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Gapped 2' modified oligonucleotides
| Details |
Inventors: Cook, Phillip Dan; Monia, Brett P.;
Assignee: Isis Pharmaceuticals, Inc. (Carlsbad, CA)
Primary Examiner: Schwartzman; Robert A.
Assistant Examiner: Larson; Thomas G.
Attorney, Agent or Firm: Woodcock Washburn Kurtz Mackiewicz & Norris LLP
Oligonucleotides and other macromolecules are provided that have increased nuclease resistance, substituent groups for increasing binding affinity to complementary strand, and sub-sequences of 2'-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H enzyme. Such oligonucleotides and macromolecules are useful for diagnostics and other research purposes, for modulating protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to antisense therapeutics. |
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DETAILED DESCRIPTION OF THE INVENTION In accordance with the objects of this invention, novel oligonucleotides and macromolecules that, at once, have increased nuclease resistance, increased binding affinity to complementary strands and that are substrates for RNase H are provided.
The oligonucleotides and macromolecules of the invention are assembled from a plurality of nucleotide, nucleoside or nucleobase sub-units.
Each oligonucleotide or macromolecule of the invention includes at least one nucleotide, nucleoside or nucleobase unit that is functionalized to increase the nuclease resistances of the oligonucleotide.
Further, in certain embodiments of the invention at least some of the nucleotide or nucleoside units bear a substituent group that increases the binding affinity of the oligonucleotide or macromolecule to a complementary strand of nucleic acid.
Additionally at least some of the nucleotide units comprise a 2'-deoxy-erythro-pentofuranosyl group as their sugar moiety.
In conjunction with the above guidelines, each nucleotide unit of an oligonucleotides of the invention, alternatively referred to as a subunit, can be a "natural" or a "synthetic" moiety.
Thus, in the context of this invention, the term "oligonucleotide" in a first instance refers to a polynucleotide formed from a plurality of joined nucleotide units.
The nucleotides units are joined together via native internucleoside, phosphodiester linkages.
The nucleotide units are formed from naturally-occurring bases and pentofuranosyl sugars groups.
The term "oligonucleotide" thus effectively includes naturally occurring species or synthetic species formed from naturally occurring nucleotide units.
Oligonucleotides of the invention also can include modified subunits.
The modifications can occur on the base portion of a nucleotide, on the sugar portion of a nucleotide or on the linkage joining one nucleotide to the next.
In addition, nucleoside units can be joined via connecting groups that substitute for the inter-nucleoside phosphate linkages
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Gene Therapy 
