Recent developments in the management of dry age-related macular degeneration

Abstract

Dry age-related macular degeneration (AMD), also called geographic atrophy, is characterized by the atrophy of outer retinal layers and retinal pigment epithelium (RPE) cells. Dry AMD accounts for 80% of all intermediate and advanced forms of the disease. Although vision loss is mainly due to the neovascular form (75%), dry AMD remains a challenge for ophthalmologists because of the lack of effective therapies. Actual management consists of lifestyle modification, vitamin supplements, and supportive measures in the advanced stages. The Age-Related Eye Disease Study demonstrated a statistically significant protective effect of dietary supplementation of antioxidants (vitamin C, vitamin E, beta-carotene, zinc, and copper) on dry AMD progression rate. It was also stated that the consumption of omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, has protective effects. Other antioxidants, vitamins, and minerals (such as crocetin, curcumin, and vitamins B9, B12, and B6) are under evaluation, but the results are still uncertain. New strategies aim to 1) reduce or block drusen formation, 2) reduce or eliminate inflammation, 3) lower the accumulation of toxic by-products from the visual cycle, 4) reduce or eliminate retinal oxidative stress, 5) improve choroidal perfusion, 6) replace/repair or regenerate lost RPE cells and photoreceptors with stem cell therapy, and 7) develop a target gene therapy.

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Advanced AMD takes two primary forms defined by whether neovascularization occurs; geographic atrophy (GA) (Buschini et al 2015) presents with regional RPE cell death without blood vessel intrusion, while exudative (i.e., wet) AMD does (Wong et al 2008). Over three-quarters of legal blindness results from wet AMD (Buschini et al 2015), but GA accounts for the vast majority of advanced AMD cases ). Unfortunately, no therapeutic options for dry AMD are available ).…”

“…Modifiable risk factors for dry AMD include smoking and obesity (Cheung and Eaton 2013). Smoking in particular has been associated with development and progression of AMD (Buschini et al 2015), and some evidence AMD risk has a dose-dependent relationship with smoking (Velilla et al 2013). Analysis of pooled datasets from the Beaver Dam Eye Study (Klein et al 1993), Rotterdam Study (Vingerling et al 1995), and Blue Mountains Eye Study (Mitchell et al 1995) suggests smokers have an approximately three-fold greater risk of AMD than patients who never smoked .…”

“…Because A2E is toxic to RPE and was thought to be a principal component of the autofluorescent material lipofuscin that appears in many AMD patients (Eldred 1995), several groups attempted to create therapeutics that could halt its formation and slow AMD progression. Given the well-defined functional and biochemical role of the visual cycle protein RPE-specific protein 65 kDa (RPE65) , inhibitors specific to RPE65 were developed to slow the rate of retinoid metabolism to slow A2E generation (Buschini et al 2015;Zhang et al 2015). Emixustat specifically binds RPE65 at its active site to inhibit its activity (Kubota et al 2014).…”

“…Unfortunately, the identification of both complement factor polymorphisms and complement factor proteins in AMD patients have not successfully facilitated the development of AMD therapeutics. The COMPLETE study ), which tested eculizumab, an anti-C5 antibody already approved for use in paroxysomal nocturnal hemoglobinuria (Buschini et al 2015), found complement cascade inhibition had no effect on GA progression . Similarly, the anti-C5 antibody LFG316 was ineffective in slowing or halting GA progression.…”

“…Similarly, the anti-C5 antibody LFG316 was ineffective in slowing or halting GA progression. Clinical trial data for another anti-C5 antibody, ARC1905, has not been published (Buschini et al 2015). A neutralizing antibody targeting complement factor D (CFD) in GA patients, lampalizumab, is now in phase III trials (Danis et al 2015).…”