The Role of Complement Risk Alleles and Tick-Over in the Formation of Sub-RPE Deposits and Response to Anti-Complement Drugs in AMD
Age-related macular degeneration (AMD) affects more than 2 million individuals in the US and it will reach 3 million by 2020. Current therapies can improve vision only in some patients with advanced AMD; unfortunately, there is no effective therapy that prevents disease progression in patients with early disease or genetic predisposition. My aim is to create a cell-based model to discover the primary mechanisms activated by the combination of aging and genetic variants in complement genes in patients with early AMD; so that drugs can be designed to stop these mechanisms before they lead to major damage and legal blindness.
Age-related macular degeneration (AMD) affects more than 2 million individuals in the United States, and this number will reach 3 million by 2020. Current therapies can improve vision only in some patients with advanced AMD; unfortunately, there is no effective therapy that prevents disease progression in patients with early disease or genetic predisposition. The first clinical sign of AMD is the formation of drusen, which appear as yellow spots in the fundus of the eye and whose mechanism of formation is unclear. Drugs that prevent drusen progression could cure AMD However, to develop these drugs, we need to understand how drusen form, and how aging and genes participate in this process. The most important genes associated with AMD belong to the complement system, which is an important part of the immune system that attacks bacteria. Mutations in these genes along with age, may cause the complement system to attack your own retinal cells inappropriately, which results in drusen formation. In our lab, we use retinal cells carrying typical mutations in complement genes to mimic the formation of drusen in a dish. This model helps to advance our understanding of why people with complement defects develop AMD, which is key for the design of drugs that can be administered as soon as drusen is detected, preventing disease progression to blindness.
About the Researcher
I have studied the retinal pigment epithelium (RPE) function and pathology during the last seven years, in an attempt to understand the primary mechanisms that trigger basal deposit formation in macular degenerations. Using primary murine and human RPE cells, I have created in vitro models of the early-onset type of macular generation associated with the EFEMP1 gene, in order to demonstrate that the formation of sub-RPE deposits occurs in response to local activation of complement system by the RPE. I further developed a human cell-based model that recapitulates the RPE/Bruch's membrane pathology at the early stage of AMD using engineered human RPE cells that carry the mutation in EFEMP1. These studies point to the activation of the complement system via tick-over as a potential therapeutic target for AMD.
I grew up in a little town of Spain, where going to the University was a rare privilege. My parents supported and nourished my passion for science, even though the rate of unemployment for scientists was and is huge in Spain. I was told many times that I had chosen the wrong field; that I would not get rich by doing science. However, I feel wealthy because I have been given the opportunity to make a change in other peoples' lives. I came to the United States pursuing my dream, leaving my family and friends behind, and this award is the proof that I made the right decision. When I learned that I had got the BrightFocus award, I was actually chatting with my parents by videoconference, so I could share the great news with them immediately and see the pride in their faces. I am extremely grateful to the BrightFocus Foundation and the donors for this opportunity. This award will have an enormous impact in my research career. As a young investigator, this award provides me with independence, and critical financial support for personnel. Most importantly, this grant gives me the chance to continue my research on understanding the mechanisms underlying AMD and looking for therapeutic targets that lead to the design of effective treatments.
First published on: August 10, 2018
Last modified on: May 27, 2020