{"doi":"10.1016/j.ymthe.2022.06.018","title":"Corneal fibrosis abrogation by a localized AAV-mediated inhibitor of differentiation 3 (Id3) gene therapy in rabbit eyes in vivo","abstract":"Previously we found that inhibitor of differentiation 3 (Id3) gene, a transcriptional repressor, efficiently inhibits corneal keratocyte differentiation to myofibroblasts in vitro. This study evaluated the potential of adeno-associated virus 5 (AAV5)-mediated Id3 gene therapy to treat corneal scarring using an established rabbit in vivo disease model. Corneal scarring/fibrosis in rabbit eyes was induced by alkali trauma, and 24 h thereafter corneas were administered with either balanced salt solution AAV5-naked vector, or AAV5-Id3 vector (n = 6/group) via an optimized reported method. Therapeutic effects of AAV5-Id3 gene therapy on corneal pathology and ocular health were evaluated with clinical, histological, and molecular techniques. Localized AAV5-Id3 gene therapy significantly inhibited corneal fibrosis/haze clinically from 2.7 to 0.7 on the Fantes scale in live animals (AAV5-naked versus AAV5-Id3; p < 0.001). Furthermore, AAV5-Id3 treatment significantly reduced profibrotic gene mRNA levels: α-smooth muscle actin (α-SMA) (2.8-fold; p < 0.001), fibronectin (3.2-fold; p < 0.001), collagen I (0.8-fold; p < 0.001), and collagen III (1.4-fold; p < 0.001), as well as protein levels of α-SMA (23.8%; p < 0.001) and collagens (1.8-fold; p < 0.001). The anti-fibrotic activity of AAV5-Id3 is attributed to reduced myofibroblast formation by disrupting the binding of E-box proteins to the promoter of α-SMA, a transforming growth factor-β signaling downstream target gene. In conclusion, these results indicate that localized AAV5-Id3 delivery in stroma caused no clinically relevant ocular symptoms or corneal cellular toxicity in the rabbit eyes.","journal":"Molecular Therapy","year":2022,"id":245289,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"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":880333,"name":"Michael K Fink","orcid":null,"position":1,"is_corresponding":false},{"id":336691,"name":"Duraisamy Kempuraj","orcid":"0000-0003-1148-8681","position":2,"is_corresponding":false},{"id":325814,"name":"Nishant R. Sinha","orcid":"0000-0001-8358-8433","position":3,"is_corresponding":false},{"id":325813,"name":"Lynn M. Martin","orcid":"0000-0001-9731-8071","position":4,"is_corresponding":false},{"id":880334,"name":"Landon M. Keele","orcid":null,"position":5,"is_corresponding":false},{"id":698695,"name":"Prashant R. Sinha","orcid":null,"position":6,"is_corresponding":false},{"id":503517,"name":"Elizabeth A. Giuliano","orcid":"0000-0002-9874-8935","position":7,"is_corresponding":false},{"id":880335,"name":"Nathan P. Hesemann","orcid":null,"position":8,"is_corresponding":false},{"id":336694,"name":"Sudhanshu P. Raikwar","orcid":"0000-0001-8549-8570","position":9,"is_corresponding":false},{"id":283036,"name":"Shyam S. Chaurasia","orcid":"0000-0001-8725-676X","position":10,"is_corresponding":false},{"id":325812,"name":"Rajiv R. Mohan","orcid":"0000-0002-1857-4200","position":11,"is_corresponding":false},{"id":698024,"name":"Suneel Gupta","orcid":"0000-0002-6141-3728","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T00:23:34.974895Z","pmid":"35780298","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":[]}