{"doi":"10.1101/2025.08.28.672900","title":"Broad brain biodistribution conferred by an AAV to restore TDP-43 function mitigates Frontotemporal Demenia-like deficits","abstract":"TDP-43 dysfunction is an early pathogenic determinant of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), a devastating disorder currently without effective therapy. Here, we exploit a blood-brain-barrier (BBB)-permeable AAV (AAV-PHP.eB) that confers broad brain biodistribution to restore TDP-43 function in a TDP-43 deficient model (CamKIIa-CreER;Tardbp mice) that mimics the early stage of TDP-43 dysfunction occurring in FTLD-TDP. Intracerebroventricular delivery by AAV-PHP.eB of CTR, our previously characterized splicing repressor, revealed its accumulation in ~40% of adult hippocampal neurons. Remarkably, treatment of adult CamKIIa-CreER;Tardbpf/f mice with AAV-PHP.eB-CTR restored TDP-43 function, attenuated neuronal aberrant activity and memory deficits, and rescued neuron loss. Importantly, we showed that TDP-43's autoregulatory element restricts CTR expression to a physiological range. No overt phenotype was observed after long-term exposure to AAV-PHP.eB-CTR in aged mice, highlighting a favorable safety profile for this gene therapy. These results validate that BBB-crossing AAVs can deliver CTR with a biodistribution in the adult brain that is broad enough to rescue FTD-like phenotypes, supporting clinical testing of this gene therapy for FTLD-TDP.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556721,"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":0.9523,"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":792526,"name":"Rashmi Thapa","orcid":null,"position":1,"is_corresponding":false},{"id":791979,"name":"Rongsong Liu","orcid":"0000-0002-0751-5547","position":2,"is_corresponding":false},{"id":1326989,"name":"Aswathy Peethambaran Mallika","orcid":"0000-0003-0303-5156","position":3,"is_corresponding":false},{"id":1328612,"name":"Meghraj Singh Baghel","orcid":"0000-0003-3988-6438","position":4,"is_corresponding":false},{"id":1456391,"name":"Yijun Wei","orcid":"0009-0002-3656-9998","position":5,"is_corresponding":false},{"id":763261,"name":"Irika R. Sinha","orcid":"0000-0001-6440-7019","position":6,"is_corresponding":false},{"id":1326988,"name":"G Burns","orcid":"0000-0001-8691-779X","position":7,"is_corresponding":false},{"id":1456392,"name":"Xinrui Wen","orcid":"0000-0003-2667-2983","position":8,"is_corresponding":false},{"id":1456393,"name":"Bo Pang","orcid":"0000-0002-0323-5484","position":9,"is_corresponding":false},{"id":258253,"name":"Jonathan P. Ling","orcid":"0000-0003-1927-9729","position":10,"is_corresponding":false},{"id":414448,"name":"Da‐Ting Lin","orcid":"0000-0003-0538-7892","position":11,"is_corresponding":false},{"id":671171,"name":"Yun Li","orcid":"0000-0002-5251-747X","position":12,"is_corresponding":false},{"id":664919,"name":"Philip C. Wong","orcid":"0000-0001-8162-3274","position":13,"is_corresponding":false},{"id":1456390,"name":"Tianyu Cao","orcid":"0000-0002-5299-847X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"40950145","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":[]}