Oligoribonucleotides and ribonucleases for cleaving RNA

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target and comprises;

• a first segment having at least one ribofuranosyl nucleoside subunit that is modified to improve at least one of:
• pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
• affinity or specificity of said compound to said target RNA;
• or modification of the charge of said compound as compared to unmodified compound;
• and
• a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2′-hydroxyl moieties thereon;
• said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages.

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;

• a first segment having at least one 2′-O—C1-20 alkyl, 2′-O-substituted C1-20 alkyl or 2′-fluoro modified ribofuranosyl nucleoside subunit where the substitution on said alkyl is amino, hydroxy or C1-10 alkyl ether modification;
• a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2′-hydroxyl moieties thereon;
• and
• said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages that are stable to degradation as compared to phosphodiester bonds.

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA comprising at least twelve ribofuranosyl nucleosides in a sequence;

• said nucleoside subunits being joined by internucleoside bonds which are more stable to degradation as compared to phosphodiester bonds;
• the compound having two wing portions interspaced by a gap portion;
• the wing portions each comprising at least one modified nucleoside subunit, which modified nucleoside subunit is modified to improve at least one of:
• pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
• affinity or specificity of said compound to said target RNA;
• or modification of the charge of said compound as compared to unmodified compound;
• the gap portion having at least four consecutive ribonucleoside subunits.

A synthetic oligomeric compound comprising, in sequence;

• a first segment having a plurality of 2′-O-alkyl nucleoside subunits;
• a second segment having at least four consecutive 2′-hydroxyl ribonucleoside subunits;
• and
• a third segment having a plurality of 2′-O-alkyl nucleoside subunits;
• and
• the nucleoside subunits of the oligomer being joined by phosphorothioate internucleoside linkages.

A method for specifically cleaving a preselected RNA comprising contacting said RNA with an oligomeric compound comprising at least twelve ribofuranosyl nucleosides subunits in a sequence which is specifically hybridizable with said preselected RNA;

• said nucleoside subunits being joined by internucleoside bonds which are more stable to degradation as compared to phosphodiester bonds;
• the compound having at least one segment comprising at least one modified nucleoside subunit, which modified nucleoside subunit is modified to improve at least one of:
• pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
• affinity or specificity of said compound to said target RNA;
• or modification of the charge of said compound as compared to an unmodified compound;
• said compound having a further segment having at least four consecutive 2′-hydroxyl ribonucleoside subunits.

A method for treating an organism having a disease characterized by the undesired production of a protein comprising contacting the organism with an oligomeric compound of the invention having a sequence of nucleoside subunits capable of specifically hybridizing with a complementary strand of ribonucleic acid with at least one of the nucleoside subunits being modified to improve at least one of:

• pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
• affinity or specificity of said compound to said target RNA;
• or modification of the charge of said compound as compared to unmodified compound;
• a plurality of the nucleoside subunits being located in a consecutive sequence and having 2′-hydroxyl-pentofuranosyl sugar moieties.

A compositions including a pharmaceutically effective amount of an oligomeric compound in a pharmaceutically acceptable diluent or carrier, said oligomeric compound comprising a sequence of nucleoside subunits capable of specifically hybridizing with a complementary strand of RNA wherein a plurality of the nucleoside subunits of the oligomeric compound are modified to improve at least one of:

• pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
• affinity or specificity of said compound to said target RNA;
• or modification of the charge of said compound as compared to an unmodified compound;
• wherein a further plurality of the nucleoside subunits have 2′-hydroxyl-pentofuranosyl sugar moieties.

A method of concurrently enhancing hybridization and dsRNase enzyme activation in an organism comprising contacting the organism with an oligomeric compound having a sequence of nucleoside subunits capable of specifically hybridizing to a complementary strand of target RNA, where at least one of the nucleoside subunits is modified to improve at least one of:

• pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
• affinity or specificity of said compound to said target RNA;
• or modification of the charge of said compound as compared to unmodified compound;
• wherein a plurality of the nucleoside subunits have 2′-hydroxy-pentofuranosyl sugar moieties.

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;

• a first segment including at least one surrogate nucleoside subunit;
• a second segment comprising at least four ribofuranosyl nucleoside subunits located in a consecutive sequence and having 2′-hydroxyl moieties thereon;
• and
• said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages that are stable to degradation as compared to phosphodiester bonds.

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;

• a first segment including at least two nucleoside subunits;
• said nucleoside subunits of said first segment being connected by non-phosphorus internucleoside linkages;
• a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2′-hydroxyl moieties thereon;
• and
• said nucleoside subunits of said second segment being connected by internucleoside linkages that are stable to degradation as compared to phosphodiester bonds.

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;

• a first segment including at least three nucleoside subunits;
• said nucleoside subunits of said first segment being connected by alternating phosphorus, non-phosphorus internucleoside linkages;
• a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2′-hydroxyl moieties thereon;
• and
• said nucleoside subunits of said second segment being connected by internucleoside linkages that are more stable to degradation as compared to phosphodiester bonds.

A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;

• a first segment including at least two nucleoside subunits;
• said nucleoside subunits of said first segment being connected by 3′-deoxy-3′-thio-phosphorothioate, 5′-deoxy-5′-thio-phosphorothioate, phosphorodithioate, phosphoroselenate, 3′-deoxy phosphinate, 5′-deoxy phosphinate, borano phosphate, 3′-deoxy-3′-amino phosphoramidate, 5′-deoxy-5′-amino phosphoramidate, hydrogen phosphonate, borano phosphate ester, phosphoramidate, alkyl phosphonate, aryl phosphonate or phosphotriester phosphate linkages;
• and
• a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2′-hydroxyl moieties thereon;
• and
• said nucleoside subunits of said second segment being connected by internucleoside linkages that are more stable to degradation as compared to phosphodiester bonds.