Theoretical and Natural Science
- The Open Access Proceedings Series for Conferences
Theoretical and Natural Science
Vol. 6, 03 August 2023
Open
Access | Article
RNA interference: from target validation to therapeutics
* Author to whom correspondence should be addressed.
Abstract
Generally, a new targeted medicine takes a long time, usually 5 to 15 years, from the discovery and validation of its target to its actual use in treating a disease. There is no doubt that steps such as target validation and target evaluation are essential in preclinical development of new drugs to ensure safety, bioavailability, and efficacy of the drug, and in the target validation phase, RNA interference (RNAi) is a very important method. RNAi drug has double-stranded RNA function, so the targeted mRNA of a specific gene sequence is degraded, its transcription process is abnormal, which leads to gene silencing, and related protein synthesis failure. RNAi technology could specifically shut off specific genes, and, it is a targeted drug with great potential. Therefore, RNAi technology can be used to treat some rare diseases, such as acute hepatic porphyria (AHP) in adults, by using drugs as carriers. In 1998, Andrew Fire and Craig C. Mello first defined the RNAi phenomenon and was honored with the Nobel Prize in Physiology or Medicine in 2006 for their discovery of RNAi and their outstanding contributions to the field of gene silencing. Since then, RNAi drugs have been studied by pharmaceutical scientists around the world, but many of the previous drugs have been stopped at the evaluation stage due to their chemical instability. Until October 2018, the world’s first RNAi drug (patisiran) was successfully marketed so that the RNAi drug development became popular again because of remarkable pesticide effect.
Keywords
RNAi, target validation, assessment, siRNA, miRNA, dsRNA, screening of targets, siRNA-based drug
References
1. Bolten, B.M. and DeGregorio, T. (2002) Trends in development cycles. Nature Reviews Drug Discovery 1, 335–336.
2. Sams-Dodd, Frank (2005) Target-based drug discovery: is something wrong? Drug Discovery Today 10, 139–147.
3. FDA (2004) Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. FDA White Paper.
4. Dowden, H. & Munro, J. Trends in clinical success rates and therapeutic focus. Nat. Rev. Drug Discov.18, 495–496 (2019).
5. Gashaw, I., Ellinghaus, P., Sommer, A. & Asadullah, K. What makes a good drug target? Drug Discov. Today 16, 1037–1043 (2011).
6. Everett, J. R. Academic drug discovery: current status and prospects. Expert Opin. Drug Discov. 10, 937–944 (2015).
7. Yu, H. W. H. Bridging the translational gap: collaborative drug development and dispelling the stigma of commercialization. Drug Discov. Today 21, 299–305 (2016).
8. Moore, J. D. The impact of CRISPR–Cas9 on target identification and validation. Drug Discov. Today 20, 450–457 (2015).
9. Erdogan, B. R. & Michel, M. C. Building robustness into translational research. Handb. Exp. Pharmacol. 257, 1–13 (2019).
10. Dolgos, H. et al. Translational Medicine Guide transforms drug development processes: the recent Merck experience. Drug Discov. Today 21, 517–526 (2016).
11. Andrade, E. L. et al. Non-clinical studies required for new drug development — part I: early in silico and in vitro studies, new target discovery and validation, proof of principles and robustness of animal studies. Braz. J. Med. Biol. Res. 49, e5644 (2016).
12. Sweis, R. F. Target (in)validation: a critical, sometimes unheralded, role of modern medicinal chemistry. ACS Med. Chem. Lett. 6, 618–621 (2015).
13. Jasny, B. R. et al. Fostering reproducibility in industry–academia research. Science 357, 759–761 (2017).
14. Sansone, S.-A. et al. FAIRsharing as a community approach to standards, repositories and policies. Nat. Biotechnol. 37, 358–367 (2019).
15. Rattan, A. K. Data integrity: history, issues, and remediation of issues. PDA J. Pharm. Sci. Technol. 72, 105–116 (2018).
16. Hartung, T. et al. Toward good in vitro reporting standards. ALTEX 36, 3–17 (2019).
17. Berezikov, E. Nat. Rev. Genet. Vol. 12. Nature Publishing Group; 2011. Evolution of microRNA diversity and regulation in animals; p. 846–860
18. Emmerich, C. H., Gamboa, L. M., Hofmann, M. C. J., Bonin-Andresen, M., Arbach, O., Schendel, Parnham, M. J. (2020). Improving target assessment in biomedical research: the GOT-IT recommendations. Nature Reviews Drug Discovery.
19. Fabian MR, Sonenberg N. The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nature Structural & Molecular Biology. 2012; 19(6):586–593.
20. Faller M, Toso D, Matsunaga M, Atanasov I, Senturia R, Chen Y, Zhou ZH, Guo F. DGCR8 recognizes primary transcripts of microRNAs through highly cooperative binding and formation of higher-order structures. RNA. 2010; 16(8):1570–1583.
21. Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010; 466(7308):835–840.
22. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120(1):15–20.
23. Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol. 2021 Jul;189:114432.
24. Senturia R, Faller M, Yin S, Loo JA, Cascio D, Sawaya MR, Hwang D, Clubb RT, Guo F. Structure of the dimerization domain of DiGeorge critical region 8. Protein Sci. 2010; 19(7):1354–1365.
25. Tian Y, Simanshu DK, Ascano M, Diaz-Avalos R, Park AY, Juranek SA, Rice WJ, et al. Multimeric assembly and biochemical characterization of the Trax-translin endonuclease complex. Nature Structural & Molecular Biology. 2011; 18(6):658–664.
26. Zeng Y, Cullen BR. Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences. J. Biol. Chem. 2005; 280(30):27595–27603.
27. Zou J, Chang M, Nie P, Secombes CJ. Origin and evolution of the RIG-I like RNA helicase gene family. BMC Evol. Biol. 2009; 9:85.
28. Yang J. Patisiran for the treatment of hereditary transthyretin-mediated amyloidosis. Expert Rev Clin Pharmacol. 2019 Feb;12(2):95–99.
29. Syed YY. Givosiran: A Review in Acute Hepatic Porphyria. Drugs. 2021 May;81(7):841-848.
30. Rizk M, Tüzmen Ş. Update on the clinical utility of an RNA interference-based treatment:focus on Patisiran. Pharmgenomics Pers Med. 2017;10:267–278.
31. Xu J, Liu Y, Liu S, Ou W, White A, Stewart S, Tkaczuk KHR, Ellis LM, Wan J, Lu X, HeX. Metformin Bicarbonate-Mediated Efficient RNAi for Precise Targeting of TP53 Deficiency in Colon and Rectal Cancers. Nano Today. 2022 Apr;43
Data Availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
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- Volume Title
- Proceedings of the International Conference on Modern Medicine and Global Health (ICMMGH 2023)
- ISBN (Print)
- 978-1-915371-65-2
- ISBN (Online)
- 978-1-915371-66-9
- Published Date
- 03 August 2023
- Series
- Theoretical and Natural Science
- ISSN (Print)
- 2753-8818
- ISSN (Online)
- 2753-8826
- DOI
- 10.54254/2753-8818/6/20230167
- Copyright
- 03 August 2023
- Open Access
- This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited