{"doi":"10.1172/jci.insight.178159","title":"All-in-one AAV-mediated Nrl gene inactivation rescues retinal degeneration in Pde6a mice","abstract":"Retinitis pigmentosa (RP) is a complex group of inherited retinal diseases characterized by progressive death of photoreceptor cells and eventual blindness. Pde6a, which encodes a cGMP-specific phosphodiesterase, is a crucial pathogenic gene for autosomal recessive RP (RP43); there is no effective therapy for this form of RP. The compact CRISPR/Staphylococcus aureus Cas9 (CRISPR/SaCas9) system, which can be packaged into a single adeno-associated virus (AAV), holds promise for simplifying effective gene therapy. Here, we demonstrated that all-in-one AAV-SaCas9-mediated Nrl gene inactivation can efficiently prevent retinal degeneration in a RP mouse model with Pde6anmf363/nmf363 mutation. We screened single-guide RNAs capable of efficiently editing the mouse Nrl gene in N2a cells and then achieved effective gene editing by using a single AAV to codeliver SaCas9 and an optimal Nrl-sg2 into the mouse retina. Excitingly, in vivo inactivation of Nrl improved photoreceptor cell survival and rescued retinal function in treated Pde6a-deficient mice. Thus, we showed that a practical, gene-independent method, AAV-SaCas9-mediated Nrl inactivation, holds promise for future therapeutic applications in patients with RP.","journal":"JCI Insight","year":2024,"id":462426,"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":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":true,"deposit_databanks":{"SRA":["PRJNA1121624"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1291851,"name":"Siyu Chen","orcid":"0000-0001-5745-5071","position":1,"is_corresponding":false},{"id":281722,"name":"Chien‐Hui Lo","orcid":"0000-0001-9016-0953","position":2,"is_corresponding":false},{"id":1291852,"name":"Qing Wang","orcid":"0000-0002-5471-1348","position":3,"is_corresponding":false},{"id":246156,"name":"Yang Sun","orcid":"0000-0001-8735-4765","position":4,"is_corresponding":false},{"id":1281393,"name":"Zhiquan Liu","orcid":"0000-0001-5433-5656","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:04:20.631898Z","pmid":"39499900","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":[]}