic macular edema. In conjunction with other treatments such as verteporfin or the aptamers, a synergistic effect occurs. This may mean fewer injections or more rapid re-establishment of vascular integrity.
Squalamine (Genaera Pharmaceuticals), a naturally occurring compound that is administered IV, has shown anti-angiogenic promise in early human trials.
A Bright Future?
Keep your eyes on the progress of aptamers to treat AMD as well as other disorders. As with most experimental matters, only time will tell where these molecules fit in to our practices.
Dr. Semes is an associate professor at the University of Alabama at Birmingham School of Optometry.