Triadin knockout syndrome (TKOS) is a rare inherited cardiac arrhythmia disorder caused by homozygous or compound heterozygous TRDN frameshift, nonsense, or missense mutations which render patients effectively triadin null. TKOS has been characterized by either consistent or transient QT prolongation, extensive T-wave inversions in the precordial leads, and a severe disease expression of exercise induced syncope and cardiac arrest in early childhood. Additionally, despite various treatment strategies such as beta blocker therapy and left cardiac sympathetic denervation, the majority of patients have had recurrent breakthrough cardiac events such as implantable cardioverter defibrillator shocks. Triadin is a critical component of the cardiac calcium release unit (CRU) complex where the L-type calcium channel (LTCC) is juxtaposed to the calcium release channel (RyR2) on the junctional sarcoplasmic reticulum (jSR). This complex is responsible for mediating calcium sensing and proper excitation-contraction coupling (ECC) in the heart. Ablation of triadin causes multiple structural and functional abnormalities in mice. Triadin knockout mice showed a reduction in key proteins of the CRU including RyR2, Casq2, Jph2, and Jct. These mice also exhibited a 50% reduction in LTCC co-localization to RyR2 which lead to loss of the negative feedback loop on the LTCC, resulting in slow inactivation of the LTCC and SR calcium overload, as well as ventricular arrhythmias, in the setting of ?-adrenergic stimulation. While these previous studies have provided some insights into triadin?s role in the CRU, this has never been examined in a human, triadin null cardiac cell model system. Therefore, it remains unknown whether the insights drawn from the previous triadin null mouse studies can be generalized to humans. For this reason, we propose to use human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from patients with TKOS as a novel cellular model to characterize the disease and to establish the definitive pathophysiological mechanism of TKOS in humans. In addition, we propose to assess the utility of adeno-associated virus serotype 9 (AAV9)-mediated gene delivery of wild-type (WT) triadin to treat patient-specific iPS- CMs, thus providing a proof-of-concept for an AAV9-mediated, gene-based therapy which could be advanced further someday to more effectively treat patients with TKOS.
Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin and is characterized by a particularly severe cardiac phenotype which often manifests as cardiac arrest in early childhood and breakthrough cardiac events despite various treatment strategies. While previous studies in mice have provided some insights into the role of triadin in cardiac tissue, it remains unclear how the loss of triadin leads to such a severely arrhythmic phenotype in humans. Therefore, the goal of our research is to provide major advances in our understanding of the pathophysiology of this newly described, potentially lethal syndrome, and to develop a novel gene based therapy that could potentially be used to more effectively treat patients suffering from TKOS.
