Therapeutic siRNA: state of the art

  • Signal Transduct Target Ther. 2020 Jun 19;5(1):101. doi: 10.1038/s41392-020-0207-x.
Bo Hu  #  1 ,  Liping Zhong  #  2 ,  Yuhua Weng  1 ,  Ling Peng  3 ,  Yuanyu Huang  #  4 ,  Yongxiang Zhao  5 ,  Xing-Jie Liang  6
Affiliations
  • 1. School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, 100081, Beijing, People's Republic of China.
  • 2. National Center for International Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Theranostics, Guangxi Medical University, 530021, Guangxi, People's Republic of China.
  • 3. Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Equipe Labellisée Ligue Contre le Cancer, 13288, Marseille, France.
  • 4. School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, 100081, Beijing, People's Republic of China. [email protected].
  • 5. National Center for International Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Theranostics, Guangxi Medical University, 530021, Guangxi, People's Republic of China. [email protected].
  • 6. Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 100190, Beijing, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 32561705 DOI: 10.1038/s41392-020-0207-x
Abstract

RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO® (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.