COMMENTARY

Age-Related Macular Degeneration: 5 Things to Know

William C. Ou; Charles C. Wykoff, MD, PhD

Disclosures

December 14, 2018

2. Age Is Not the Only Risk Factor for AMD

The prevalence of AMD increases with age. However, there are a number of additional modifiable and nonmodifiable risk factors for AMD development and progression.

Perhaps the most well-characterized modifiable risk factor is smoking, which is linked to both incidence and progression of AMD.[17,18,19] Smoking cessation should be strongly encouraged in all patients.

Diet and nutrient supplementation also appear to play a role in AMD prevention. It has been hypothesized that oxidative stress contributes to the pathogenesis of AMD, which has led many physicians to recommend consumption of antioxidant-rich foods such as leafy green vegetables.[20] Additionally, the prospective Age-Related Eye Disease Study (AREDS) and AREDS2 reported that supplementation with a specific formulation of antioxidants and minerals reduces the likelihood of progression from intermediate AMD to wet AMD by approximately 25%.[21,22]

In regard to nonmodifiable factors, a number of genetic polymorphisms have been linked to AMD, with the most well established being the complement factor H (CFH) locus. CFH is a regulator of the complement cascade, a component of the innate immune system that is believed to play a role in the pathogenesis of AMD. Individuals homozygous for a certain CFH polymorphism have a sevenfold increased risk of developing AMD.[23] Despite an awareness that one's genetic profile may contribute to AMD development and progression, routine genetic testing to determine the risk for AMD development is not standard practice at this time.

3. Geographic Atrophy Remains a Tremendous Area of Unmet Need

Advanced dry AMD, or geographic atrophy, is also capable of causing significant vision loss and impairment. Although geographic atrophy may coexist with CNV, it is not driven by VEGF, and therefore available therapies for wet AMD are ineffective. In fact, there is no proven treatment for geographic atrophy.

To date, the focus in this realm has largely been on modulation of the complement cascade. As alluded to above, inappropriate activation of complement in AMD is believed to mediate an inflammatory response that ultimately leads to cell death and atrophy.[24]

Many pharmaceutical agents targeting complement components have been developed, but thus far data from trials of these agents have been mixed. The failures of eculizumab, a complement C5 inhibitor,[25] and lampalizumab,[26] a selective inhibitor of complement factor D, have highlighted the reality that pharmacologic manipulation of the complement cascade is substantially more complex than inhibition of VEGF in wet AMD. Nevertheless, several promising complement-modulating agents remain in development, such as APL-2, an inhibitor of complement C3 cleavage, which met its primary endpoint of reducing geographic atrophy growth in the phase 2 FILLY trial.[27] This pharmaceutical has entered phase 3 studies.[28]

Although current therapeutic approaches for geographic atrophy primarily aim to slow the disease, the ultimate hope is that innovations such as stem cell–based therapies may provide an avenue for tissue regeneration or replacement. These approaches remain in early stages of development, however.[29]

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