Description
Inflammation and fibrosis, which contribute to epithelial and endothelial dysfunction, are common pathological features of ocular diseases such as eye infections and age-related macular degeneration (AMD). Guanine nucleotide exchange factor H1 (GEF-H1) activates RhoA signalling to promote inflammatory and fibrotic responses (PMID: 35681428). Under physiological conditions, GEF-H1 expression is low but is upregulated in patients with ocular diseases (PMID: 20089843), making it a promising therapeutic target.
Using in silico approaches, we have developed peptide- and stapled peptide-based inhibitors (PMID: 35681428; doi.org/10.1101/2024.11.18.624118), as well as more recently identified small-molecule inhibitors targeting GEF-H1. The efficacy of these inhibitors was evaluated using in vitro and in vivo models of ocular disease. In Madin–Darby canine kidney (MDCK) epithelial cells overexpressing GEF-H1, the inhibitors attenuated NF-κB activation and reduced cell elongation. Similarly, they rescued LPS-induced morphological changes in primary human dermal microvascular endothelial cells (HDMECs).
Furthermore, the small molecule SM762 reduced choroidal neovascularization (CNV) lesions in a laser-induced CNV mouse model of AMD, as demonstrated by in vivo imaging, including fundoscopy, spectral-domain optical coherence tomography (SD-OCT), and fundus fluorescein angiography (FFA), as well as RPE–choroid flat-mount staining. In addition, SM762 decreased retinal vascular leakage in oxygen-induced retinopathy (OIR) and Arhgef18 Müller glia-specific knockout (Arhgef18 MG-KO) mouse models, as evidenced by FFA.
Taken together, these findings demonstrate that GEF-H1 inhibitors reduce subretinal neovascularization, fibrosis, and retinal vascular leakage, highlighting their therapeutic potential for ocular diseases associated with inflammation and fibrosis.
Lay Abstract
Many eye diseases, including age-related macular degeneration (AMD), lead to vision loss due to inflammation, scarring (fibrosis), and leakage from retinal blood vessels. These processes damage the cells that are essential for maintaining healthy vision. In our research, we focus on a protein called GEF-H1, which drives inflammatory and fibrotic responses. GEF-H1 is normally present at low levels but becomes more active in diseased eyes, making it a promising target for new treatments.
We developed a range of inhibitors that block GEF-H1 activity, including peptide-based and small-molecule compounds. These were tested in cell-based systems and mouse models that mimic human eye diseases. The inhibitors reduced inflammatory signalling, abnormal cell shape changes, and fibrosis, while improving the integrity of cell–cell junctions in retinal cells.
In particular, the small molecule SM762 showed strong protective effects. It reduced abnormal blood vessel growth in a model of AMD and decreased retinal vascular leakage in models of retinopathy.
Overall, our findings demonstrate that targeting GEF-H1 can reduce key disease processes and may offer a new therapeutic strategy for preserving vision in inflammatory and degenerative eye diseases.
| Lay Title | Targeting GEF-H1 to Treat Vision Loss in Eye Diseases |
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| Role | Postdoctoral Researcher |