Development of an Isogenic Model of Long QT Syndrome 3 using induced pluripotent human stem cells

• Grant number: 24/09281-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: João Bosco Pesquero
• Grantee: Vinicius Fogaça dos Santos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 20/14635-1 - Modeling of monogenic diseases for physiopathological studies and pharmacological tests using specialized cells derived from iPSCs, AP.TEM

Abstract

Voltage-sensitive sodium channels (NaV) are distributed in several excitable tissues of the human organism, being responsible in most cases for the genesis of the action potential in these cells, totaling a total of 9 subtypes. The Nav1.5 isoform is the isoform of the cardiac sodium channel, present abundantly in the myocardium, where its alpha subunit is encoded by the SCN5A gene. In cardiomyocytes, NaV1.5 is responsible for the rapid depolarization of the action potential. Several mutations in the gene that encodes this channel can lead to gain or loss of function. Long QT syndrome 3 is characterized by a prolongation of the QT interval on the electrocardiogram. This syndrome is associated with gain-of-function mutations in the SCN5A gene, which causes an increase in the late sodium current, prolonging the action potential of cardiomyocytes, which can result in an arrhythmic event in the heart. The E17854K variant is considered the most common variant among cases of long QT syndrome 3, accounting for around 34% of cases. For a long time, the study of channelopathies, such as long QT syndrome 3, depended on heterologous expression systems and/or animal models to study the pathophysiology and analysis of new drugs, however, such models present some limitations when applied in the clinic. The use of human induced pluripotent stem cells (hiPSCs) and their ability to be reprogrammed into different cell types, in line with gene editing techniques such as CRISPR/Cas-9, have demonstrated to be powerful tools for the study and modeling of monogenic diseases in in vitro. Given this scenario, the present work aims to establish an isogenic model of long QT syndrome 3 in functional cardiomyocytes derived from hiPSCs genetically edited for the E1784K variant. The study of functional consequences in different physiological contexts relevant to the disease will enable the screening of new medications and the study of the mechanisms of action of medications already used in order to offer better target-directed therapy.