{"doi":"10.1101/2022.03.30.486275","title":"PRMT5 is a therapeutic target in choroidal neovascularization","abstract":"Abstract Ocular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients’ non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-κB), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-κB. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-κB activity and the expression of its target genes, such as tumor necrosis factor α (TNF-α) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G1/S-phase in a dose-dependent manner in these cells. Thus, we provide the first evidence that inhibition of PRMT5 impedes angiogenesis in ocular endothelial cells, suggesting PRMT5 as a potential therapeutic target to ameliorate ocular neovascularization.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":306304,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":465315,"name":"Matthew Martin","orcid":"0000-0002-3961-5809","position":1,"is_corresponding":false},{"id":292114,"name":"Mengyao Sun","orcid":"0000-0002-9682-4586","position":2,"is_corresponding":false},{"id":338868,"name":"Kamakshi Sishtla","orcid":"0000-0002-1525-0155","position":3,"is_corresponding":false},{"id":195572,"name":"Nathan R. Jensen","orcid":null,"position":4,"is_corresponding":false},{"id":465314,"name":"Aishat Motolani","orcid":"0000-0002-5909-3446","position":5,"is_corresponding":false},{"id":419228,"name":"Xiaoping Qi","orcid":null,"position":6,"is_corresponding":false},{"id":295847,"name":"Michael E. Boulton","orcid":"0000-0002-0796-1766","position":7,"is_corresponding":false},{"id":469755,"name":"Lakshmi Prabhu","orcid":"0000-0002-2093-1115","position":8,"is_corresponding":false},{"id":292117,"name":"Tao Lu","orcid":"0000-0002-0013-4987","position":9,"is_corresponding":false},{"id":338870,"name":"Timothy W. Corson","orcid":"0000-0002-1402-7875","position":10,"is_corresponding":false},{"id":764547,"name":"Anbukkarasi Muniyandi","orcid":"0000-0002-4684-5258","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:48.984902Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}