Complement-Based Immunotherapy for Macular Degeneration

Genetic studies have shown that people who are lacking in two proteins (called CFHR1 and CFHR3) of the immune system are at a decreased risk of developing age-related macular degeneration (AMD), the most common cause of vision impairment in the aging population of industrial countries. The immunological function of these proteins is not known. We will shed light on the mechanism of CFHR1 and CFHR3 action in the human body. For this research, we will generate an array of protein tools, designed such that some of them will eventually be developed into novel therapeutics for the inhibition of overactive inflammation in the human eye during AMD pathology.

AMD is a multifactorial disease associated with polymorphisms of complement factor genes and immune system activation. Deletion of the potential complement regulator genes CFHR3/1 goes along with a decreased risk of AMD, although the functions of the CFHR proteins remain unclear. Dr. Pauly`s group aims to investigate the role of CFHR1 and 3 antibody-dependent inhibitions on human complement. The group will further determine their function in the degenerative processes of AMD. Effective anti-CFHR1 and 3 therapies may include monoclonal antibodies developed and used in combination as a treatment option for inflammatory processes in AMD pathology.

In light of recent genome-wide association studies suggesting an important role of the complement system in the pathogenicity of AMD, several groups around the world have started to develop therapeutic approaches directly targeting complement components. In contrast, this project will provide unique and comprehensive insights into the functional role of the complement system via its regulators CFHR1/3. The revolutionary concept behind the strategy of Dr. Pauly`s group is that they will be able to up- and/or down-regulate this important pathway of the immune system without completely over- or deactivating it. The anti-CFHR1 and 3 antibodies generated and characterized in the course of this project will be applied for further research in different AMD animal models and prospective clinical studies. Moreover, their approach will help to uncover how genetic alterations may result in protective or harmful inflammatory processes.

By 2020, around 196 million people worldwide will suffer from AMD in all its diverse pathological manifestations. Of them, half will suffer from the so far untreatable atrophic form known as geographic atrophy. Thus, in theory, these almost 100 million patients stand to benefit the most from this project. However, recent studies have revealed that AMD pathology is so heterogeneous that a one-size-fits-all drug may never be found. For individualized therapies targeting such a multifactorial disease, it will be necessary to provide a “drug toolbox” for different proteins, which can be used for AMD diagnosis and/or therapy. Dr. Pauly`s research aims to contribute to this toolbox by generating tools that identify, measure, and manipulate key components of the inflammatory processes underlying AMD pathology.