Abstract
Purpose :
Complement factor H (CFH) regulates alternative complement pathway activation. The non-canonical functions of CFH in the eye are also of interest, as recombinant human CFH (rhCFH; GEM103) is in development for the treatment of geographic atrophy in a genetically-defined age-related macular degeneration population. The hypothesis that rhCFH has anti-angiogenic activity in the eye was tested in a laser induced choroidal neovascularization (CNV) mouse model. To better understand the CNV phenotype reported in mice locally treated with polyethylene glycol (PEG;PMID:25088354), we tested the hypothesis that PEG treatment increases vascular endothelial growth factor (VEGF) production in retinal pigment epithelial (RPE) cells.
Methods :
In mice, CNV was induced using a 532nm laser. Three days post laser, both eyes of each animal were intravitreally (IVT) treated with either rhCFH, aflibercept (anti-VEGF; positive control) or vehicle. CNV severity was determined by fluorescein angiography (FA), optical coherence tomography (OCT) in live animals on days 12 & 15, and isolectin B4 (ISB4) staining intensity on day 15 retinal flatmounts. In the cell-based model, induced pluripotent stem cell derived (iPS) RPE were treated for 28 days with either of PEG or vehicle. Conditioned media and cell lysates were collected on days 0, 2, 14 and 28 for VEGF protein and mRNA assessment, respectively.
Results :
FA grades in rhCFH treated animals were decreased compared to vehicle at days 12 and 15 (P<0.0001) and were comparable to aflibercept treated mice (P>0.99). OCT-defined CNV area was also reduced in the rhCFH cohort at d12 (P<0.001) and 15 (P<0.05). A decrease in ISB4 staining intensity was observed in retinal flat mounts from rhCFH- vs PBS- treated mice (P=0.008). In cultured iPS RPE, an increase in VEGF mRNA and protein was observed following 2 or 4 weeks of treatment with PEG compared to vehicle (P<0.0001).
Conclusions :
CNV severity was significantly reduced in rhCFH-treated mice compared to PBS group while being similar to aflibercept-treated controls, as measured by FA grading, OCT area, and ISB4 staining. These results demonstrate that IVT administration of rhCFH can provide anti-angiogenic effects in the eye and would not pose an increased risk of CNV development. In contrast, treatment with PEGylated molecules, has a potential to enhance VEGF secretion from RPE cells.
This is a 2021 ARVO Annual Meeting abstract.