Academic Journal
CR2-fH, A Targeted Inhibitor of Alternative Complement Pathway Reduces Dry AMD-Like Phenotype in AMD Patient iPSC-derived RPE Cells.
| Τίτλος: | CR2-fH, A Targeted Inhibitor of Alternative Complement Pathway Reduces Dry AMD-Like Phenotype in AMD Patient iPSC-derived RPE Cells. |
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| Συγγραφείς: | Navneet S; Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States., Rohrer B; Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.; Ralph H. Johnson VA Medical Center, Division of Research, Charleston, South Carolina, United States. |
| Πηγή: | Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2026 Feb 02; Vol. 67 (2), pp. 9. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Association For Research In Vision And Ophthalmology (Arvo) Country of Publication: United States NLM ID: 7703701 Publication Model: Print Cited Medium: Internet ISSN: 1552-5783 (Electronic) Linking ISSN: 01460404 NLM ISO Abbreviation: Invest Ophthalmol Vis Sci Subsets: MEDLINE |
| Imprint Name(s): | Publication: Brookline Ma : Association For Research In Vision And Ophthalmology (Arvo) Original Publication: St. Louis, Mosby. |
| Ιατρικοί όροι (MeSH): | Induced Pluripotent Stem Cells*/metabolism , Retinal Pigment Epithelium*/metabolism , Retinal Pigment Epithelium*/pathology , Retinal Pigment Epithelium*/drug effects , Macular Degeneration*/pathology , Macular Degeneration*/metabolism , Macular Degeneration*/drug therapy , Complement Pathway, Alternative*/drug effects , Complement Factor H*/pharmacology , Receptors, Complement 3d*, Zonula Occludens-1 Protein/metabolism ; Humans ; Phenotype ; Cells, Cultured |
| Περίληψη: | Purpose: To investigate whether the alternative pathway (AP) of complement inhibition restores the epithelial phenotype and ameliorates dry AMD biomarkers in AMD patient induced pluripotent stem cell-derived RPE (iPSC-RPE) monolayers. Methods: iPSC-RPE monolayers were established from an AMD patient iPSC line; ARPE-19 monolayers were used for comparison. For AP inhibition, monolayers were treated with CR2-fH (fusion protein composed of the iC3b/C3d/C3dg-binding region of complement receptor type 2 [CR2] linked to the inhibitory domain of human factor H [fH]) either as a soluble protein or by adeno-associated virus transduction. Complement challenge used 5% complement competent human serum (CC-HS); 5% heat-inactivated serum served as a control. Membrane attack complex, apolipoprotein E, lipid deposits, and autophagy were analyzed by immunostaining. Morphology and integrity were evaluated in brightfield images, using zonula occludens-1 (ZO-1) immunostaining, followed by ImageJ analysis, and transepithelial electrical resistance measurements. Results: iPSC-RPE monolayers expressed the RPE-specific markers zonula occludens-1 and RPE65 and exhibited a honeycomb pattern, as confirmed by nearest-neighbor analysis. Exposure to CC-HS significantly reduced transepithelial electrical resistance; increased membrane attack complex, apolipoprotein E, and lipid deposits; and altered levels of autophagy-related proteins. Preincubation with soluble CR2-fH or CR2-fH expression reversed these features. Quantitatively, similar changes were observed in ARPE-19 cell monolayers. Conclusions: The AP inhibitor CR2-fH delivered either as a soluble protein or via gene therapy is efficacious in preventing serum-induced complement activation that led to monolayer disruption and AMD-like pathology in iPSC-RPE cells. These results contribute to existing data highlighting the importance of the AP of complement in dry AMD pathology and its potential role in AMD treatment. |
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| Grant Information: | I01 BX003050 United States BX BLRD VA; I01 RX000444 United States RX RRD VA; IK6 BX004858 United States BX BLRD VA; R01 EY030072 United States EY NEI NIH HHS |
| Substance Nomenclature: | 0 (Receptors, Complement 3d) 80295-65-4 (Complement Factor H) 0 (Zonula Occludens-1 Protein) |
| Entry Date(s): | Date Created: 20260203 Date Completed: 20260706 Latest Revision: 20260716 |
| Update Code: | 20260716 |
| PubMed Central ID: | PMC12882102 |
| DOI: | 10.1167/iovs.67.2.9 |
| PMID: | 41631752 |
| Βάση Δεδομένων: | MEDLINE |
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