Mouse RPE-Choroids mRNA profiles of 4-week subretinal injection of AAV-GFP/PDGF-D
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE164972 | GEO | 2021/06/01
REPOSITORIES: GEO
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Project description:Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-VEGF biologics, there is a need for the novel development of less invasive treatments. Here, we developed a novel inhibitor of microtubule-associated End Binding 3 protein (EB3), herein termed EBIN, which blocked pathological Ca2+ signaling in activated endothelial cells and suppressed leakage of choroidal neovessels. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of AMD prevented neovascular leakage and neovascularization as effectively as intravitreal injection of anti-VEGF therapy. EBIN activated Meis2-Pax6 regenerative pathways in metabolic-active endothelial cells comprising neovessels and promoted tissue regeneration. Furthermore, single nuclei assay for transposase-accessible chromatin sequencing (sn-ATAC-seq) analysis demonstrated that in metabolic-active endothelial cells, the RPE, and photoreceptors, EBIN induced global increases in chromatin accessibility, the biological process progressively inhibited in AMD patients. These results suggest the unique therapeutic mode of action of this novel drug candidate, which can potentially promote regeneration of eye tissue by reversing the degenerative processes underlying both the neovascular and atrophic forms of AMD.
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