Allele-specific silencing of the mutant KCNH2 allele by 70% reduced APD90 prolongation from 166% to 99% in severe LQTS2 mutations in the BPS2020 human ventricular cardiomyocyte model.
Does allele-specific suppression of the mutant KCNH2 allele reduce action potential prolongation in simulated human ventricular cardiomyocytes with LQTS2 mutations?
In silico modeling shows that silencing the mutant KCNH2 allele only partially corrects action potential prolongation in LQTS2, indicating that suppression must be paired with replacement gene therapy.
Estimación del efecto: -67% prolongation reduction for severe mutation in BPS2020 model at 70% silencing (from +166% to +99%)
Tasa de eventos absoluta: 99% vs 166%
Silencing of the mutant allele can substantially, but only partially, counteract the effects of mild or severe LQTS2 mutations on IKr. Allele-specific inhibition of the mutant KCNH2 allele alone is not sufficient to fully treat the effects of LQTS2 mutations and should be accompanied by a replacement gene therapy, creating a suppression-and-replacement ("SupRep") gene therapy.
Ronald Wilders (Thu,) conducted a other in Human ventricular cardiomyocytes with heterozygous dominant-negative KCNH2 mutations causing Long QT Syndrome type 2. Allele-specific silencing of mutant KCNH2 allele vs. No silencing (control) was evaluated on Action potential duration at 90% repolarization (APD90) prolongation and APD90 restitution curve slope reflecting arrhythmogenic potential (-67% prolongation reduction for severe mutation in BPS2020 model at 70% silencing (from +166% to +99%)). Allele-specific silencing of the mutant KCNH2 allele by 70% reduced APD90 prolongation from 166% to 99% in severe LQTS2 mutations in the BPS2020 human ventricular cardiomyocyte model.