Insights into the modulation of age-related macular degeneration: Molecular and systems-level perspectives

In developed countries, age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population. Understanding of its pathogenesis is limited and the number of patients is predicted to continue rising. AMD is classified into two main forms: dry and neovascular AMD (dAMD and nAMD, respectively). Dry AMD is the most prevalent form (80-90%) of AMD cases and has no approved treatment in Europe. Neovascular AMD (10-20% of AMD cases) is treated with frequent intravitreal injections with medicines intervening with vascular growth, but unfortunately, treatment is not curative and only a portion of patients respond to the current treatments. Increasing number of patients will create a challenge to the healthcare system and will underline the need to find either novel, more durable treatment options or ways to intervene with the disease course already in its early stages and prevent or delay disease escalation. Thus, understanding factors behind development of the disease and treatment response is important. Currently, the information on the factors influencing the progression and incidence of the disease is fragmented and does not provide sufficient tools for individualised patient care. In this study, our aim was to create a deeper understanding of factors modulating development and progression of AMD. By analysing data from nAMD patients treated in Kuopio University Hospital, we were able to identify that heavy smoking and high BMI increase the probability for earlier emergence of nAMD, while the presence of intraretinal fluid (IRF) resulted in a fast-progressing disease. We also observed a relationship between IRF and the appearance of subretinal drusenoid deposits, HRF and retinal atrophy. Thus, we observed that IRF plays a role in the escalation of the disease towards non-reversible changes in retinal anatomy. By analysing serum RNA profile of nAMD patients, we observed that the RNA profile of nAMD patients corresponds with anatomical changes observed in the retinal fluid compartments as well as atrophic changes in retinal layers. Especially, thioredoxin-related transmembrane protein 4 (TMX4) was identified as a protein whose function during AMD development should be evaluated more in detail in the future. Moreover, long-term follow-up of women living in the North Savo region revealed the role of systemic components during AMD progression and showed that people with long-term corticosteroid and immunosuppressant use have an increased risk for developing AMD. Our results highlight that further research on how systemic components behind corticosteroid and immunosuppressant use modulate AMD progression is needed. Thus, results of this study build more evidence from factors modulating AMD development and progression. Giving guidance to future analyses in a situation where comprehensive understanding from factors influencing AMD progression and development are lacking.