Can Proteins Block Inflammation in the Eye and Ameliorate AMD-Pathology?

Diana Pauly, PhD
University Hospital Regensburg (Regensburg, Germany)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2017
Disease:
Macular Degeneration
Award Amount:
$160,000
Grant Reference ID:
M2015186
Award Type:
Standard
Award Region:
International
Diana Pauly, PhD

Complement-Based Immunotherapy for Macular Degeneration

Summary

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 for 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.

Details

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 deactivate 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 at contributing to this toolbox by generating tools that identify, measure and manipulate key components of the inflammatory processes underlying AMD pathology.

About the Researcher

Diana Pauly, PhD, is currently employed as a non-tenured scientist at the Department of Ophthalmology of the University Hospital in Regensburg (Germany). She has long-term research interests in specific stereochemical interference with biological and immunological processes. She earned her diploma in human biology focusing on immunology at the University of Greifswald (Germany). In her doctoral work (PhD) at the University of Potsdam (Germany), she developed high-affinity antibodies against plant and bacterial toxins relevant to bioterrorism. After a brief postdoctoral period concluding these projects at the Robert-Koch Institute (Berlin, Germany), she started her own group at the University of Regensburg (Germany). To maximize her impact, she decided to focus on her core training as an immunologist and applied her expertise to novel immunotherapies against degenerative eye diseases. Currently, her team is working on understanding what causes an altered homeostasis in the complement cascade in AMD. Their goal is to elucidate key proteins in AMD pathology to develop antibody therapies to prevent or subsequently reduce the morbidity associated with AMD. Startup funds from the University of Regensburg, the ProRetina Foundation and Maloch Foundation, as well as a scholarship from the Humboldt Foundation, were used to generate the preliminary data for this work.



“You`re passionate about research, but you can`t help me. Why?” This was one of the last questions of a good friend of mine, who died unexpectedly from Creuzfeldt Jakob disease. It became a significant moment in my life, where I decided to change the focus of my research from bioterrorism to a more relevant topic in human diseases.

Several months later, in summer 2012, I came into contact with research into eye diseases when I attended the Retina International World Congress” in Hamburg (Germany). These two days were unbelievably affecting. For the first time, I experienced the strong connection between scientists and patients. I met very well-educated people whose lives consisted of reading and thinking. They were affected by the late stages of a so-far untreatable disease, “dry” age-related macular degeneration (also known as geographic atrophy), and their whole purpose of life was destroyed. I met also a fantastic trumpet player who did not lose his love for life, although retinitis pigmentosa is stealing him every year more of his visual field. However, I also learned about amazing therapy developments and options. I felt that therapeutic antibodies and my knowledge about these molecules could be used effectively in the development of a “drug-toolbox” for retinal degeneration."

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