I Can See You Clearly Now: Use of Aptamer-Based Therapeutics to Treat Age-Related Macular Degeneration

What do you enjoy looking at the most? A grinning baby? A beautiful sunset? A cherished loved one? What if you learned that you would no longer be able look at those ever again? For the nearly two million people who are diagnosed with some form of age-related macular degeneration (AMD) each year in the U.S., this is a brutally cold reality (Brown et al., 2005).

Two forms of AMD exist (American Macular Degeneration Foundation, 2016). The first form, known as the “dry” version, constitutes the majority of AMD cases. The dry version is characterized by the thinning of the macula (the portion of the retina responsible for the fine details we can see) and by the buildup of drusen (yellow clumps). The second form, known as the “wet” version, only makes up 10% of AMD cases. The growth of new blood vessels that grow into the layer between the white of the eye and the retina causes the wet version. Being very weak, the blood vessels tend to leak behind the macula, which causes the macula to distort and impair vision. In both types, the peripheral vision remains intact, but the central vision becomes compromised and blurry.

Although the wet version is not as prevalent as the dry form, several treatments do exist. One subset of these vision-saving drugs are based on aptamers (Drolet, Green, Gold, & Janjic, 2016), similar to molecules that underlie SomaLogic’s unique protein measurement technology.

Several decades ago, vascular endothelial growth factor (VEGF) emerged as a key player for eye disorders, such as AMD. VEGF was responsible for not only the leakage of blood vessels, but also inducing the growth of new ones, which had been observed in the wet form of AMD. Treatment of AMD with aptamer-based drugs became attractive for several reasons. For administering a drug into the eye, only a small amount of the aptamer would be required.  The addition of the drug to the eye has a reduced chance of triggering an immune response. Also, the retention of the drug in the eye typically is much longer than elsewhere in the body. With an aging population with deteriorating eyesight, demand for an effective AMD drug definitely existed.

As evidence mounted for VEGF being an attractive target for AMD, concern also grew that inhibiting all the different forms of VEGF could lead to undesirable side effects. Therefore, a group of researchers at a biotech company called NeXagen (which later became NeXstar, and was subsequently acquired by Gilead) focused on a short and relatively abundant version of VEGF, so-called VEGF-165, which seemed to be a target for inhibition without the same range of side effects.

After a decade involving development, optimization, and clinical trials, the aptamer inhibitor for VEGF-165 (referred to now as Macugen) became the first aptamer-based therapeutic to receive FDA approval. This drug indeed improved the vision of many wet AMD sufferers. In its first year, the sales of Macugen were ~$185 million dollars (U.S). But, as often happened, Macugen soon had competition from compounds that targeted all versions of VEGF, and which outperformed Macugen.

During the time that Macugen was being developed, the scientists also began development of an inhibitor towards another protein of interest, platelet-derived growth factor (PDGF). They had learned that the new blood vessels in the eye become less reactive to VEGF inhibition as they mature. Thus, inhibiting both VEGF and PDGF may reduce the spread of slightly more mature blood vessels. In AMD animal models, combining Macugen and a PDGF inhibitor worked better than the use of either one alone.

The Ophthotech Corporation took this new PDGF inhibitor (now called Fovista) through several phases of clinical testing. In a Phase 1 study, the combined use of Fovista and Lucentis (a Macugen competitor drug aimed at VEGF) significantly increased the number of participants whose vision improved compared to individuals who received only Lucentis. This study also yielded a first for AMD treatment: The new problematic blood vessels began to disappear for all the participants who received the combination therapy. Further positive results in Phase 2 studies prompted Ophthotech  to move forward with Phase 3 clinical studies.

PDGF and VEGF are not the only targets that have had new aptamers inhibitors created. A potent aptamer-based inhibitor has been made to Complement component 5 (C5), another protein implicated in AMD. This aptamer (called Zimura by Ophthotech) is showing promise in early clinical trials.

Decades ago, AMD patients did not have a lot of options for how to preserve their sight. With more drugs coming onto the market and new technology being developed, the potential of maintaining clearer vision becomes greater. Also, the reality for AMD patients becomes rosier. They have a better chance of prolonging their ability to clearly witness the beauty around them and see the smiles of happy loved ones.


American Macular Degeneration Foundation. (2016). About Macular Degeneration. Retrieved on August 19, 2016 from https://www.macular.org/about-macular-degeneration.

Brown, G. C., Brown, M. M., Sharma, S., Stein, J. D., Roth, Z., Campanella, J., & Beauchamp, G. R. (2005). The burden of age-related macular degeneration: a value-based medicine analysis. Trans Am Ophthalmol Soc, 103, 173-184; discussion 184-176.

Drolet, D. W., Green, L. S., Gold, L., & Janjic, N. (2016). Fit for the Eye: Aptamers in Ocular Disorders. Nucleic Acid Ther, 26(3), 127-146. doi:10.1089/nat.2015.0573