A recent study, carried out by researchers form the NIH’s National Eye Institute, has identified rare genetic variants that could explain the onset of age-related macular degeneration (AMD). The variants in question may lead to chronic inflammation in the retina and subsequent vision loss.
What is AMD?
AMD is one of the leading causes of vision loss in adults. Whilst the condition does not lead to total blindness, it causes blurring, black spots and vision loss in the central area, typically leaving peripheral vision unaffected. This can lead to trouble reading, driving and ultimately affects the lives of patients significantly.
The condition can be split into two sub-categories: wet and dry. Wet AMD occurs due to abnormal blood vessels that leak into the eye. It typically progresses very quickly. Dry AMD, on the other hand, has a much slower onset and is not linked to problems with blood vessels. There are some treatments to alleviate symptoms for those with the more severe wet form of the disease, but there are very limited treatment options for those with dry AMD. Moreover, there is no treatment that can completely cure the disease.
The condition is known to be somewhat hereditary, and genetic variants have previously been identified that explain some of the risk. However, these links are tenuous and the variants only marginally explain one’s risk of AMD. To find stronger links to the condition, Anand Swaroop and researchers from the National Eye Institute set out to find rare, but strongly associated, variants in family groups suffering from AMD.
A complex cascade
The researchers found that AMD patients from four families harboured rare variation within two genes: C8-alpha and C8-beta. The proteins encoded by these genes form part of the membrane attack complex (MAC), a component of the immune complement pathway. The complement pathway is part of a host’s innate immune system, activation of which leads to a cascade of protein cleavage that ultimately results in the formation of the MAC. The MAC forms a pore on the cell surface, causing lysis and ultimately cell death.
Figure 1: Image showing a side view of the membrane attack complex. The C8-alpha, -beta and -gamma subunits are highlighted. Adapted from Zelinger et al., 2023.
The mutations in C8-alpha and C8-beta prevent the MAC from forming correctly, leaving proteins unable to “stick” together. This impacts the stability of the complex, and it is believed that this disruption could lead to chronic inflammation in the retina and result in the vision loss observed in AMD.
Looking to the future
AMD can be an extremely distressing condition, made worse by the lack of effective treatments. The current study highlights the MAC as a therapeutic target, but the implications of these findings do not end there. Given that the formation of the MAC is the final step in the complement pathway, there is potential that any mutations within the cascade that affect the MAC’s stability could be implicated in the disease. Speaking of the significance of the work, lead author Anand Swaroop stated: “Given that MAC is the end of the immune system’s complement pathway, and because there’s such a strong link between these rare variants and disease, we think that targeting it may be a more effective strategy to control AMD. With a small molecule drug, we might be able to control how strongly MAC drives inflammation, and from there slow down progression of AMD.”