{"doi":"10.1101/2024.07.28.604986","title":"12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice","abstract":"ABSTRACT Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":488788,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":563213,"name":"Charanya Muralidharan","orcid":"0000-0002-4909-7056","position":1,"is_corresponding":false},{"id":347804,"name":"Jacob R. Enriquez","orcid":"0000-0002-5858-6759","position":2,"is_corresponding":false},{"id":1178150,"name":"Jiayi E. Wang","orcid":null,"position":3,"is_corresponding":false},{"id":1258268,"name":"Kerim B. Kaylan","orcid":"0000-0001-7147-0614","position":4,"is_corresponding":false},{"id":1178151,"name":"Advaita Chakraborty","orcid":null,"position":5,"is_corresponding":false},{"id":659646,"name":"Sarida Pratuangtham","orcid":"0000-0002-1105-1001","position":6,"is_corresponding":false},{"id":1178152,"name":"Kayla Figatner","orcid":null,"position":7,"is_corresponding":false},{"id":501847,"name":"Jennifer B. Nelson","orcid":null,"position":8,"is_corresponding":false},{"id":762196,"name":"Sarah C. May","orcid":"0000-0003-4567-7480","position":9,"is_corresponding":false},{"id":439667,"name":"Jerry L. Nadler","orcid":"0000-0002-4200-6991","position":10,"is_corresponding":false},{"id":605304,"name":"Matthew B. Boxer","orcid":null,"position":11,"is_corresponding":false},{"id":268309,"name":"David J. Maloney","orcid":"0000-0002-5607-4178","position":12,"is_corresponding":false},{"id":244408,"name":"Sarah A. Tersey","orcid":"0000-0003-0667-2361","position":13,"is_corresponding":false},{"id":244409,"name":"Raghavendra G. Mirmira","orcid":"0000-0002-5013-6075","position":14,"is_corresponding":false},{"id":877624,"name":"Titli Nargis","orcid":"0009-0005-2823-0873","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:08:19.655720Z","pmid":"39091839","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":[]}