A Spotlight On One Of The Most Prevalent Eye Diseases

It’s easy to take our ability to see for granted. On a day-to-day basis, we rely on vision to process information and to navigate the world without giving it a second thought. For the millions of people affected by eye disease, vision loss, and blindness, impaired vision is a daily reality that changes how they interact with the world.

Age-related macular degeneration (AMD) is one of the most common eye diseases, affecting 13.4 million people in the United States and is the leading cause of vision loss in those over the age of 50. In this WEEKLY, we get out our funduscope to peer into the science behind this devastating disease of the retina.

Term of the Week: Retina

The retina is composed of light-sensitive nervous tissue which forms the thin membranous lining in the rear two-thirds of the eyeball. Its job is to convert images from the optical system of the eye into electrical impulses that are sent along the optic nerve to the brain.

Human_eye_cross-sectional_view_grayscale

The anatomy of the eye (The National Eye Institute).

Considered an extension of the brain, the retina is formed embryonically from brain tissue and connects directly to the brain via the optic nerve. The macula is the small central area of the retina and is the area of acute central vision.

AMD Explained

AMD is caused by damage to the macula, resulting in blurred vision progressing to vision loss in the center of the patient’s field of vision. The exact cause of macular damage is not known, but AMD is associated with the buildup of proteins and lipids just beneath the retina. These deposits are referred to as “drusen,” and are a normal part of aging but are increased in AMD. As the disease progresses, vision loss increases. Advanced AMD is classified into two types: neovascular (wet) or atrophic (dry).

The Wet

In wet AMD, macular damage is caused by an infiltration of blood vessels into the retina. These abnormal vessels often leak fluid and blood, causing damage. Wet AMD progresses quickly, and can lead to rapid loss of central vision if not treated. About 10% of advanced AMD cases are wet.

FDA-approved treatments available include Lucentis (Genentech; South San Francisco) and Eylea (Regeneron Pharmaceuticals, Tarrytown, NY). Both work by “mopping up” excess vascular endothelial growth factor (VEGF), which causes the excess abnormal blood vessel growth. Lucentis is a monoclonal antibody specific for VEGF. Eyelea is a fusion protein consisting of the VEGF-receptor fused to the constant region of an antibody for stability. Similar to a mAb, this construct is highly specific for VEGF and binds to the abnormal blood vessels before it binds to any other blood vessel receptors found in the eye. These VEGF-blocking treatments have proven to be very effective at stopping the progression of AMD, but they do not cure the disease.

Ophthotech (New York, NY) is developing a new treatment, Fovista, for wet AMD that targets platelet-derived growth factor (PDGF), a second growth factor critical for the formation and maintenance of new blood vessels. Currently in Phase III clinical studies, Fovista in combination with a VEGF inhibitor appears to be more effective than the VEGF inhibitor alone. Fovista is a DNA-aptamer drug, meaning that it is a short DNA sequence selected for its ability to bind and inhibit PDGF.

The Dry

Dry AMD involves a gradual breakdown in the light-sensitive cells of the macula. The dry variety progresses much more slowly than wet and accounts for about 90% of AMD cases. Currently, there are no treatments available for dry AMD, although some studies have suggested that taking high doses of antioxidants including C and E vitamins, copper, zinc, and beta-carotene may slow progression.

Inflammation and the activation of the complement pathway is associated with drusen buildup and dry AMD progression. There are a number of drugs in clinical development targeting the complement pathway:

  • Roche’s (Basel, Switzerland) Phase III clinical studies on lampalizumab. Lampalizumab is a Fab, or antigen-binding fragment of a monoclonal antibody, and targets complement factor D.
  • Apellis Pharmaceuticals’s (Crestwood, KY) peptide APL-2 in Phase II development.
  • Novartis’s (Basel, Switzerland) mAb Tesidolumab/LFG316 in Phase II.
  • Ophthotech’s (Princeton, NJ) DNA aptamer Zimura in Phase IIa.

The Genetically Based

Most cases of macular degeneration are associated with aging. However, juvenile forms, such as Stargadt disease, are associated with several different genes and symptoms of blurred central vision which start to occur in adolescence, usually progressing to legal blindness. Also referred to as macular dystrophy, all varieties of juvenile macular degeneration are an inherited disease with no current cure.

As the rate of the aging population grows, projections point to 20 million suffering from AMD by 2020. The need to discover therapies for wet and dry AMD is in high demand. As the pipeline evolves, we look to drug development to treat our treasured sense of sight.

 

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