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Inhibition of microfibrillar-associated protein 4 as a potential therapy targeting choroidal neovascularization in agerelated macular degeneration Bartosz Pilecki Institute of Molecular Medicine University of Southern Denmark 20.01.2016 Age-Related Macular Degeneration (AMD) Leading cause of blindness in people over 50 Affects > 30 million people worldwide Characterized by the loss of central vision due to the gradual deterioration of the macula (angiogenesis, inflammation, fibrosis) 2 AMD pathogenesis Photo receptors RPE BM Choroid RPE – retinal pigment epithelium BM – Bruchs membrane 3 Current treatment options Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors has become the standard treatment for wet AMD Anti-VEGF therapy does not affect inflammation and fibrosis and gives rise to side effects Laser-based therapies are the only solution for the subpopulations of non-responders to anti-VEGF monotherapy (15-25%) New treatment strategies are warranted Ref. Datamonitor Microfibrillar-associated protein 4 Extracellular matrix elastin-binding protein (Pilecki, Holm et al 2016) RGD-dependent integrin ligand Promotes integrin-dependent smooth muscle cell proliferation and macrophage chemotaxis (Schlosser, Pilecki et al 2016; Pilecki et al, 2015) Mediates endothelial cell adhesion and integrin signaling activation (Ormhøj et al, unpublished) Suggests a potential involvement of MFAP4 in AMD pathogenesis αMFAP4 actions in AMD Extracellular matrix MFAP4 Endothelial cells Inflammatory cells Integrin receptor Neovascularization and inflammation of the eye MFAP4 MFAP4 blocking antibody 6 Choroidal neovascularization (CNV) rodent model CNV is the hallmark lesion of advanced AMD Similar to the CNV that occurs in human ocular disease Laser-induced injury Administration of αVEGF, αMFAP4 and IgG control at days 0 and 7 Endpoints analyzed at days 7 and 14 after surgery 7 Figure adapted from Singh-SR, Gene Therapy, 2009 αMFAP4 reduces lesion size at day 7, in contrast to αVEGF Trend for superiority of high dose αMFAP4 8 αMFAP4 andαVEGF have similar effects in reduction of lesion size at day 14 Trend for superiority of high doseαMFAP4 9 αMFAP4 andαVEGF have similar effects in reduction of inflammation at day 14 Trend for superiority of high doseαMFAP4 10 Summary: No adverse tolerability, assessed by electroretinography, physical defects, gross observations of ocular irritation and histological observation of retinal tissue Treatment with αMFAP4, particularly at higher dose, was able to consistently reduce lesion size and density and limit leukocyte infiltration into the burn area Effects of αMFAP4 were already detectable 7 days after lesion formation αMFAP4-based therapy can potentially be used to treat the pathological angiogenesis and inflammation in AMD 11 Perspectives: Efficacy of prophylactic αMFAP4 treatment Combinational αMFAP4/αVEGF treatment In vitro MFAP4/anti-MFAP4 effects on ocular angiogenesis, vessel permeability, cell proliferation and cytokine secretion 12 Acknowledgements: School of Medicine, University of Nottingham, UK: Zoe Blackley Nikita Ved David Bates UFFE KARIN CHARLOTTE BARTEK KIMMIE 13 GRITH ANDERS KIRSTEN VICKI SEBASTIA N LINE CHRISTI NE SOFIE ANDERS ANITA