Chimeric oligomeric compounds and their use in gene modulation

• US 9,096,636 B2
• Filed: 11/04/2003
• Issued: 08/04/2015
• Est. Priority Date: 06/06/1996
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Crooke, Stanley T.
• Primary Examiner(s): MCDONALD, JENNIFER SUE PITRAK
• Application Number:
  US10/701,265
• Publication Number:
  US 20040147023A1
• Time in Patent Office: 4,291 Days
• US Class Current: 1/1
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/342 Hemimers, i.e. of the type ====----
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3533 Halogen
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/51 modulating the chemical stability, e.g. nuclease-resistance

Abstract

Oligomer compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capble of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes at least one nucleotide comprising a chimeric organic composition. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleotide comprising a chimeric organic composition.

Claims

1. A composition comprising a duplex consisting of a first chemically synthesized oligonucleotide and a second chemically synthesized oligonucleotide, wherein:

each of the first chemically synthesized oligonucleotide and the second chemically synthesized oligonucleotide independently consists of 17 to 25 linked nucleosides, each nucleoside comprising a nucleobase and a sugar;

the first chemically synthesized oligonucleotide is 100% complementary to the second chemically synthesized oligonucleotide and to a target mRNA;

the first chemically synthesized oligonucleotide and the second chemically synthesized oligonucleotide are not covalently linked to each other; and

the first chemically synthesized oligonucleotide is a gapmer, wherein the gap comprises at least 4 nucleosides, each comprising a 2′

-hydroxy-pentofuranosyl sugar moiety, and wherein each nucleoside of each wing comprises a 2′

-sugar modification; and

the second chemically synthesized oligonucleotide comprises at least one nucleoside that comprises a 2′

-sugar modification.

2. The composition of claim 1, wherein the second chemically synthesized oligonucleotide is a gapmer, wherein the gap comprises at least 4 nucleosides, each comprising a 2′

-hydroxyl pentofuranosyl sugar moiety, and wherein each nucleoside of each wing comprises a 2′

modification.

3. The composition of claim 1, wherein each nucleoside of at least one of the wings of the gapmer comprises a 2′

sugar modification selected from fluoro, alkoxy, amino-alkoxy, allyloxy, imidazolylalkoxy, and methoxyethoxy.

4. The composition of claim 1, wherein each nucleoside of the 3′

wing of the gapmer comprises a 2′

-OCH₃.

5. The composition of claim 1, wherein each wing of the gapmer is from two to seven nucleosides in length.

6. The composition of claim 1, wherein at least one of the first chemically synthesized oligonucleotide and the second chemically synthesized oligonucleotide comprises at least one phosphorothioate linkage.

7. The composition of claim 6, wherein each of the first chemically synthesized oligonucleotide and the second chemically synthesized oligonucleotide comprises at least one phosphorothioate linkage.