Personalized medicine for long QT syndrome: Restoration of ion channel function with RNA interference technology

Abstract

With a prevalence of 1/2500, long QT Syndrome (LQTS) is one of the leading causes of sudden cardiac death in young and otherwise healthy individuals. LQTS is a proarrhythmic disorder hallmarked by prolongation of cardiac repolarization due to underlying ion channelopathies. This translates to the typical electrocardiographic (ECG) findings of prolonged QT interval, notched or biphasic T waves, and T wave alternans, and puts individuals at high risk of developing ventricular tachyarrhythmias and sudden cardiac death. To date, there are 13 subtypes of LQTS classified according to the 13 identified genetic defects, all encoding subunits of cardiac ion channels (Kþ , Naþ , Ca2þ) or ion channel regulatory proteins. Current treatment options for LQTS including beta-blockers, left cardiac sympathetic denervation, and implantable cardioverter-defibrillators are largely palliative [1]. Each of these existing modalities is associated with limitations such as adverse effects related to drug and surgical therapies and the limited lifespan of implantable devices. In the age of molecular genetics, a molecular diagnosis of the underlying ion channel defect not only establishes the disease state but paves the way for personalized medicine. Recently, Lu et al. adopted the use of RNA interference technology to target and rescue the channelopathy phenotype observed in LQTS type 2 due to KCNH2 mutation [2]. RNA interference therapy is based on the concept derived from the natural cellular mechanism where sequence-specific gene silencing can be achieved by creation of double-stranded RNA [3]. A synthetic effector small