{"doi":"10.1167/iovs.64.10.25","title":"AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a Mouse Model","abstract":"Purpose: Complement dysregulation in the eye has been implicated in the pathogenesis of age-related macular degeneration (AMD), and genetic variants of complement factor H (CFH) are strongly associated with AMD risk. We therefore aimed to untangle the role of CFH and its splice variant, factor H-like 1 (FHL-1), in ocular complement regulation derived from local versus circulating sources. We assessed the therapeutic efficacy of adeno-associated viruses (AAVs) expressing human FHL-1 and a truncated version of CFH (tCFH), which retains the functional N- and C-terminal ends of the CFH protein, in restoring the alternative complement pathway in Cfh-/- mouse eyes and plasma. Methods: Using Cfh-/- mice as a model of complement dysregulation, AAV vectors expressing tCFH or FHL-1 were injected subretinally or via tail vein, and the efficacy of the constructs was evaluated. Results: Following subretinal injections, tCFH expression rescued factor B (FB) retention in the eye, but FHL-1 expression did not. By contrast, both constructs restored FB detection in plasma following tail vein injections. Both tCFH and FHL-1 proteins accumulated in the posterior eyecup from the circulation following liver transduction; however, neither was able to significantly regulate local ocular complement. Conclusions: Our findings demonstrate that the C-terminus of human CFH is necessary for complement regulation in the murine eye. Furthermore, exogenous CFH must be synthesized locally to maximize complement regulation in the retina. These findings establish a critical foundation for development of CFH augmentation-based gene therapies for the eye.","journal":"Investigative Ophthalmology & Visual Science","year":2023,"id":360960,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":650119,"name":"Mikael Klingeborn","orcid":"0000-0003-2907-0371","position":1,"is_corresponding":false},{"id":1113156,"name":"Una Kelly","orcid":null,"position":2,"is_corresponding":false},{"id":566922,"name":"Lindsey A. Chew","orcid":"0000-0002-2040-1579","position":3,"is_corresponding":false},{"id":265976,"name":"Aravind Asokan","orcid":"0000-0001-5563-4877","position":4,"is_corresponding":false},{"id":324731,"name":"Garth Devlin","orcid":null,"position":5,"is_corresponding":false},{"id":1112757,"name":"Sharon Smith","orcid":"0000-0002-4101-4287","position":6,"is_corresponding":false},{"id":1113157,"name":"Lisa R. Keyes","orcid":null,"position":7,"is_corresponding":false},{"id":1113158,"name":"Adrian M. Timmers","orcid":null,"position":8,"is_corresponding":false},{"id":959862,"name":"Abraham Scaria","orcid":null,"position":9,"is_corresponding":false},{"id":851572,"name":"Catherine Bowes Rickman","orcid":"0000-0002-8555-9596","position":10,"is_corresponding":false},{"id":1113155,"name":"Daniel Grigsby","orcid":null,"position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T01:14:06.433417Z","pmid":"37471073","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":[]}