RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.

中文翻译：

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心血管疾病非编码 RNA 疗法的临床前和临床开发。


RNA 调节已成为治疗多种疾病的一种有前途的治疗方法。基于非编码 RNA 的新兴疗法现已引起心血管研究的关注，与当前的药物疗法（如小分子药物或抗体）相比，它可以提供有价值的进步。在这篇综述中，我们重点关注主要在大型动物模型中进行的基于非编码 RNA 的研究，包括猪、兔、狗和非人灵长类动物。特别讨论了以长非编码 RNA 和 circRNA 作为人类治疗方式的障碍和前景。我们还描述了基于人体细胞和组织的新型离体方法，例如工程心脏组织和活体心肌切片，这些方法可以帮助缩小未来体内模型和临床应用之间的差距。最后，我们总结了已经获得FDA批准用于靶向mRNA的反义寡核苷酸药物，并讨论了基于非编码RNA的药物在临床试验中的进展。本综述还包括其他因素，例如药物化学、药物配方、不同的给药途径以及基于 RNA 的药物的优点。最近，第一个基于 miRNA 的治疗抑制策略已在心力衰竭患者和健康志愿者中进行了测试，以研究对伤口愈合的影响（NCT04045405；NCT03603431）。总之，新型治疗性 RNA 靶标、大型动物模型、人体细胞/组织的离体研究以及新的递送技术的结合可能会导致基于非编码 RNA 的下一代心血管疾病疗法的开发取得重大进展。