{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Moore OM"],"funding":["NIDDK NIH HHS","NHLBI NIH HHS","NHGRI NIH HHS","NIH HHS"],"pagination":["8"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10919902"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["4(1)"],"pubmed_abstract":["<h4>Introduction</h4>Heterozygous autosomal-dominant single nucleotide variants in <i>RYR2</i> 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 <i>RYR2</i> allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model.<h4>Aim</h4>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 <i>Ryr2</i> variant p.Arg176Gln (R176Q/+).<h4>Methods and results</h4>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 <i>Ryr2</i> 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.<h4>Conclusion</h4>Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant <i>Ryr2</i> allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT."],"journal":["The journal of cardiovascular aging"],"pubmed_title":["Long-term efficacy and safety of cardiac genome editing for catecholaminergic polymorphic ventricular tachycardia."],"pmcid":["PMC10919902"],"funding_grant_id":["R01 HL132840","R01 HL153350","R01 DK114356","K23 HL136932","R01 HL152314","R01 DK124477","R01 HL169761","F30 HL156669","UM1 HG006348","R01 HL147108","U42 OD026645","R01 HL160992","S10 OD032380","T32 HL139430","R01 HL089598"],"pubmed_authors":["Wehrens XHT","Barazi D","Miyake CY","Lahiri SK","Alberto Navarro-Garcia J","Parthasarathy V","Lagor WR","Munivez EM","Hulsurkar MM","Moore OM","Bao G","Aguilar-Sanchez Y","Park SH","Moore CT","Davidson J","Word TA","Keefe JA"],"additional_accession":[]},"is_claimable":false,"name":"Long-term efficacy and safety of cardiac genome editing for catecholaminergic polymorphic ventricular tachycardia.","description":"<h4>Introduction</h4>Heterozygous autosomal-dominant single nucleotide variants in <i>RYR2</i> 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 <i>RYR2</i> allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model.<h4>Aim</h4>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 <i>Ryr2</i> variant p.Arg176Gln (R176Q/+).<h4>Methods and results</h4>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 <i>Ryr2</i> 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.<h4>Conclusion</h4>Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant <i>Ryr2</i> allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jan","modification":"2026-06-01T11:07:34.408Z","creation":"2025-04-04T12:02:46.443Z"},"accession":"S-EPMC10919902","cross_references":{"pubmed":["38464671"],"doi":["10.20517/jca.2023.42"]}}