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5898031 52 US Cl...435/1723 USOO5898.031A United States Patent (19) 11 Patent Number: 5,898,031 Crooke (45) Date of Patent: Apr. 27, 1999 54) OLIGORIBONUCLEOTIDES FOR CLEAVING 5,457,191 10/1995 Cook et al. .......................... 536/27.13 RNA 5,459,255 10/1995 Cook et al. .......................... 536/27.13 5,466,786 11/1995 Buhr et al. ...... ... 536/26.26 75 Inventor: Stanley T. Crooke, Carlsbad, Calif. 5,476.925 12/1995 Letsinger et al. ...................... 536/23.1 5,484,908 1/1996 Froehler et al. ..................... 536/24.31 5,489,677 2/1996 Sanghvi et al. ..... ... 53.6/2.2.1 73 ASSignee: sis Pharmaceuticals, Inc., Carlsbad, 5,506,337 4/1996 Summerton et al. ................... 528/391 a. 5,506,351 4/1996 McGee ................ 536/55.3 5,508,270 4/1996 Baxter et al. ... 514/47 21 Appl. No.: 08/659,440 5,514,786 5/1996 Cook et al.. 5,539,083 7/1996 Cook et al. ............................. 530/333 22 Filed: Jun. 6, 1996 FOREIGN PATENT DOCUMENTS 51) Int. Cl. ............................. C12N 15700; C12O 1/68; CO7H 21/04 339842 11/1989 European Pat. Off.. 52 U.S. Cl. ........................... 435/1723; 435/6, 435/375, WC. E. W.E. 536/23.1536/24.5• us WO 92/22651 12/1992 WIPO. 58 Field of Search .............................. 514/44; 536/23.1, WO 94/O2499 2/1994 WIPO. 536/24.5, 25.1; 435/6, 375, 172.3 WO 94/O2501 2/1994 WIPO. WO 94/17093 8/1994 WIPO. 56) References Cited Primary Examiner John L. LeGuyader U.S. PATENT DOCUMENTS Attorney, Agent, or Firm Woodcock Washburn Kurtz Mackiewicz & Norris LLP 3,687,808 8/1972 Merigan et al. .......................... 195/28 5,013,830 5/1991. Ohtsuka et al. .......................... 536/27 57 ABSTRACT 5,023,243 6/1991 Tullis ........................................ 514/44 - 5,130,302 7/1992 Spielvogel et al. ....................... 514/45 Oligomeric compounds including oligoribonucleotides and 5,142,047 8/1992 Tullis ........................................ 514/44 oligoribonucleosides are provided that have Subsequences of 5,149,797 9/1992 Pederson et al. ......................... 536/27 2-pentoribofuranosyl nucleosides that activate dsRNase. 5,177,198 1/1993 Spielvogel et al. ....................... 514/45 The oligoribonucleotides and oligoribonucleosides can 5,223,618 6/1993 Cook et al. ........... ... 544/276 include Substituent groups for increasing binding affinity to 5,235,033 8/1993 Summerton et al ... 528/391 complementary nucleic acid Strand as well as Substituent 1. R r 2. groups for increasing nuclease resistance. The oligomeric 5264564 HE NE r : compounds are useful for diagnostics and other research 5,359,044 10/1994 Cook et al. ... ... 536/23.1 purposes, for modulating the expression of a protein in 5,366,878 11/1994 Pederson et al. ... 435/91.3 organisms, and for the diagnosis, detection and treatment of 5,378.825 1/1995 Cook et al. ....... ... 536/25.34 other conditions Susceptible to oligonucleotide therapeutics. 5,386,023 1/1995 Sanghvi et al. ... ... 536/25.3 5,403,711 4/1995 Walder et al. .............................. 435/6 66 Claims, 5 Drawing Sheets U.S. Patent Apr. 27, 1999 Sheet 1 of 5 5,898,031 FIGURE 1 H-RAS TARGETED ANTISENSE OLIGOS: FULL 2" methoxy cc ACACCGACGGCGCCC 3 BASE RNA GAP DDDDDDOOODDDD 5 BASE RNA GAP OOOOOOOOOOOOO 7 BASE RNA GAP OOOOOOOOOOOOOOOOO 9 BASE RNA GAP DOOOOOOOOOOOOOOOO FULL RNA (OOOOOOOOOOOOOOOOO U.S. Patent Apr. 27, 1999 Sheet 2 of 5 5,898,031 :88 giga 83-88 3:38 ...& : 88: 88: 8:8 3 : & 8 23: 388 800 838 :::::::38 :::::::: or 3:38: 3. 8 88: 88: 8: 88: 3. 8:88 8888. 83. 28. U.S. Patent Apr. 27, 1999 Sheet 4 of 5 5,898,031 Our Ex: SENSE9GAP RNA : 8-XE EXTRACT (wir U.S. Patent Apr. 27, 1999 Sheet 5 of 5 5,898,031 . {x : SEx8: 83.3° is: SENSEE his SENSE8 3AR RNA 5,898,031 1 2 OLIGORIBONUCLEOTDES FOR CLEAVING ing both unmodified phosphodiester internucleoside link RNA ages and modified phosphorothioate internucleoside link ages are substrates for cellular RNase H. Since they are FIELD OF THE INVENTION Substrates, they activate the cleavage of target RNA by This invention is directed to the synthesis and use of RNase H. However, these authors further noted that in oligomeric compounds, including oligoribonucleotides and Xenopus embryos, both phosphodiester linkages and phos oligoribonucleosides, useful for Strand cleavage of target phorothioate linkages are also Subject to exonuclease deg RNA strands. Included in the invention are oligoribonucle radation. Nuclease degradation is detrimental Since it rapidly otides having modified Sugars, bases or phosphate back depletes the oligonucleotide. bones and oligoribonucleosides having Standard Sugars and AS described in references (1), (2) and (4), to stabilize bases or modified Sugars and bases linked together via oligonucleotides against nuclease degradation while Still non-phosphate backbones. Further included in the invention providing for RNase H activation, 2'-deoxy oligonucleotides are chimeric oligoribonucleotides and oligoribonucleosides having a short Section of phosphodiester linked nucleosides having mixed backbones, either phosphate or non positioned between Sections of phosphoramidate, alkyl phosphate. The oligoribonucleotides and oligoribonucleo 15 phosphonate or phosphotriester linkages were constructed. Sides of the invention are complementary to target Strands of While the phosphoramidate-containing oligonucleotides ribonucleic acids and are useful for therapeutics, diagnostics were Stabilized against exonucleases, in reference (4) the and as research reagents. authors noted that each phosphoramidate linkage resulted in a loss of 1.6 C. in the measured T value of the BACKGROUND OF THE INVENTION phosphoramidate-containing oligonucleotides. Such a Oligonucleotides are known to hybridize to Single decrease in the T value is indicative of a decrease in stranded DNA or RNA molecules. Hybridization is the hybridization between the oligonucleotide and its target Sequence-specific base pair hydrogen bonding of nucleo Strand. bases of the oligonucleotides to nucleobases of target DNA Other authors have commented on the effect Such a loss or RNA. Such nucleobase pairs are Said to be complemen 25 of hybridization between an oligonucleotide and its target tary to one another. strand can have. Saison-Behmoaras et al. (EMBO Journal, The complementarity of oligonucleotides has been used 1991, 10, 1111) observed that even though an oligonucle for inhibition of a number of cellular targets. Such comple otide could be a Substrate for Rnase H, cleavage efficiency mentary oligonucleotides are commonly described as being by Rnase H was low because of weak hybridization to the antisense oligonucleotides. Various reviews describing the MRNA. The authors also noted that the inclusion of an results of these Studies have been published including acridine substitution at the 3' end of the oligonucleotide Progress. In AntiSense Oligonucleotide Therapeutics, protected the oligonucleotide from exonucleases. Crooke, S. T. and Bennett, C. F., Annu. Rev. Pharmacol. U.S. Pat. No. 5,013,830, issued May 7, 1991, discloses Toxicol., 1996, 36, 107-129. These oligonucleotides have mixed oligomers comprising an RNA oligomer, or a deriva proven to be very powerful research tools and diagnostic 35 tive thereof, conjugated to a DNA oligomer via a phosphodi agents. Further, certain oligonucleotides that have been ester linkage. The RNA oligomers also bear 2'-O-alkyl shown to be efficacious are currently in human clinical trials. Substituents. However, being phosphodiesters, the oligomers To date most oligonucleotides Studied have been oligode are Susceptible to nuclease cleavage. oxynucleotides. AntiSense oligodeoxynucleotides are 40 European Patent application 339,842, published Nov. 2, believed to cause a reduction in target RNA levels princi 1989, discloses 2'-O-substituted phosphorothioate pally through the action of RNase H, an endonuclease that oligonucleotides, including 2'-O-methylribooligonucleotide cleaves the RNA strand of DNA:RNA duplexes. This phosphorothioate derivatives. The above-mentioned appli enzyme, thought to play a role in DNA replication, has been cation also discloses 2'-O-methyl phosphodiester oligo nucleotides which lack nuclease resistance. shown to be capable of cleaving the RNA component of the 45 DNA:RNA duplexes in cell free systems as well as in U.S. Pat. No. 5,149,797, issued Sep. 22, 1992, discloses Xenopus oocytes. Rnase H is very Sensitive to structural mixed phosphate backbone oligonucleotides which include alterations in antisense oligonucleotides. This Sensitivity is an internal portion of deoxynucleotides linked by phos Such that prior attempts to increase the potency of oligo phodiester linkages, and flanked on each Side by a portion of nucleotides by increasing affinity, Stability, lipophilicity and 50 modified DNA or RNA sequences. The flanking sequences other characteristics by chemical modifications of the oli include methyl phosphonate, phosphoromorpholidate, phos gonucleotide have often resulted in oligonucleotides that are phoropiperaZidate or phosphoramidate linkages. no longer Substrates for Rnase H. In addition, Rnase H U.S. Pat. No. 5,256,775, issued Oct. 26, 1993, describes activity is quite variable. Thus a given disease State may not mixed oligonucleotides that incorporate phosphoramidate be a candidate for antisense therapy only because the target 55 linkages and phosphorothioate or phosphorodithioate link tissue has insufficient Rnase H activity. Therefore it is clear ageS. that effective terminating mechanisms in addition to Rnase U.S. Pat. No. 5,403,711, issued Apr. 4,
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