Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach
Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI’s MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/7/3621 |
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| author | Morgane Blanot Ricardo Pedro Casaroli-Marano Jordi Mondéjar-Medrano Thaïs Sallén Esther Ramírez Cristina Segú-Vergés Laura Artigas |
| author_facet | Morgane Blanot Ricardo Pedro Casaroli-Marano Jordi Mondéjar-Medrano Thaïs Sallén Esther Ramírez Cristina Segú-Vergés Laura Artigas |
| author_sort | Morgane Blanot |
| collection | DOAJ |
| description | Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI’s MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors’ predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI’s MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood–retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition. |
| first_indexed | 2024-04-24T10:44:14Z |
| format | Article |
| id | doaj.art-307e137bb4174450b2ae162bec607ba5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:44:14Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-307e137bb4174450b2ae162bec607ba52024-04-12T13:19:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01257362110.3390/ijms25073621Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling ApproachMorgane Blanot0Ricardo Pedro Casaroli-Marano1Jordi Mondéjar-Medrano2Thaïs Sallén3Esther Ramírez4Cristina Segú-Vergés5Laura Artigas6Anaxomics Biotech S.L., 08007 Barcelona, SpainDepartment of Surgery (FMCS), Universitat de Barcelona, 08007 Barcelona, SpainBayer Hispania S.L., 08970 Sant Joan Despí, SpainBayer Hispania S.L., 08970 Sant Joan Despí, SpainAnaxomics Biotech S.L., 08007 Barcelona, SpainAnaxomics Biotech S.L., 08007 Barcelona, SpainAnaxomics Biotech S.L., 08007 Barcelona, SpainIntravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI’s MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors’ predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI’s MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood–retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition.https://www.mdpi.com/1422-0067/25/7/3621intravitreal aflibercept injectionsystems biologyvascular endothelial growth factorinflammationoxidative stressangiogenesis |
| spellingShingle | Morgane Blanot Ricardo Pedro Casaroli-Marano Jordi Mondéjar-Medrano Thaïs Sallén Esther Ramírez Cristina Segú-Vergés Laura Artigas Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach International Journal of Molecular Sciences intravitreal aflibercept injection systems biology vascular endothelial growth factor inflammation oxidative stress angiogenesis |
| title | Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach |
| title_full | Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach |
| title_fullStr | Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach |
| title_full_unstemmed | Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach |
| title_short | Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach |
| title_sort | aflibercept off target effects in diabetic macular edema an in silico modeling approach |
| topic | intravitreal aflibercept injection systems biology vascular endothelial growth factor inflammation oxidative stress angiogenesis |
| url | https://www.mdpi.com/1422-0067/25/7/3621 |
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