{"doi":"10.1101/2025.08.21.671454","title":"AAV2-mediated intravitreal delivery of exon-specific U1 snRNA rescues optic neuropathy in a mouse model of familial dysautonomia","abstract":"Abstract Familial dysautonomia (FD) is a rare autosomal recessive neurodegenerative disorder caused by a splicing mutation in the ELP1 gene. It predominantly affects the sensory and autonomic nervous systems, with progressive vision loss due to optic neuropathy being a universal and debilitating symptom. Retinal pathology in FD involves progressive thinning of the retinal nerve fiber layer (RNFL), resulting from the degeneration of retinal ganglion cells (RGCs). Notably, FD-associated vision loss has a postnatal onset, offering a critical window for therapeutic intervention before severe visual impairment develops in adolescence. Currently, no approved treatments exist to prevent or reverse vision loss in FD. In this study, we present a novel RNA-based therapeutic approach targeting ELP1 pre-mRNA splicing in the retina. We engineered exon-specific U1 small nuclear RNAs (ExSpeU1s) to enhance inclusion of exon 20 in the mutant ELP1 transcripts in the retina, thereby restoring full-length ELP1 expression. Delivery of ExSpeU1 via adeno-associated virus serotype 2 (AAV2) to the retina improved ELP1 splicing, rescued RGC loss, and visual function in an FD mouse model. These findings highlight ExSpeU1-mediated splicing correction as a promising therapeutic approach for treating optic neuropathy in FD, offering potential to preserve vision and improve quality of life for patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556683,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"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":0.9649,"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":288328,"name":"Krishnakanth Kondabolu","orcid":"0000-0002-9453-1499","position":1,"is_corresponding":false},{"id":998743,"name":"Emily Kirchner","orcid":null,"position":2,"is_corresponding":false},{"id":672514,"name":"Swanand Koli","orcid":"0000-0002-4742-4439","position":3,"is_corresponding":false},{"id":1456752,"name":"Matthew Chagnon","orcid":null,"position":4,"is_corresponding":false},{"id":1456753,"name":"Drenushe Krasniqi-Vanmeter","orcid":null,"position":5,"is_corresponding":false},{"id":1456754,"name":"Max E. Stern","orcid":null,"position":6,"is_corresponding":false},{"id":573103,"name":"Jessica Bolduc","orcid":null,"position":7,"is_corresponding":false},{"id":1456363,"name":"Giulia Romano","orcid":"0000-0003-0356-4947","position":8,"is_corresponding":false},{"id":1456755,"name":"Franco Pagani","orcid":"0000-0002-2678-3459","position":9,"is_corresponding":false},{"id":457588,"name":"Luk H. Vandenberghe","orcid":"0000-0002-3508-4924","position":10,"is_corresponding":false},{"id":142178,"name":"Elisabetta Morini","orcid":"0000-0002-1658-5213","position":11,"is_corresponding":false},{"id":560191,"name":"Anil Chekuri","orcid":"0000-0002-0652-2630","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:13.130091Z","pmid":"40894547","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":[]}