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Injectable anti-inflammatory supramolecular nanofiber hydrogel to promote ranibizumab therapy in age-related macular degeneration treatment

ABSTRACT: The exact pathogenesis of age-related macular degeneration (AMD) leading to visual impairment and severe vision loss is still unclear, and the currently available treatments are often unsatisfactory. Previous studies have demonstrated both oxidative stress-induced damage to the retinal pigment epithelium (RPE) and inflammation are involved in AMD. Although anti-vascular endothelial growth factor (VEGF) therapy can impair the growth of new blood vessels, serious side effects were found with repeated monthly intravitreal injections. Here, an injectable hydrogel based on an anti-inflammatory betamethasone phosphate (BetP) drug (BetP-Gel) was designed to enable long-term efficient release of ranibizumab (RZB) to attenuate choroidal neovascularization (CNV), reduce vascular leakage and inhibit vascular proliferation in the retina, which significantly increased the effective treatment time of ranibizumab compared with that in clinical practice. In particular, experimental data with in vitro and in vivo models revealed that BetP-Gel itself had a strong ability to scavenge intracellular reactive oxygen species (ROS) and reduce tumour necrosis factor-α (TNF-α) as well as interleukin (IL-1β, IL-6, IL-8, and IL-18) inflammatory cytokines, inhibiting ROS- and inflammation-induced retinal damage. Altogether, the carrier-free system (RZB@BetP-Gel) could serve as a novel antioxidant, anti-inflammatory and anti-neovascularization agent for the treatment of AMD.

ORGANISM(S): Mus musculus

PROVIDER: GSE165702 | GEO | 2024/01/28

REPOSITORIES: GEO

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Project description:Background Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Recent studies have demonstrated strong genetic associations between AMD and single nucleotide polymorphisms (SNPs) within genes such as CFH and HTRA1. However, we have identified monozygotic twins discordant for AMD phenotypes (one with disease, the other without disease), suggesting that an epigenetic mechanism may also contribute to the pathogenesis of AMD. Methods We identified two twin pairs with phenotypic discordance of AMD. We obtained genomic DNA from their peripheral blood mononuclear cells (PBMCs) and subjected them to DNA methylation-chip analysis (MeDIP-chip) that profiled genome-wide DNA methylation patterns on promoters of all genes and microRNAs. We next utilized the Methyl-Profiler DNA methylation assays to detect the methylation status of selected promoters. Flow cytometry and quantitative real-time PCR were used to detect the expression of the selected gene in peripheral blood cells, as well as in retinal and choroidal tissues of AMD patients and non-AMD controls. Results Our MeDIP-chip analysis identified 256 genes with hypo-methylated promoters only in the twins with AMD and 744 genes with hyper-methylated promoters only in the twins with AMD. Importantly, the promoter region of IL17RC was associated with hypo-methylated CpG sites only in the twins with AMD but not in the twins without AMD. We also found the association of the hypo-methylated IL17RC promoter with AMD in 7 pairs of siblings with discordant AMD pathology (P=0.003), as well as an independent patient cohort (95 neovascular wet and 107 geographic atrophy dry AMD patients as well as 96 non-AMD controls (95% CI, 0.01-0.10, P=9.8x10-8 for wet AMD vs. control; 95% CI, 0.05-0.32, P=2.2x10-5 for dry AMD vs. control)). Interestingly, we did not find an association between the levels of methylation on the IL17RC promoter with the previously identified genetic risk alleles in CFH, HTRA1, and ARMS2. We demonstrated an elevated expression of the IL-17RC protein in CD14+ monocytes in the peripheral blood of AMD patients as compared to non-AMD controls. These IL-17RC+ monocytes have elevated expression of CXCR1, CXCR2, and CXCR4. In addition, IL17RC was expressed only in the retinal and choroidal tissues from AMD patients but not from age-matched controls. Conclusions We show an association of the hypo-methylated IL17RC promoter with AMD, which resulted in the elevated expression of IL-17RC in peripheral blood cells as well as the retinal and choroidal tissues of AMD patients. Our study suggests that the hypo-methylated IL17RC promoter and elevated expression of IL-17RC can potentially serve as biomarkers for the diagnosis of AMD, while IL-17RC can be a new therapeutic target for AMD. In addition, our results strongly suggest an epigenetic control mechanism of AMD pathogenesis. The Affymetrix MOE430 2.0 GeneChip was used to detect gene expression patterns within the whole eye of C57B/6 normal mice.

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Injectable anti-inflammatory supramolecular nanofiber hydrogel to promote ranibizumab therapy in age-related macular degeneration treatment

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