RNAi-based Therapeutics-current Status, Challenges and Prospects

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2010 Jan 6

PMID 20049714

Citations 95

Authors

Katrin Tiemann

John J Rossi

Affiliations

Soon will be listed here.

Abstract

RNA interference (RNAi) is a collection of small RNA directed mechanisms that result in sequence specific inhibition of gene expression. The notion that RNAi could lead to a new class of therapeutics caught the attention of many investigators soon after its discovery. The field of applied RNAi therapeutics has moved very quickly from lab to bedside. The RNAi approach has been widely used for drug development and several phase I and II clinical trials are under way. However, there are still some concerns and challenges to overcome for therapeutic applications. These include the potential for off-target effects, triggering innate immune responses and most importantly obtaining specific delivery into the cytoplasm of target cells. This review focuses on the current status of RNAi-based therapeutics, the challenges it faces and how to overcome them.

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References

Shay D, Holman R, Roosevelt G, Clarke M, Anderson L . Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979-1997. J Infect Dis. 2000; 183(1):16-22. DOI: 10.1086/317655. View

Hammond S, Bernstein E, Beach D, Hannon G . An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000; 404(6775):293-6. DOI: 10.1038/35005107. View

Krutzfeldt J, Rajewsky N, Braich R, Rajeev K, Tuschl T, Manoharan M . Silencing of microRNAs in vivo with 'antagomirs'. Nature. 2005; 438(7068):685-9. DOI: 10.1038/nature04303. View

Tarwadi , Jazayeri J, Prankerd R, Pouton C . Preparation and in vitro evaluation of novel lipopeptide transfection agents for efficient gene delivery. Bioconjug Chem. 2008; 19(4):940-50. DOI: 10.1021/bc700463q. View

Hu-Lieskovan S, Heidel J, Bartlett D, Davis M, Triche T . Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res. 2005; 65(19):8984-92. DOI: 10.1158/0008-5472.CAN-05-0565. View

Krutzfeldt J, Kuwajima S, Braich R, Rajeev K, Pena J, Tuschl T . Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res. 2007; 35(9):2885-92. PMC: 1888827. DOI: 10.1093/nar/gkm024. View

Wahlestedt C, Salmi P, Good L, Kela J, JOHNSSON T, Hokfelt T . Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc Natl Acad Sci U S A. 2000; 97(10):5633-8. PMC: 25880. DOI: 10.1073/pnas.97.10.5633. View

Henke J, Goergen D, Zheng J, Song Y, Schuttler C, Fehr C . microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J. 2008; 27(24):3300-10. PMC: 2586803. DOI: 10.1038/emboj.2008.244. View

Boris-Lawrie K, Temin H . The retroviral vector. Replication cycle and safety considerations for retrovirus-mediated gene therapy. Ann N Y Acad Sci. 1994; 716:59-70; discussion 71. DOI: 10.1111/j.1749-6632.1994.tb21703.x. View

10.

Dannull J, Lesher D, Holzknecht R, Qi W, Hanna G, Seigler H . Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity. Blood. 2007; 110(13):4341-50. DOI: 10.1182/blood-2007-04-083188. View

11.

Robbins M, Judge A, Liang L, McClintock K, Yaworski E, MacLachlan I . 2'-O-methyl-modified RNAs act as TLR7 antagonists. Mol Ther. 2007; 15(9):1663-9. DOI: 10.1038/sj.mt.6300240. View

12.

Gardiner K, Marsh T, Pace N, Altman S . The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell. 1983; 35(3 Pt 2):849-57. DOI: 10.1016/0092-8674(83)90117-4. View

13.

Tuschl T, Zamore P, Lehmann R, Bartel D, Sharp P . Targeted mRNA degradation by double-stranded RNA in vitro. Genes Dev. 2000; 13(24):3191-7. PMC: 317199. DOI: 10.1101/gad.13.24.3191. View

14.

Shay D, Holman R, Newman R, Liu L, Stout J, Anderson L . Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999; 282(15):1440-6. DOI: 10.1001/jama.282.15.1440. View

15.

Chu T, Twu K, Ellington A, Levy M . Aptamer mediated siRNA delivery. Nucleic Acids Res. 2006; 34(10):e73. PMC: 1474074. DOI: 10.1093/nar/gkl388. View

16.

Judge A, Sood V, Shaw J, Fang D, McClintock K, MacLachlan I . Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005; 23(4):457-62. DOI: 10.1038/nbt1081. View

17.

Kleinman M, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi J . Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008; 452(7187):591-7. PMC: 2642938. DOI: 10.1038/nature06765. View

18.

Xu C, Jere D, Jin H, Chang S, Chung Y, Shin J . Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am J Respir Crit Care Med. 2008; 178(1):60-73. PMC: 2441927. DOI: 10.1164/rccm.200707-1022OC. View

19.

Falsey A . Respiratory syncytial virus infection in elderly and high-risk adults. Exp Lung Res. 2006; 31 Suppl 1:77. View

20.

Zhang K, Hu S, Wu J, Chen L, Lu J, Wang X . Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis. Mol Cancer. 2009; 8:11. PMC: 2662784. DOI: 10.1186/1476-4598-8-11. View