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-box 转录因子 18 （TBX18） 基因的体细胞转移可以将腔室心肌细胞转化为诱导的起搏细胞。然而，治疗性 TBX18 诱导的心脏起搏的翻译面临安全性挑战。在这里，我们表明合成 TBX18 mRNA 在动物体内的心肌表达会产生从头起搏并限制先天性和炎症性免疫反应。在大鼠中，心肌内注射的 mRNA 保持局部，而直接心肌注射携带报告基因的腺病毒导致弥散表达并大量溢出到肝脏、脾脏和肺。大鼠中 TBX18 mRNA 的瞬时表达导致从头自动性和起搏器特性，与注射腺病毒相比，炎症基因表达和活化巨噬细胞群的表达显着降低。在啮齿动物和临床相关的完全心脏传导阻滞猪模型中，心肌内注射的 TBX18 mRNA 提供了为期一个月的心率自适应心脏起搏，这与动物的窦性心律和身体活动密切相关。TBX18 mRNA 可能有助于生物起搏器的发育。