A single injection of AAV9-ABEmax in a mouse model of long QT syndrome type 3 corrected up to 99.2% of Scn5a transcripts, eliminating or alleviating QT prolongation without off-target editing.
Does AAV9-ABEmax base editing improve QT prolongation and correct the Scn5a variant in a mouse model of Long QT syndrome type 3?
In vivo adenine base editing via AAV9 effectively corrects the Scn5a pathogenic variant and rescues the arrhythmia phenotype in a mouse model of Long QT syndrome type 3.
BACKGROUND: Pathogenic variants in SCN5A can result in long QT syndrome type 3, a life-threatening genetic disease. Adenine base editors can convert targeted A T base pairs to G C base pairs, offering a promising tool to correct pathogenic variants. METHODS: We generated a long QT syndrome type 3 mouse model by introducing the T1307M pathogenic variant into the Scn5a gene. The adenine base editor was split into 2 smaller parts and delivered into the heart by adeno-associated virus serotype 9 (AAV9-ABEmax) to correct the T1307M pathogenic variant. RESULTS: Both homozygous and heterozygous T1307M mice showed significant QT prolongation. Carbachol administration induced Torsades de Pointes or ventricular tachycardia for homozygous T1307M mice (20%) but not for heterozygous or wild-type mice. A single intraperitoneal injection of AAV9-ABEmax at postnatal day 14 resulted in up to 99.20% Scn5a transcripts corrected in T1307M mice. Scn5a mRNA correction rate >60% eliminated QT prolongation; Scn5a mRNA correction rate <60% alleviated QT prolongation. Partial Scn5a correction resulted in cardiomyocytes heterogeneity, which did not induce severe arrhythmias. We did not detect off-target DNA or RNA editing events in ABEmax-treated mouse hearts. CONCLUSIONS: These findings show that in vivo AAV9-ABEmax editing can correct the variant Scn5a allele, effectively ameliorating arrhythmia phenotypes. Our results offer a proof of concept for the treatment of hereditary arrhythmias.
Qi et al. (Wed,) conducted a other in Long QT syndrome type 3. AAV9-ABEmax was evaluated on Scn5a transcript correction rate. A single injection of AAV9-ABEmax in a mouse model of long QT syndrome type 3 corrected up to 99.2% of Scn5a transcripts, eliminating or alleviating QT prolongation without off-target editing.