{"doi":"10.1167/tvst.11.9.19","title":"SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy","abstract":null,"journal":"Translational Vision Science &amp; Technology","year":2022,"id":649995,"datarank":0.5289540786924243,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"self_citation_contribution":0.5289540786924243,"citation_network_contribution":0.0,"self_endowment_contribution":0.5289540786924243,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":808905,"name":"Hui Chen","orcid":"0000-0002-0048-0193","position":1,"is_corresponding":false},{"id":998009,"name":"Meghah Vuppalapaty","orcid":null,"position":2,"is_corresponding":false},{"id":1694728,"name":"Elizabeth Whisler","orcid":null,"position":3,"is_corresponding":false},{"id":1694729,"name":"Kelsey Ronarda Logas","orcid":null,"position":4,"is_corresponding":false},{"id":1197079,"name":"Parthasarathy Sampathkumar","orcid":null,"position":5,"is_corresponding":false},{"id":1694730,"name":"Russell Byron Fletcher","orcid":null,"position":6,"is_corresponding":false},{"id":998010,"name":"Asmiti Sura","orcid":null,"position":7,"is_corresponding":false},{"id":1196738,"name":"Nicholas Suen","orcid":"0000-0002-6388-024X","position":8,"is_corresponding":false},{"id":1274659,"name":"Suhani Gupta","orcid":null,"position":9,"is_corresponding":false},{"id":521868,"name":"Tom Lopez","orcid":"0000-0002-8256-9668","position":10,"is_corresponding":false},{"id":1197081,"name":"Jay Ye","orcid":null,"position":11,"is_corresponding":false},{"id":455289,"name":"Shengjiang Tu","orcid":"0000-0003-3616-3242","position":12,"is_corresponding":false},{"id":1694731,"name":"Menaka Bolaki","orcid":null,"position":13,"is_corresponding":false},{"id":1626169,"name":"Wen-Chen Yeh","orcid":null,"position":14,"is_corresponding":false},{"id":429967,"name":"Yang Li","orcid":"0000-0002-5882-2301","position":15,"is_corresponding":false},{"id":1626170,"name":"Sung-Jin Lee","orcid":null,"position":16,"is_corresponding":false},{"id":1108945,"name":"Huy Nguyen","orcid":"0000-0002-8856-477X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy","abstract":"Purpose: There remains a high unmet need for therapies with new mechanisms of action to achieve reperfusion of ischemic retina in diabetic retinopathy. We examined whether a novel frizzled class receptor 4 (FZD4) agonist could promote regeneration of functional blood vessels in animal models of retinopathy. Methods: We developed a novel Norrin mimetic (SZN-413-p) targeting FZD4 and low-density lipoprotein receptor-related protein 5 (LRP5) and examined its effect on retinal and brain endothelial cells in vitro. SZN-413-p was subsequently humanized, resulting in the therapeutic candidate SZN-413, and was examined in animal models of retinopathy. In an oxygen-induced retinopathy mouse model, avascular and neovascularization areas were measured. Furthermore, in a vascular endothelial growth factor (VEGF)-induced retinal vascular leakage rabbit model, the impact on vascular leakage by SZN-413 was examined by measuring fluorescein leakage. Results: SZN-413-p induced Wnt/β-catenin signaling and upregulated blood-brain barrier/blood-retina barrier gene expressions in endothelial cells. In the oxygen-induced retinopathy mouse model, SZN-413-p and SZN-413 significantly reduced the neovascularization area size (P < 0.001) to a level comparable to, or better than the positive control aflibercept. Both agonists also showed a reduction in avascular area size compared to vehicle (P < 0.001) and aflibercept groups (P < 0.05 and P < 0.01 for SZN-413-p and SZN-413, respectively). In the VEGF-induced retinal vascular leakage rabbit model, SZN-413 reduced retinal vascular leakage by ∼80%, compared to the vehicle-treated group (P < 0.01). Conclusions: Reduction of neovascular tufts and avascular areas and of VEGF-driven retinal vascular leakage suggests that SZN-413 can simultaneously address retinal non-perfusion and vascular leakage. Translational Relevance: FZD4 signaling modulation by SZN-413 is a novel mechanism of action that can offer a new therapeutic strategy for diabetic retinopathy.","is_dataset_classified":null,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36149648","pmcid":"PMC9520515","openalex_id":"https://openalex.org/W4296808853","authors":[],"funders":[],"total_grants":0,"fwci":5.095,"citation_percentile":0.96688079,"influential_citations":0,"citation_trend":[{"year":2022,"count":2},{"year":2023,"count":4},{"year":2024,"count":12},{"year":2025,"count":8},{"year":2026,"count":7}],"oa_status":"gold","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1167/tvst.11.9.19","host_type":"journal"},{"url":"https://doi.org/10.1167/tvst.11.9.19","host_type":"publisher"},{"url":"https://tvst.arvojournals.org/article.aspx?articleid=2783673","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36149648","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9520515","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9520515","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9520515?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Retinal Diseases and Treatments","Cell Adhesion Molecules Research","Wnt/β-catenin signaling in development and cancer","Animals","Diabetes Mellitus","Diabetic Retinopathy","Disease Models, Animal","Endothelial Cells","Fluoresceins","Low Density Lipoprotein Receptor-Related Protein-5","Mice","Neovascularization, Pathologic","Oxygen","Rabbits","Vascular Endothelial Growth Factor A","beta Catenin"],"mesh_terms":["Animals","Diabetes Mellitus","Diabetic Retinopathy","Disease Models, Animal","Fluoresceins","Neovascularization, Pathologic","Oxygen","Rabbits","Vascular Endothelial Growth Factor A","Endothelial Cells","beta Catenin","Mice","Low Density Lipoprotein Receptor-Related Protein-5"],"keywords":["Diabetic retinopathy","Agonist","Retinal","Neovascularization","Retinopathy","Medicine","Retina","Wnt signaling pathway","Vascular permeability","Endocrinology","Internal medicine","Pharmacology","Receptor","Signal transduction","Ophthalmology","Biology","Angiogenesis","Cell biology","Neuroscience","Diabetes mellitus"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T04:39:33.240645Z","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":[]}