Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18

IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Nature Biomedical Engineering Pub Date : 2024-05-02 DOI:10.1038/s41551-024-01211-9
David W. Wolfson, Nam Kyun Kim, Ki Hong Lee, Jared P. Beyersdorf, Jonathan J. Langberg, Natasha Fernandez, Dahim Choi, Nadine Zureick, Tae Yun Kim, Seongho Bae, Jin-Mo Gu, Jonathan L. Kirschman, Jinqi Fan, Christina Y. Sheng, Danielle Gottlieb Sen, Bret Mettler, Jung Hoon Sung, Young-sup Yoon, Sung-Jin Park, Philip J. Santangelo, Hee Cheol Cho
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Abstract

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. Intramyocardial injection of synthetic mRNA coding for the embryonic T-box transcription factor 18 gene generates rate-adaptive cardiac pacing and limits innate and inflammatory immune responses, as shown in rodents and pigs.

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通过向心肌注射编码 T-box 转录因子 18 的 mRNA,对完全性心脏传导阻滞的猪进行瞬时起搏
腺病毒介导的胚胎 T-box 转录因子 18(TBX18)基因体细胞转移可将心室心肌细胞转化为诱导起搏细胞。然而,治疗性 TBX18 诱导心脏起搏的转化面临着安全性挑战。在这里,我们展示了合成 TBX18 mRNA 在动物心肌中的表达可产生新的起搏,并限制先天性和炎症性免疫反应。在大鼠体内,心肌内注射的 mRNA 保持局部表达,而直接在心肌内注射携带报告基因的腺病毒会导致弥散表达,并大量溢出到肝脏、脾脏和肺部。在大鼠体内瞬时表达 TBX18 mRNA 会导致新的自动性和起搏器特性,而且与注射腺病毒相比,炎症基因的表达和活化的巨噬细胞群大幅减少。在啮齿动物和临床相关的完全性心脏传导阻滞猪模型中,心肌内注射 TBX18 mRNA 可提供为期一个月的速率自适应心脏起搏,这与动物的窦性心律和体力活动密切相关。TBX18 mRNA 可能有助于生物心脏起搏器的开发。
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来源期刊
Nature Biomedical Engineering
Nature Biomedical Engineering Medicine-Medicine (miscellaneous)
CiteScore
45.30
自引率
1.10%
发文量
138
期刊介绍: Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.
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