Corydon Ida Juhl, Fabian-Jessing Bjørn Kristensen, Jakobsen Thomas Stax, Jørgensen Asbjørn Cortnum, Jensen Emilie Grarup, Askou Anne Louise, Aagaard Lars, Corydon Thomas Juhl
Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000 Aarhus C, Denmark.
Department of Ophthalmology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 167, Aarhus N, Denmark.
Mol Ther Nucleic Acids. 2023 Jul 18;33:469-482. doi: 10.1016/j.omtn.2023.07.018. eCollection 2023 Sep 12.
The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules through complementary base-pairing. A systematic review of published and ongoing clinical trials was performed. Web of Science, PubMed, and Embase were searched from January 1, 1998, to December 30, 2022 for clinical trials using RNAi. Following inclusion, data from the articles were extracted according to a predefined protocol. A total of 90 trials published in 81 articles were included. In addition, ongoing clinical trials were retrieved from ClinicalTrials.gov, resulting in the inclusion of 48 trials. We investigated how maturation of RNAi-based therapeutics and developments in delivery platforms, administration routes, and potential targets shape the current landscape of clinically applied RNAi. Notably, most contemporary clinical trials used either -acetylgalactosamine delivery and subcutaneous administration or lipid nanoparticle delivery and intravenous administration. In conclusion, RNAi therapeutics have gained great momentum during the past decade, resulting in five approved therapeutics targeting the liver for treatment of severe diseases, and the trajectory depicted by the ongoing trials emphasizes that even more RNAi-based medicines also targeting extra-hepatic tissues are likely to be available in the years to come.
2023年是RNA干扰发现25周年。基于RNA干扰的疗法通过互补碱基配对消除靶RNA分子，实现序列特异性基因敲低。我们对已发表和正在进行的临床试验进行了系统综述。检索了1998年1月1日至2022年12月30日期间Web of Science、PubMed和Embase数据库中使用RNA干扰的临床试验。纳入研究后，根据预先定义的方案提取文章中的数据。共纳入81篇文章中发表的90项试验。此外，从ClinicalTrials.gov检索到正在进行的临床试验，又纳入了48项试验。我们研究了基于RNA干扰的疗法的成熟过程以及递送平台、给药途径和潜在靶点的发展如何塑造了临床应用RNA干扰的当前格局。值得注意的是，大多数当代临床试验采用N-乙酰半乳糖胺递送和皮下给药，或脂质纳米颗粒递送和静脉给药。总之，RNA干扰疗法在过去十年中取得了巨大进展，已有五种针对肝脏治疗严重疾病的获批疗法，而正在进行的试验所描绘的发展轨迹表明，未来几年可能会有更多针对肝外组织的基于RNA干扰的药物问世。
