{"doi":"10.20517/jca.2023.42","title":"Long-term efficacy and safety of cardiac genome editing for catecholaminergic polymorphic ventricular tachycardia","abstract":"Introduction: Heterozygous autosomal-dominant single nucleotide variants in RYR2 account for 60% of cases of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia disorder associated with high mortality rates. CRISPR/Cas9-mediated genome editing is a promising therapeutic approach that can permanently cure the disease by removing the mutant RYR2 allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model. Aim: The purpose of this study was to assess whether adeno-associated virus type-9 (AAV9)-mediated somatic genome editing could prevent ventricular arrhythmias by removal of the mutant allele in mice that are heterozygous for Ryr2 variant p.Arg176Gln (R176Q/+). Methods and Results: Guide RNA and SaCas9 were delivered using AAV9 vectors injected subcutaneously in 10-day -old mice. At 6 weeks after injection, R176Q/+ mice had a 100% reduction in ventricular arrhythmias compared to controls. When aged to 12 months, injected R176Q/+ mice maintained a 100% reduction in arrhythmia induction. Deep RNA sequencing revealed the formation of insertions/deletions at the target site with minimal off-target editing on the wild-type allele. Consequently, CRISPR/SaCas9 editing resulted in a 45% reduction of total Ryr2 mRNA and a 38% reduction in RyR2 protein. Genome editing was well tolerated based on serial echocardiography, revealing unaltered cardiac function and structure up to 12 months after AAV9 injection. Conclusion: Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant Ryr2 allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT.","journal":"The Journal of Cardiovascular Aging","year":2024,"id":437585,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"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":477022,"name":"Yuriana Aguilar-Sánchez","orcid":"0000-0002-5516-8877","position":1,"is_corresponding":false},{"id":329252,"name":"Satadru K. Lahiri","orcid":"0000-0001-9502-1530","position":2,"is_corresponding":false},{"id":329254,"name":"Mohit Hulsurkar","orcid":"0000-0003-0595-6661","position":3,"is_corresponding":false},{"id":863106,"name":"José Alberto Navarro‐García","orcid":"0000-0002-0317-4888","position":4,"is_corresponding":false},{"id":705538,"name":"Tarah A. Word","orcid":null,"position":5,"is_corresponding":false},{"id":447844,"name":"Joshua A. Keefe","orcid":"0000-0002-6209-6488","position":6,"is_corresponding":false},{"id":1247604,"name":"D Barazi","orcid":null,"position":7,"is_corresponding":false},{"id":500136,"name":"Elda Munivez","orcid":null,"position":8,"is_corresponding":false},{"id":1247605,"name":"Charles Thomas Moore","orcid":null,"position":9,"is_corresponding":false},{"id":1064045,"name":"Vaidya Parthasarathy","orcid":null,"position":10,"is_corresponding":false},{"id":42603,"name":"Jaysón Davidson","orcid":"0000-0001-9066-9872","position":11,"is_corresponding":false},{"id":241984,"name":"William R. Lagor","orcid":"0000-0002-1703-5125","position":12,"is_corresponding":false},{"id":874196,"name":"So Hyun Park","orcid":"0000-0002-5283-4619","position":13,"is_corresponding":false},{"id":241982,"name":"Gang Bao","orcid":"0000-0001-5501-554X","position":14,"is_corresponding":false},{"id":704631,"name":"Christina Y. Miyake","orcid":"0000-0002-3120-9320","position":15,"is_corresponding":false},{"id":298615,"name":"Xander H.T. Wehrens","orcid":"0000-0001-5044-672X","position":16,"is_corresponding":false},{"id":884464,"name":"Oliver M. Moore","orcid":"0000-0003-3986-7982","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:00:34.490087Z","pmid":"38464671","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":[]}