From the Institute of Molecular and Translational Therapeutic Strategies (C.-K.H., S.K.-K., T.T.), Hannover Medical School, Germany.
REBIRTH Center of Translational Regenerative Medicine (T.T.), Hannover Medical School, Germany.
Circ Res. 2020 Feb 28;126(5):663-678. doi: 10.1161/CIRCRESAHA.119.315856. Epub 2020 Feb 27.
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.
RNA 调节已成为治疗多种类型疾病的一种有前途的治疗方法。基于非编码 RNA 的治疗方法这一新兴领域现在引起了心血管研究的关注，与小分子药物或抗体等当前的药物治疗相比，它可能在心血管研究中提供有价值的进展。在这篇综述中，我们主要关注在大型动物模型（包括猪、兔、狗和非人类灵长类动物）中进行的基于非编码 RNA 的研究。特别讨论了将长非编码 RNA 和环状 RNA 作为治疗模式在人类中的靶向的障碍和前景。我们还描述了基于人类细胞和组织的新型离体方法，例如工程化心脏组织和活体心肌切片，这些方法可能有助于弥合体内模型和未来临床应用之间的差距。最后，我们总结了已经被美国食品和药物管理局批准用于靶向 mRNAs 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，如药物化学、药物配方、不同的给药途径以及 RNA 药物的优势。最近，基于 miRNA 的抑制策略的首次治疗性研究已经在心力衰竭患者和健康志愿者中进行，以研究其对伤口愈合的影响（NCT04045405；NCT03603431）。总之，新型治疗性 RNA 靶标、大型动物模型、基于人类细胞/组织的离体研究以及新的给药技术的结合，可能会推动基于非编码 RNA 的心血管疾病下一代治疗方法的发展取得重大进展。
