Summary: Researchers have identified rare genetic variants that can drive age-related macular degeneration. The findings could be key to developing new treatments that can slow the progression of AMD.
A National Eye Institute (NEI) study has identified rare genetic variants that may indicate one of the common mechanisms driving age-related macular degeneration (AMD), a common cause of vision loss in older adults.
The variants produce aberrant proteins that alter the stability of the membrane attack complex (MAC), which can drive a chronic inflammatory response in the retina. The results, published in the journal iScience, point to MAC as a potential therapeutic target to slow or prevent the development of AMD. NEI is part of the National Institutes of Health.
There are many known genetic variants that increase or decrease a person’s risk of developing AMD; However, the contribution of each of these genetic alterations to AMD is small.
To discover genetic variants—and proteins—with direct links to disease, Anand Swarup, PhD, head of NEI’s Neurobiology, Neurodegeneration and Repair Laboratory and the study’s lead author, Michael Klein, MD, undertook a collaboration. A leading AMD clinician at Oregon Health Sciences University (OHSU), Portland. Klein collected clinical data for hundreds of patients, as well as a large number of people with AMD.
As such, Klein and colleagues looked for families carrying very rare AMD-causing variants, where the effect of the gene variant is very strong, and where the variant directly affects protein structure and function. Such rare variants may reveal the underlying cause of the disease.
“Although we know of many genetic variants that affect AMD risk, only a few have directly pointed to protein changes that may lead to AMD,” Swarup said.
“By looking at large families with ultra-rare variants that closely track the disease across generations, we found two proteins that may be directly driving AMD pathology in affected patients. These proteins may be future drug targets.”
Although there are currently some treatments for vision loss in people with the wet form of AMD, there is no treatment for most patients and no cure for the disease.
As such, Klein and colleagues found that in four families, individuals with AMD had mutations in one of the two proteins that make up one end of the MAC: C8-alpha and C8-beta. The team found that variants of the four AMD families affect the ability of the C8 protein to stick to each other, which can change how MAC behaves in the eye’s retina.
The MAC forms a circular pore, closed at one end by the C8 protein; MAC pores allow the flow of ions through the outer membrane of the cell. This pore is the final step in the ‘complement cascade’, a part of the immune system that helps protect the body against pathogens.
Although scientists initially thought that MAC’s only function was to penetrate bacterial cell membranes and kill pathogens, more recent evidence shows that MAC plays a complex role in regulating inflammatory processes in tissues such as the retina.
Genetic data from NEI’s age-related eye disease study suggested a role for the C8 protein, as well as other proteins elevated in the complement cascade in AMD. Because the MAC is the final step in the complement cascade, variants affecting any complement protein can be funneled into altering MAC function.
Researchers believe that too much or too little stable MAC in the retina can lead to destructive inflammation, which in turn leads to AMD progression.
“Given that MAC is the end of the complement pathway of the immune system, and because there is a strong link between this rare form and the disease, we think that targeting it may be a more effective strategy for controlling AMD,” Swarup said. “With a small molecule drug, we may be able to control how strongly MAC drives inflammation and thereby slow the progression of AMD.”
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Original Research: The result will be displayed iScience