{"doi":"10.1016/j.celrep.2025.116419","title":"AAVs targeting human carbonic anhydrase IV enhance gene delivery to the brain","abstract":"Gene therapies using natural adeno-associated virus (AAV) serotypes have restricted applications, particularly in the brain, due to their poor targeting and resulting safety concerns. Directed evolution has identified brain-enhanced engineered AAV capsids for various model organisms, but inter-species differences challenge their translation. Here, we engineer AAVs to target human carbonic anhydrase IV (CA-IV), a recently identified blood-brain barrier transcytosis receptor with several favorable properties. We perform in vitro on-column selection of an AAV library to exclude capsids that do not target human CA-IV. We subsequently screen the top 0.01% of variants in vivo in mice expressing human CA-IV in brain endothelial cells. Notably, two top-performing capsids in \"humanized\" mice are relatively lower ranked in vitro and outperform several top-ranked in vitro candidates. One of these, AAV-hCA4-IV77, achieves 100-fold-greater brain transduction than AAV9, with robust neuronal and astrocytic coverage across brain regions. These results advance our understanding of receptor-targeted capsid design and support the therapeutic potential of human CA-IV-engaging AAVs.","journal":"Cell Reports","year":2025,"id":520220,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245902,"name":"Xinhong Chen","orcid":"0000-0003-0408-0813","position":1,"is_corresponding":false},{"id":355560,"name":"Jonathan D. Hoang","orcid":"0000-0002-3762-9596","position":2,"is_corresponding":false},{"id":1390211,"name":"Fiona Ristic","orcid":null,"position":3,"is_corresponding":false},{"id":554397,"name":"Yujie Fan","orcid":"0000-0001-8642-0695","position":4,"is_corresponding":false},{"id":873663,"name":"Seongmin Jang","orcid":"0000-0002-9822-6790","position":5,"is_corresponding":false},{"id":776069,"name":"Jin Hyung Alex Chung","orcid":"0000-0003-2965-9530","position":6,"is_corresponding":false},{"id":1020960,"name":"Erin E. Sullivan","orcid":"0000-0002-1724-6520","position":7,"is_corresponding":false},{"id":1169098,"name":"Tomasz Gawda","orcid":"0000-0001-7906-0097","position":8,"is_corresponding":false},{"id":1127518,"name":"Bill Kavvathas","orcid":null,"position":9,"is_corresponding":false},{"id":1390212,"name":"Irene Tran","orcid":null,"position":10,"is_corresponding":false},{"id":666486,"name":"Yitong Li","orcid":"0000-0003-3402-4484","position":11,"is_corresponding":false},{"id":524262,"name":"Andrew D. Steele","orcid":"0000-0001-8777-4970","position":12,"is_corresponding":false},{"id":1018303,"name":"Timothy F. Shay","orcid":"0000-0001-6591-3271","position":13,"is_corresponding":false},{"id":228771,"name":"Viviana Gradinaru","orcid":"0000-0001-5868-348X","position":14,"is_corresponding":false},{"id":678557,"name":"Changfan Lin","orcid":"0000-0002-8119-9845","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:49:28.470782Z","pmid":"41175373","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":[]}