5'-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo

Nucleic Acids Research

Volumn 45, Issue 13, 2017, Pages 7581-7592

  Haraszti, Reka A ^a   Roux, Loic ^a   Coles, Andrew H ^a   Turanov, Anton A ^a   Alterman, Julia F ^a   Echeverria, Dimas ^a   Godinho, Bruno M D C ^a   Aronin, Neil ^a   Khvorova, Anastasia ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5' VINYLPHOSPHONATE; MESSENGER RNA; PHOSPHODIESTERASE I; PHOSPHONIC ACID DERIVATIVE; SMALL INTERFERING RNA; SPLEEN EXONUCLEASE; UNCLASSIFIED DRUG; EXORIBONUCLEASE; GUIDE RNA; RNA INDUCED SILENCING COMPLEX; VINYL DERIVATIVE; VINYLPHOSPHONIC ACID;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BIOACCUMULATION; CHEMICAL MODIFICATION; CONTROLLED STUDY; DEPHOSPHORYLATION; DRUG EFFICACY; FEMALE; GENE SILENCING; IC50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; RNA STABILITY; SYSTEMIC THERAPY; ANIMAL; CHEMICAL PHENOMENA; CHEMISTRY; CONFORMATION; DRUG EFFECTS; GENETICS; HELA CELL LINE; HUMAN; KIDNEY; LIVER; METABOLISM; MOLECULAR MODEL; PHOSPHORYLATION; TISSUE DISTRIBUTION;

ANIMALS; EXORIBONUCLEASES; FEMALE; GENE SILENCING; HELA CELLS; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; KIDNEY; LIVER; MICE; MODELS, MOLECULAR; NUCLEIC ACID CONFORMATION; ORGANOPHOSPHONATES; PHOSPHORYLATION; RNA STABILITY; RNA, GUIDE; RNA, SMALL INTERFERING; RNA-INDUCED SILENCING COMPLEX; TISSUE DISTRIBUTION; VINYL COMPOUNDS;

EID: 85026287048     PISSN: 03051048     EISSN: 13624962     Source Type: Journal    
DOI: 10.1093/nar/gkx507     Document Type: Article

References (50)

1. Fire, A., Xu, S., Montgomery, M.K., Kostas, S.A., Driver, S.E. and Mello, C.C. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 391, 806–811.
2. Zamore, P.D. (2001) RNA interference: listening to the sound of silence. Nat. Struct. Biol., 8, 746–750.
3. Khvorova, A. and Watts, J.K. (2017) The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol., 35, 238–248.
4. Byrne, M., Tzekov, R., Wang, Y., Rodgers, A., Cardia, J., Ford, G., Holton, K., Pandarinathan, L., Lapierre, J., Stanney, W. et al. (2013) Novel hydrophobically modified asymmetric RNAi compounds (sd-rxRNA) demonstrate robust efficacy in the eye. J. Ocul. Pharmacol. Ther., 29, 855–864.
5. Allerson, C.R., Sioufi, N., Jarres, R., Prakash, T.P., Naik, N., Berdeja, A., Wanders, L., Griffey, R.H., Swayze, E.E. and Bhat,B. (2005) Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J. Med. Chem., 48, 901–904.
6. Deleavey, G.F., Watts, J.K., Alain, T., Robert, F., Kalota, A., Aishwarya, V., Pelletier, J., Gewirtz, A.M., Sonenberg, N. and Damha, M.J. (2010) Synergistic effects between analogs of DNA and RNA improve the potency of siRNA-mediated gene silencing. Nucleic Acids Res., 38, 4547–4557.
7. Nair, J.K., Willoughby, J.L., Chan, A., Charisse, K., Alam, M.R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A.V., Milstein, S. et al. (2014) Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc., 136, 16958–16961.
8. Khan, T., Weber, H., DiMuzio, J., Matter, A., Dogdas, B., Shah, T., Thankappan, A., Disa, J., Jadhav, V., Lubbers, L. et al. (2016) Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth. Mol. Ther. Nucleic Acids, 5, e342.
9. Matsuda, S., Keiser, K., Nair, J.K., Charisse, K., Manoharan, R.M., Kretschmer, P., Peng, C.G., A, V.K.i., Kandasamy, P., Willoughby, J.L. et al. (2015) siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chem. Biol., 10, 1181–1187.
10. Sehgal, A., Vaishnaw, A. and Fitzgerald, K. (2013) Liver as a target for oligonucleotide therapeutics. J. Hepatol., 59, 1354–1359.
11. Fitzgerald, K., White, S., Borodovsky, A., Bettencourt, B.R., Strahs, A., Clausen, V., Wijngaard, P., Horton, J.D., Taubel, J., Brooks, A. et al. (2016) A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med., 376, 41–51.
12. Martinez, J., Patkaniowska, A., Urlaub, H., Luhrmann, R. and Tuschl, T. (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell, 110, 563–574.
13. Ma, J.B., Yuan, Y.R., Meister, G., Pei, Y., Tuschl, T. and Patel, D.J. (2005) Structural basis for 5'-end-specific recognition of guide RNA by the A. fulgidus Piwi protein. Nature, 434, 666–670.
14. Frank, F., Sonenberg, N. and Nagar, B. (2010) Structural basis for 5'[prime]-nucleotide base-specific recognition of guide RNA by human AGO2. Nature, 465, 818–822.
15. Weitzer, S. and Martinez, J. (2007) The human RNA kinase hClp1 is active on 3 transfer RNA exons and short interfering RNAs. Nature, 447, 222–226.
16. Kenski, D.M., Cooper, A.J., Li, J.J., Willingham, A.T., Haringsma, H.J., Young, T.A., Kuklin, N.A., Jones, J.J., Cancilla, M.T., McMasters, D.R. et al. (2010) Analysis of acyclic nucleoside modifications in siRNAs finds sensitivity at position 1 that is restored by 5'-terminal phosphorylation both in vitro and in vivo. Nucleic Acids Res., 38, 660–671.
17. Engel, R. (1977) Phosphonates as analogues of natural phosphates. Chem. Rev., 77, 349–367.
18. Lima, W.F., Prakash, T.P., Murray, H.M., Kinberger, G.A., Li, W., Chappell, A.E., Li, C.S., Murray, S.F., Gaus, H., Seth, P.P. et al. (2012) Single-stranded siRNAs activate RNAi in animals. Cell, 150, 883–894.
19. Yu, D., Pendergraff, H., Liu, J., Kordasiewicz, H.B., Cleveland, D.W., Swayze, E.E., Lima, W.F., Crooke, S.T., Prakash, T.P. and Corey, D.R. (2012) Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin Expression. Cell, 150, 895–908.
20. Hampton, A., Kappler, F. and Perini, F. (1976) Evidence for the conformation about the C(5')-O(5') bond of AMP complexed to AMP kinase: Substrate properties of a vinyl phosphonate analog of AMP. Bioorg. Chem., 5, 31–35.
21. Kappler, F., Hai, T.T. and Hampton, A. (1985) Use of a vinyl phosphonate analog of ATP as a rotationally constrained probe of the C5'·O5' torsion angle in ATP complexed to methionine adenosyl transferase. Bioorg. Chem., 13, 289–295.
22. Prakash, T.P., Lima, W.F., Murray, H.M., Elbashir, S., Cantley, W., Foster, D., Jayaraman, M., Chappell, A.E., Manoharan, M., Swayze, E.E. et al. (2013) Lipid nanoparticles improve activity of single-stranded siRNA and gapmer antisense oligonucleotides in animals. ACS Chem. Biol., 8, 1402–1406.
23. Parmar, R., Willoughby, J.L., Liu, J., Foster, D.J., Brigham, B., Theile, C.S., Charisse, K., Akinc, A., Guidry, E., Pei, Y. et al. (2016) 5'-(E)-Vinylphosphonate: a stable phosphate mimic can improve the RNAi activity of siRNA-GalNAc conjugates. Chembiochem, 17, 985–989.
24. Prakash, T.P., Kinberger, G.A., Murray, H.M., Chappell, A., Riney, S., Graham, M.J., Lima, W.F., Swayze, E.E. and Seth, P.P. (2016) Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA. Bioor. Med. Chem. Lett., 26, 2817–2820.
25. Elkayam, E., Parmar, R., Brown, C.R., Willoughby, J.L., Theile, C.S., Manoharan, M. and Joshua-Tor, L. (2016) siRNA carrying an (E)-vinylphosphonate moiety at the 5' end of the guide strand augments gene silencing by enhanced binding to human Argonaute-2. Nucleic Acids Res., 45, 3528–3536.
26. Coles, A.H., Osborn, M.F., Alterman, J.F., Turanov, A.A., Godinho, B.M., Kennington, L., Chase, K., Aronin, N. and Khvorova, A. (2016) A high-throughput method for direct detection of therapeutic oligonucleotide-induced gene silencing in vivo. Nucleic Acid Ther., 26, 86–92.
27. Ly, S., Navaroli, D.M., Didiot, M.C., Cardia, J., Pandarinathan, L., Alterman, J.F., Fogarty, K., Standley, C., Lifshitz, L.M., Bellve, K.D. et al. (2016) Visualization of self-delivering hydrophobically modified siRNA cellular internalization. Nucleic Acids Res., 45, 15–25.
28. Alterman, J.F., Hall, L.M., Coles, A.H., Hassler, M.R., Didiot, M.C., Chase, K., Abraham, J., Sottosanti, E., Johnson, E., Sapp, E. et al. (2015) Hydrophobically modified siRNAs silence Huntingtin mRNA in primary neurons and mouse brain. Mol. Ther. Nucleic Acids, 4, e266.
29. Nikan, M., Osborn, M.F., Coles, A.H., Godinho, B.M., Hall, L.M., Haraszti, R.A., Hassler, M.R., Echeverria, D., Aronin, N. and Khvorova, A. (2016) Docosahexaenoic acid conjugation enhances distribution and safety of siRNA upon local administration in mouse brain. Mol. Ther. Nucleic Acids, 5, e344.
30. Roehl, I., Schuster, M. and Seiffert, S. (2011) Vol. US20110201006 A1.
31. Birmingham, A., Anderson, E., Sullivan, K., Reynolds, A., Boese, Q., Leake, D., Karpilow, J. and Khvorova, A. (2007) A protocol for designing siRNAs with high functionality and specificity. Nat. Protoc., 2, 2068–2078.
32. Birmingham, A., Anderson, E.M., Reynolds, A., Ilsley-Tyree, D., Leake, D., Fedorov, Y., Baskerville, S., Maksimova, E., Robinson, K., Karpilow, J. et al. (2006) 3' UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat. Methods, 3, 199–204.
33. Ruegger, S. and Grosshans, H. (2012) MicroRNA turnover: when, how, and why. Trends Biochem. Sci., 37, 436–446.
34. Chatterjee, S., Fasler, M., Bussing, I. and Grosshans, H. (2011) Target-mediated protection of endogenous microRNAs in C. elegans. Dev. Cell, 20, 388–396.
35. Bail, S., Swerdel, M., Liu, H., Jiao, X., Goff, L.A., Hart, R.P. and Kiledjian, M. (2010) Differential regulation of microRNA stability. RNA, 16, 1032–1039.
36. Chatterjee, S. and Grosshans, H. (2009) Active turnover modulates mature microRNA activity in Caenorhabditis elegans. Nature, 461, 546–549.
37. Zangari, J., Ilie, M., Rouaud, F., Signetti, L., Ohanna, M., Didier, R., Romeo, B., Goldoni, D., Nottet, N., Staedel, C. et al. (2016) Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition. Nucleic Acids Res., 45, 4131–4141.
38. Burgess, H.M. and Mohr, I. (2015) Cellular 5'-3' mRNA exonuclease Xrn1 controls double-stranded RNA accumulation and anti-viral responses. Cell Host Microbe, 17, 332–344.
39. Trubetskoy, V.S., Griffin, J.B., Nicholas, A.L., Nord, E.M., Xu, Z., Peterson, R.M., Wooddell, C.I., Rozema, D.B., Wakefield, D.H., Lewis, D.L. et al. (2017) Phosphorylation-specific status of RNAi triggers in pharmacokinetic and biodistribution analyses. Nucleic Acids Res., 45, 1469–1478.
40. Kenski, D.M., Willingham, A.T., Haringsma, H.J., Li, J.J. and Flanagan, W.M. (2012) In vivo activity and duration of short interfering RNAs containing a synthetic 5'-phosphate. Nucleic Acid Ther., 22, 90–95.
41. Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P.N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E. et al. (2013) Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med., 369, 819–829.
42. Sehgal, A., Barros, S., Ivanciu, L., Cooley, B., Qin, J., Racie, T., Hettinger, J., Carioto, M., Jiang, Y., Brodsky, J. et al. (2015) An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat. Med., 21, 492–497.
43. Wolfrum, C., Shi, ., Jayaprakash, K.N., Jayaraman, M., Wang, G., Pandey, R.K., Rajeev, K.G., Nakayama, T., Charrise, K., Ndungo, E.M. et al. (2007) Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat. Biotechnol., 25, 1149–1157.
44. Lonn, P., Kacsinta, A.D., Cui, X.S., Hamil, A.S., Kaulich, M., Gogoi, K. and Dowdy, S.F. (2016) Enhancing endosomal escape for intracellular delivery of macromolecular biologic therapeutics. Sci. Rep., 6, 32301.
45. Khvorova, A. (2017) Oligonucleotide therapeutics––a new class of cholesterol-lowering drugs. N. Engl. J. Med., 376, 4–7.
46. Shen, W., Liang, X.H., Sun, H. and Crooke, S.T. (2015) 2-Fluoro-modified phosphorothioate oligonucleotide can cause rapid degradation of P54nrb and PSF. Nucleic Acids Res., 43, 4569–4578.
47. Garber, K. (2016) Alnylam terminates revusiran program, stock plunges. Nat. Biotech., 34, 1213–1214.
48. Carroll, J.B., Bates, G.P., Steffan, J., Saft, C. and Tabrizi, S.J. (2015) Treating the whole body in Huntington’s disease. Lancet Neurol., 14, 1135–1142.
49. Albin, R.L. (2015) Out of one mutation, many Huntington’s disease effects. Lancet Neurol., 14, 1071–1072.
50. Martin, B., Golden, E., Keselman, A., Stone, M., Mattson, M.P., Egan, J.M. and Maudsley, S. (2008) Therapeutic perspectives for the treatment of Huntington’s disease: treating the whole body. Histol. Histopathol., 23, 237–250.