BACKGROUND: Cardiac channelopathies, caused by mutaIons in ion-channel genes, can lead to sudden cardiac death (SCD) via ventricular arrhythmias. Brugada syndrome (BrS) is a rare inherited channelopathy characterized by a unique ECG paiern and a high incidence of ventricular fibrillaIon leading to SCD in the absence of structural heart defects. The main gene responsible for 20-25% of BrS cases is SCN5A, encoding the cardiac sodium channel a-subunit Nav1.5, which carries the sodium current (INa) responsible for the rapid depolarizaIon phase of the acIon potenIal (AP). While current treatments do not target the geneIc cause of channelopathies, this study explores the therapeuIc potenIal of overexpressing the Nterminal region of Nav1.5 (Nter) to restore electrical acIvity by rescuing INa, in the context of SCN5A deficiency. METHODS: We overexpressed the Nter pepIde using viral vectors in Scn5a +/-mice, in CRISPR/Cas9 edited-SCN5A +/-cardiomyocytes derived from inducedpluripotent stem cells (iPSC-CMs) and in BrS paIent iPSC-CMs. We assessed molecular and funcIonal effects of Nter overexpression in vitro and in vivo by measuring Nav1.5 subcellular expression and electrophysiological acIvity and by recording ECGs and arrhythmias. RESULTS: Whereas Scn5a +/-mice showed an impaired INa associated with a slowed-cardiac conducIon characterisIc of the BrS phenotype, cardiac-specific overexpression of Nter corrected AP parameters by restoring INa density in Scn5a +/-mouse cardiomyocytes. This increase in INa density was caused by a translocaIon of Nav1.5 to the cell membrane in Nter-overexpressing mice. Most importantly, Nter overexpression normalized atrioventricular and ventricular conducIon and protected Scn5a +/-mice from arrhythmias triggered by programmed electrical sImulaIon. Similarly, Nter overexpression in SCN5A +/-human iPSC-CMs led to a 2-fold increase in Nav1.5 cell-surface expression, resulIng in normalizaIon of INa and AP parameters and aboliIon of early aner depolarizaIons observed during spontaneous AP recordings. Similar results were obtained in iPSC-CMs derived from a BrS paIent, confirming the potenIal of this therapy in human models. CONCLUSIONS: This study idenIfied a novel therapeuIc pepIde effecIve in restoring cardiac excitability in animal and cellular models of BrS, paving the way for future development of therapies for life-threatening arrhythmias in paIents with SCN5A deficiency.