The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal’s sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers.

腺病毒介导的胚胎T盒转录因子18（TBX18）基因的体细胞转移可以将心室心肌细胞转化为诱导起搏细胞。然而，治疗性 TBX18 诱导的心脏起搏的转化面临安全挑战。在这里，我们展示了动物中合成 TBX18 mRNA 的心肌表达产生从头起搏并限制先天和炎症免疫反应。在大鼠中，心肌内注射的 mRNA 保持局部化，而直接心肌注射携带报告基因的腺病毒会导致弥漫性表达，并大量溢出到肝脏、脾脏和肺。 TBX18 mRNA 在大鼠体内的瞬时表达导致从头开始的自动化和起搏器特性，并且与注射腺病毒相比，导致炎症基因表达和活化巨噬细胞群的大幅减少。在啮齿动物和临床相关猪的完全性心脏传导阻滞模型中，心肌内注射 TBX18 mRNA 提供为期一个月的速率自适应心脏起搏，与动物的窦性心律和体力活动密切相关。 TBX18 mRNA 可能有助于生物起搏器的开发。