{Reference Type}: Journal Article {Title}: Long-term efficacy and safety of cardiac genome editing for catecholaminergic polymorphic ventricular tachycardia. {Author}: Moore OM;Aguilar-Sanchez Y;Lahiri SK;Hulsurkar MM;Alberto Navarro-Garcia J;Word TA;Keefe JA;Barazi D;Munivez EM;Moore CT;Parthasarathy V;Davidson J;Lagor WR;Park SH;Bao G;Miyake CY;Wehrens XHT; {Journal}: J Cardiovasc Aging {Volume}: 4 {Issue}: 1 {Year}: 2024 Jan 暂无{DOI}: 10.20517/jca.2023.42 {Abstract}: UNASSIGNED: 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.
UNASSIGNED: 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/+).
UNASSIGNED: 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.
UNASSIGNED: 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.