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Disease Overview
Geographic Atrophy (GA)
The macula is a small central section of the retina. It is responsible for providing the sharp vision that you need for reading, recognizing faces and driving.1 Age-related macular degeneration (AMD) is a leading cause of sight loss in people over the age of 65 in the United States and other Western countries.2 In the United States, more than 2 million people have the advanced forms of AMD.3
The early and intermediate stages of AMD usually are asymptomatic. However, an eyecare professional can detect early and intermediate AMD by examining the back of your eye.1 In a healthy middle-aged to elderly person, this examination may reveal a few tiny yellowish dots beneath the retina of one or both eyes. These tiny dots, called drusen, are deposits of protein and fat from damaged cells. The presence of a few, tiny drusen may do no harm. However, the presence of medium-sized drusen is a sign of early AMD.1
In people with intermediate AMD, the drusen have become large, and there are often changes in the pigmentation of the retina. As the drusen grow larger, some pigmented cells beneath the retina may break down and release their pigment. This change can be seen as dark spots (hyperpigmentation). Later, this pigment may be cleared away, leaving light-colored spots (hypopigmentation). At this stage, the patient may start noticing some vision loss, especially at night.1
There are 2 types of late AMD, “dry age-related macular degeneration” and “wet age-related macular degeneration.” In dry AMD (also called geographic atrophy [GA]), there is a gradual, patchy breakdown in the light-sensitive cells of the macula, as well as of the supporting cells beneath the macula. In “wet” AMD (also called exudative or neovascular AMD), abnormal new blood vessels grow beneath the retina. These new blood vessels may leak fluid.1
Geographic atrophy (GA) is a chronic, irreversible progressive condition that can cause permanent blind spots and/or blindness, and it affects more than 5 million people globally.14 While approximately 20% of all patients with GA have visual acuity of 20/200 (or worse), more than half of all patients with GA experience substantial decreases in everyday visual function,4,5 which may significantly affect their quality of life. As GA progresses, it can destroy the central fovea, which is the part of the macula responsible for fine vision making it particularly hard to see in low-light conditions, to recognize faces, and to read.6,7
Macula Overview6,7
The Complement System
The complement system is an important part of the immune system. It is a set of proteins that acts (sometimes in concert with antibodies and white blood cells) to kill germs, destroy unnecessary cells that need to be removed, and to clean up the debris afterward. Through these normal processes, the complement system promotes inflammation.8 The complement system consists of more than 50 proteins, which are normally present in an inactive state. However, they can be activated by a process called cleavage, which means that a portion is split off, usually through the action of an enzyme. When one of these complement proteins becomes activated, it can act as an enzyme to activate another kind of complement protein. This chain reaction, in which one kind of complement protein sequentially activates another, is called a cascade. Complement system activation can start from any of 3 pathways, all of which trigger the cascade reaction that leads to cell destruction and removal.8
The 3 complement pathways include the classical pathway, the lectin pathway, and the alternative pathway. The classical complement pathway is activated when an antibody binds to an antigen, which is usually a foreign protein, such as a protein on a bacterium or virus. In contrast, the lectin pathway activates complement when a protein called mannose-binding lectin, which is made in the liver, binds to a foreign carbohydrate, such as those found on the outside of many bacteria, viruses, protozoa, or fungi. The alternative complement pathway can be initiated by spontaneously activated complement attaching to pathogens or cells.8
All 3 pathways (classical, lectin, and alternative) eventually lead to the cleavage of complement factor C3 into C3a and C3b. The cleavage of C3 must occur for the complement system to have its intended effects on cells. C3a promotes inflammation, while C3b opsonizes (labels) cells so that they will be cleared from the system by white blood cells. C3b also activates C5 by splitting it into C5a and C5b. C5a promotes inflammation by attracting inflammatory cells. C5b also makes up part of the membrane attack complex (MAC), which kills cells by drilling a hole in their cell membrane, resulting in their lysis (rupture).8
In a healthy person, the complement system is under tight control, to keep an immune response from damaging the body itself. Genetic and environmental risk factors can cause the body to lose control over the complement system, resulting in an overactivation (dysregulation) of the immune system.8
Role of Complement in GA7-9
There are several reasons to believe that inappropriate activation of the complement system plays a role in causing GA. Several complement activation products (including C3, C5, CFH, and activated MAC) have been found in drusen.9 Furthermore, elevated levels of complement proteins have been found in specimens of eye tissue (vitreous, Bruch’s membrane, and choroid) from advanced AMD patients who died, as compared to tissue from healthy eyes.10 In addition, a reduced amount of complement inhibitors (eg, CD59 and MCP) has been found in eyes with GA.10
People who have an unusual version of the gene for one of the complement proteins (eg, complement factor H and complement factor I) may be at higher risk for the development of wet or dry AMD.10 Also, patients with AMD and GA have been shown to have elevated plasma levels of complement breakdown products.9
Complement hyperactivity leading to overactivation of the immune system and chronic inflammation in the macula is a contributing factor to GA.10 Dysregulation of the complement system is thought to play an important role in the development and progression of AMD to GA. Several potential triggers of the complement system in AMD have been described, including photo-oxidized A2E, amyloid beta, and oxidative stress.10-13Common Questions About Geographic Atrophy
AMD is the leading cause of severe vision loss in people over the age of 65 in the United States and other Western countries.3 It is characterized by a progressive degeneration of the central retina associated with central vision loss.2
Geographic atrophy is the “dry” form of the late stage of age-related macular degeneration (AMD).14 (You may also hear people refer to this condition as dry macular degeneration.) As the “dry” form of AMD progresses, cells in the light-sensitive portion of the macula, as well as the cells in the supporting structures (the retinal pigment epithelium and the choriocapillaris), start to die.14 This damage starts as small spots that grow into larger patches. As the light-sensitive cells in the macula die off, the person starts to lose vision in that eye. At first, the person may notice problems with reading or night vision.9 Eventually, the person will develop large, permanent blind spots (scotomata) in the center of the visual field. When the central fovea of the macula is involved, the person loses the ability to have sharp vision, such as that needed for reading and for recognizing faces.9
It’s important to note that while GA is commonly associated with people with visual acuity (VA) of 20/200 (or worse) caused by advanced AMD, more than half of all people who develop GA may experience substantial impairment of everyday visual function, which may significantly affect their quality of life.15
The early signs of AMD (drusen and pigmentary changes) are common in individuals over age 65 and precede the late stage forms.14
While the mechanisms that cause GA are not fully understood, the cause of GA is thought to be multifactorial, with numerous environmental and genetic risk factors. The dysregulation of the complement cascade, an important part of the body’s immune system, may play a pivotal role.9
GA is not a hereditary disease. Nevertheless, some genes do increase the risk that a person’s AMD will progress to GA.16
GA can be distinguished from other forms of dry AMD by ophthalmic exam and color fundus photography.14
Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) allow for noninvasive and rapid quantitative morphological assessment of GA in the clinical setting.14
So far, there is no approved treatment to prevent the onset and progression of GA.14 Several therapeutics are in various stages of clinical development.
The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens or of the body’s own cells that need to be removed. It also has proinflammatory capabilities.8
Complement activation is regulated to avoid its overactivation and to protect the body against inappropriate immune attack. When regulation is compromised, hyperactivation of the complement cascade can lead to inflammation and inappropriate cell destruction.8
Three pathways converge with the cleavage of complement factor C3, which induces inflammation and labels cells for phagocytosis (destruction by special white blood cells). The complement cascade continues with the cleavage of complement factor C5, which triggers cell death via phagocytosis, inflammation, and ultimately activation of the membrane attack complex (MAC) which causes damage and cell death.8
- Some complement activation products have been identified in drusen.9
- Samples of vitreous, Bruch’s membrane, and choroid from patients with advanced AMD have been shown to contain elevated levels of complement proteins.9
- Reduced levels of complement inhibitors (eg, CD59, MCP) have been found in eyes with GA.
- Patients with AMD also have signs of systemic complement activation.9
- Complement hyperactivity leading to overactivation of the immune system and chronic inflammation in the macula is a contributing factor to GA.10
- Dysregulation of the complement system is thought to play an important role in the development and progression of AMD to GA.9
Resources
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