Editorial Focus: Understanding Off-target Effects As the Key to Successful RNAi Therapy

Overview

Journal Cell Mol Biol Lett

Publisher Biomed Central

Specialties Biochemistry
Cell Biology
Molecular Biology

Date 2019 Dec 24

PMID 31867046

Citations 58

Authors

Rafal Bartoszewski

Aleksander F Sikorski

Affiliations

Soon will be listed here.

Abstract

With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.

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References

van Dijk E, Cougot N, Meyer S, Babajko S, Wahle E, Seraphin B . Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO J. 2002; 21(24):6915-24. PMC: 139098. DOI: 10.1093/emboj/cdf678. View

Zhang Z, Han Y, Sun G, Liu X, Jia X, Yu X . MicroRNA-325-3p inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma by down-regulation of aquaporin 5. Cell Mol Biol Lett. 2019; 24:13. PMC: 6373077. DOI: 10.1186/s11658-019-0137-1. View

Layzer J, McCaffrey A, Tanner A, Huang Z, Kay M, Sullenger B . In vivo activity of nuclease-resistant siRNAs. RNA. 2004; 10(5):766-71. PMC: 1370566. DOI: 10.1261/rna.5239604. View

Zhu J, Chen G, Zhu S, Li S, Wen Z, Li B . Identification of Tissue-Specific Protein-Coding and Noncoding Transcripts across 14 Human Tissues Using RNA-seq. Sci Rep. 2016; 6:28400. PMC: 4916594. DOI: 10.1038/srep28400. View

Ehlert E, Eggers R, Niclou S, Verhaagen J . Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system. BMC Neurosci. 2010; 11:20. PMC: 2841193. DOI: 10.1186/1471-2202-11-20. View

Luck M, Muljo S, Collins C . Prospects for Therapeutic Targeting of MicroRNAs in Human Immunological Diseases. J Immunol. 2015; 194(11):5047-52. PMC: 4435821. DOI: 10.4049/jimmunol.1403146. View

Balaratnam S, West N, Basu S . A piRNA utilizes HILI and HIWI2 mediated pathway to down-regulate ferritin heavy chain 1 mRNA in human somatic cells. Nucleic Acids Res. 2018; 46(20):10635-10648. PMC: 6237762. DOI: 10.1093/nar/gky728. View

Aagaard L, Rossi J . RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007; 59(2-3):75-86. PMC: 1978219. DOI: 10.1016/j.addr.2007.03.005. View

Wang Y, Zou X, Guo Y, Wang L, Liu Y, Zeng Q . Mechanical Strain Affects Some Microrna Profiles in Pre-Oeteoblasts. Cell Mol Biol Lett. 2015; 20(4):586-96. DOI: 10.1515/cmble-2015-0034. View

10.

Pentin J, Smith J . Drug calculations: are they safer with or without a calculator?. Br J Nurs. 2006; 15(14):778-81. DOI: 10.12968/bjon.2006.15.14.21582. View

11.

Lim L, Lau N, Garrett-Engele P, Grimson A, Schelter J, Castle J . Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433(7027):769-73. DOI: 10.1038/nature03315. View

12.

Carthew R, Sontheimer E . Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009; 136(4):642-55. PMC: 2675692. DOI: 10.1016/j.cell.2009.01.035. View

13.

Van Rooij E, Kauppinen S . Development of microRNA therapeutics is coming of age. EMBO Mol Med. 2014; 6(7):851-64. PMC: 4119351. DOI: 10.15252/emmm.201100899. View

14.

Yu D, Pendergraff H, Liu J, Kordasiewicz H, Cleveland D, Swayze E . Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012; 150(5):895-908. PMC: 3444165. DOI: 10.1016/j.cell.2012.08.002. View

15.

Kozomara A, Birgaoanu M, Griffiths-Jones S . miRBase: from microRNA sequences to function. Nucleic Acids Res. 2018; 47(D1):D155-D162. PMC: 6323917. DOI: 10.1093/nar/gky1141. View

16.

Tebbutt S, He J, Burkett K, Ruan J, Opushnyev I, Tripp B . Microarray genotyping resource to determine population stratification in genetic association studies of complex disease. Biotechniques. 2004; 37(6):977-85. DOI: 10.2144/04376RR02. View

17.

Elbashir S, Lendeckel W, Tuschl T . RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev. 2001; 15(2):188-200. PMC: 312613. DOI: 10.1101/gad.862301. View

18.

Nagano T, Mitchell J, Sanz L, Pauler F, Ferguson-Smith A, Feil R . The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008; 322(5908):1717-20. DOI: 10.1126/science.1163802. View

19.

Bartoszewski R, Sikorski A . Editorial focus: entering into the non-coding RNA era. Cell Mol Biol Lett. 2018; 23:45. PMC: 6145373. DOI: 10.1186/s11658-018-0111-3. View

20.

Behlke M . Progress towards in vivo use of siRNAs. Mol Ther. 2006; 13(4):644-70. PMC: 7106286. DOI: 10.1016/j.ymthe.2006.01.001. View