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
{"title":"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","authors":"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","doi":"10.1038/s41551-024-01211-9","DOIUrl":null,"url":null,"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.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 9","pages":"1124-1141"},"PeriodicalIF":26.8000,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01211-9.pdf","citationCount":"0","resultStr":"{\"title\":\"Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18\",\"authors\":\"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\",\"doi\":\"10.1038/s41551-024-01211-9\",\"DOIUrl\":null,\"url\":null,\"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.\",\"PeriodicalId\":19063,\"journal\":{\"name\":\"Nature Biomedical Engineering\",\"volume\":\"8 9\",\"pages\":\"1124-1141\"},\"PeriodicalIF\":26.8000,\"publicationDate\":\"2024-05-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.nature.com/articles/s41551-024-01211-9.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Biomedical Engineering\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://www.nature.com/articles/s41551-024-01211-9\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENGINEERING, BIOMEDICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Biomedical Engineering","FirstCategoryId":"5","ListUrlMain":"https://www.nature.com/articles/s41551-024-01211-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18
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.
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.