Ali Adel Ne’ma Abdullah
Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment amongst the elderly, affecting 30-50 million worldwide. Although the treatment of wet AMD has come far, the treatment of dry AMD has had more limited success. This article will explore present treatment options for dry AMD, including the AREDS 2 formula and vitamin D supplementation, as well as consider what the future may hold, from complement system inhibitors to stem-cell-derived RPE cells to visual cycle modulators.
Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment amongst the elderly, affecting 30-50 million worldwide (1). It is divided into two major categories: ‘dry’ and ‘wet’. Dry AMD is characterised by drusen accumulation and progressive degeneration of the retinal pigment epithelium (RPE), thus leading to photoreceptor loss (2). Wet AMD is characterised by angiogenesis – the formation of a choroidal neovascular membrane that leads to the accumulation of subretinal fluid, haemorrhage, exudation, RPE detachment, and scarring (2).
The treatment of wet AMD has been revolutionised by the introduction of anti-angiogenic agents that block vascular endothelial growth factor (VEGF) in the retina, hence stifling angiogenesis. Visual prognosis changed from almost-certain blindness to more than 90% chance of three-line visual improvement after two years of treatment (3-4). However, the treatment of dry AMD has had more limited success. This article will explore present treatment options for dry AMD as well as consider what the future may hold.
At present, there is no known treatment for dry AMD able to reliably reverse the disease process and improve visual acuity (5). However, long-term prophylactic oral nutrient supplementation has been demonstrated to inhibit disease progression, namely the AREDS 2 formula (6). This is a combination of oral supplements consisting of vitamin C (500 mg), vitamin E (400 IU), lutein (10 mg), zeaxanthin (2 mg), zinc (80 mg) and copper (2 mg) (7). Many of these agents are antioxidants and have anti-inflammatory effects; inflammation is thought to play a central role in AMD progression given the substantial evidence implicating leukocytes, autoantibodies and complement activation in AMD (1). Whereas the original AREDS formula reduced the risk of progression to late AMD by 25% (8), the lutein/zeaxanthin component of AREDS 2 resulted in a 10% reduction in the risk of developing advanced AMD when compared to supplements (e.g. original AREDS formula) containing no lutein/zeaxanthin (9).
Similarly, there is some evidence that vitamin D supplementation can protect against the development of AMD. One cross-sectional study found that consistent vitamin D supplementation resulted in reduced early AMD risk in individuals who did not consume milk daily (10). Another study found that high vitamin D levels resulted in decreased odds of AMD development in women younger than 75 (11). Furthermore, a genetic study demonstrated that variants in the CYP24A1 gene (involved in vitamin D metabolism) were demonstrated to influence AMD risk (12). It is posited that these effects may be a result of vitamin D’s anti-inflammatory effects and clearance of amyloid beta (13).
Promising data have emerged from agents designed to inhibit the complement system, which is central to the progression to advanced dry AMD (14). Pegcetacoplan (APL-2), currently in phase III of trials, is a synthetic molecule that selectively inhibits C3, thus downregulating all three complement pathways (15). Data from phase II trials on 246 patients internationally demonstrated that at 12 months, monthly intravitreal APL-2 led to a 29% lower rate of AMD progression compared with sham (p=0.008) (16). However, no difference in best corrected visual acuity was noted between the two groups. Data from two 30-month phase III trials are awaited.
Mitochondrial dysfunction and oxidative stress have been posited to affect the progression of dry AMD (17). A novel drug, Elamipretide, currently in phase II trials is thought to reduce mitochondrial dysfunction and hence reduce progression of dry AMD (18). Phase I data demonstrated that at week 24 there was a statistically significant increase in best corrected visual acuity and low luminance visual acuity from baseline in groups that received elamipretide (18). Phase II data is awaited.
Another area of interest for future therapies are visual cycle modulators. These are medications which take part in the phototransduction cascade with the aim of reducing toxic byproduct production, thereby reducing inflammation and progression to advanced dry AMD. One example is ALK-001, a synthetic vitamin A product administered orally that takes part in phototransduction and generates toxic vitamin A dimers more slowly compared to ‘normal’ vitamin A (19). Theoretically, this should reduce advanced AMD progression, although this has not yet been demonstrated clinically; phase III results are awaited.
The use of stem cell therapy is an exciting prospect and has demonstrated some encouraging early results. In AMD patients, new RPE cells re-programmed from stem cells can be delivered to the subretinal space in a bid to maintain or improve the health of existing photoreceptors (20). Phase I and II studies of human-embryonic-cell-derived RPE cells transplanted into 9 AMD and 9 Stargardt patients led to 72% of patients showing increased subretinal pigment. Furthermore, improved visual function was seen at 1-year follow-up in nine eyes and stable vision in seven patients (20). Trials are ongoing. Some studies have also demonstrated that harvesting RPE cells from the peripheral retina of patients with AMD and transplanting them into the diseased macula can result in improvements in best corrected visual acuity when measured years later (21). However, this means potentially damaging the peripheral vision of the patient, a disadvantage that stem cell therapy does not share.
As inflammation has a central role in AMD progression, there have been trials to evaluate the role of anti-inflammatories in hindering AMD progression. Doxycycline is a well-known antibiotic that also has anti-inflammatory properties; a phase III trial is currently underway to evaluate the effect of daily 40mg doxycycline on AMD progression (22).
Dry AMD, once advanced, can be devastating. Current treatment models rely on long-term nutrient supplementation to prevent progression to advanced stages. However, numerous novel therapeutic options have shown great promise which could lead to a paradigm shift in AMD management in the near future. As the world ages and AMD incidence rises, further data on new endeavours is eagerly awaited.