The long-term goal of this project is to elucidate the role of complement in the pathogenesis of age-related macular degeneration (AMD), and to identify complement inhibitors that prevent disease progression. Though AMD has emerged as the predominant cause of blindness in elderly people, our knowledge of the underlying molecular processes and the availability of treatment options remain largely limited. Accumulating evidence suggests a crucial role for complement in the progression of AMD, and several genotyping studies have identified polymorphisms in the genes for C3, factor B, and factor H as important risk factors for development of this disease. However, the functional significance of these genetic findings remains unknown and need to be translated into a disease model. To elucidate the functions of complement in AMD on the protein level, we propose two specific aims.
In Aim 1 we perform a comprehensive in-depth analysis of complement proteins and their AMD- associated alloforms, by expressing them in mammalian cells and by isolating them from the plasma of AMD patients and healthy individuals. Sequence modifications will be determined by mass spectrometry, and the direct binding and functional activities of all individual proteins and their various combinations will be systematically tested in a panel of well-established biophysical and biochemical assays. Finally, the effect of these protein modifications on the structure and contact interface of the involved complement components will be analyzed by correlating our findings with available crystal structures, solution-based structural analysis, and computational models. The development and testing of AMD-targeting drugs is often hampered by restricted access to disease-relevant animal models and unfavorable pharmacokinetic profiles.
In Aim 2, we will utilize a clinically relevant monkey model of macular degeneration for testing the effect of complement inhibitors on disease progression. The peptidic inhibitor compstatin will be injected intravitreally and its effect on drusen formation will be evaluated. Furthermore, a sustained drug release in the eye as a result of intravitreal gel formation will be explored. The systematic assessment of the functional consequences for AMD-associated complement modifications and the testing of complement inhibition in a disease-relevant animal model will contribute to our understanding of AMD, as well as contribute to the development of more effective treatments.
The purpose of our study is to describe the contributions of complement activation and inhibition to the pathogenesis of age-related macular degeneration. This will be accomplished by systematically evaluating the effect of disease-related polymorphisms on the structure, binding, and function of complement components, and by assessing the impact of complement inhibitors on disease progression in a monkey model of macular degeneration. Thus, these studies will likely improve our capacity for describing and treating the disease.
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|Huang, Yijun; Reis, Edimara S; Knerr, Patrick J et al. (2014) Conjugation to albumin-binding molecule tags as a strategy to improve both efficacy and pharmacokinetic properties of the complement inhibitor compstatin. ChemMedChem 9:2223-6|
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|Garland, Donita L; Fernandez-Godino, Rosario; Kaur, Inderjeet et al. (2014) Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration. Hum Mol Genet 23:52-68|
|Sweigard, J Harry; Yanai, Ryoji; Gaissert, Philipp et al. (2014) The alternative complement pathway regulates pathological angiogenesis in the retina. FASEB J 28:3171-82|
|Risitano, Antonio M; Ricklin, Daniel; Huang, Yijun et al. (2014) Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123:2094-101|
|Oikonomopoulou, Katerina; DeAngelis, Robert A; Chen, Hui et al. (2013) Induction of complement C3a receptor responses by kallikrein-related peptidase 14. J Immunol 191:3858-66|
|Phieler, Julia; Garcia-Martin, Ruben; Lambris, John D et al. (2013) The role of the complement system in metabolic organs and metabolic diseases. Semin Immunol 25:47-53|
|Kourtzelis, Ioannis; Rafail, Stavros; DeAngelis, Robert A et al. (2013) Inhibition of biomaterial-induced complement activation attenuates the inflammatory host response to implantation. FASEB J 27:2768-76|
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