Single Construct Suppression and Replacement Gene Therapy for the Treatment of All <i>CALM1</i> -, <i>CALM2</i> -, and <i>CALM3</i> -Mediated Arrhythmia Disorders

Abstract

We provide the first proof-of-principle suppression-replacement gene therapy for CaM-mediated long-QT syndrome. The CALM-SupRep gene therapy shortened the pathologically prolonged APD90 in <i>CALM1</i>-, <i>CALM2</i>-, and <i>CALM3-variant</i> CaM-mediated long-QT syndrome induced pluripotent stem cell-derived CM lines. The single CALM-SupRep construct may be able to treat all calmodulinopathies, regardless of which of the 3 CaM-encoding genes are affected.