Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage
Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αVβ3/5/6 ligand present in the extracellular matrix. Single...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
5 March 2025
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| In: |
Molecular therapy
Year: 2025, Jahrgang: 33, Heft: 3, Pages: 1048-1072 |
| ISSN: | 1525-0024 |
| DOI: | 10.1016/j.ymthe.2025.01.038 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.ymthe.2025.01.038 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1525001625000425 
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| Verfasserangaben: | Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V. Benest, Amy P. Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L. Andersen, Dorle Hennig, Jonas H. Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T. Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S. Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S. Laursen, Gregers R. Andersen, Uffe Holmskov, David O. Bates, and Grith L. Sorensen |
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| 245 | 1 | 0 | |a Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage |c Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V. Benest, Amy P. Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L. Andersen, Dorle Hennig, Jonas H. Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T. Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S. Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S. Laursen, Gregers R. Andersen, Uffe Holmskov, David O. Bates, and Grith L. Sorensen |
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| 520 | |a Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αVβ3/5/6 ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell types in close proximity to vascular endothelial cells, including choroidal vascular mural cells, retinal astrocytes, and Müller cells. Binding of the anti-MFAP4 antibody, hAS0326, makes MFAP4 inaccessible for integrin receptor interaction, and thereby hAS0326 blocked endothelial cell motility in vitro. Intravitreal hAS0326 inhibited retinal vascular lesion area and neovessel volume in a laser-induced choroidal neovascularization mouse model, vascular permeability in streptozotocin-induced retinopathy, and vascular leakage area in a chronic non-human primate model of DL-2-aminoadipic acid-induced retinopathy. One dose of hAS0326 showed duration of efficacy of at least 12 weeks in the latter model. Moreover, hAS0326 treatment significantly enriched Gene Ontology terms involving reduction of integrin binding. Our data suggest that hAS0326 constitutes a promising treatment of neovascularization and vascular leakage in retinal diseases. | ||
| 650 | 4 | |a diabetic macular edema | |
| 650 | 4 | |a DME | |
| 650 | 4 | |a extracellular matrix | |
| 650 | 4 | |a glycoprotein | |
| 650 | 4 | |a integrin | |
| 650 | 4 | |a MFAP4 | |
| 650 | 4 | |a microfibrillar-associated protein 4 | |
| 650 | 4 | |a nAMD | |
| 650 | 4 | |a neovascular age-related macular degeneration | |
| 650 | 4 | |a therapeutic antibody | |
| 650 | 4 | |a vascular leakage | |
| 650 | 4 | |a x-ray crystallography | |
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