Antisense modulation of serum amyloid A4 expression

• US 6,455,308 B1
• Filed: 08/01/2001
• Issued: 09/24/2002
• Est. Priority Date: 08/01/2001
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Freier, Susan M.
• Primary Examiner(s): LeGuyader, John L.
• Assistant Examiner(s): SCHMIDT, MARY M
• Application Number:
  US09/920,672
• Time in Patent Office: 419 Days
• Field of Search: 435/6, 435/366, 435/325, 435/375, 536/23.1, 536/24.5, 514/44
• US Class Current: 435/375
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of serum amyloid A4. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding serum amyloid A4. Methods of using these compounds for modulation of serum amyloid A4 expression and for treatment of diseases associated with expression of serum amyloid A4 are provided.

Claims

1. A compound 18 to 50 nucleobases in length targeted to nucleobases 114 through 137, nucleobases 158 through 223, nucleobases 230 through 249, nucleobases 282 through 357, or nucleobases 385 through 406 of a coding region of a nucleic acid molecule encoding human serum amyloid A4 of SEQ ID NO:

3, wherein said compound specifically hybridizes with one of said regions and inhibits the expression of human serum amyloid A4.

2. The compound of claim 1 which is an antisense oligonucleotide.

4. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.

5. The compound of claim 4 wherein the modified internucleoside linkage is a phosphorothioate linkage.

6. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

7. The compound of claim 6 wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

8. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

9. The compound of claim 8 wherein the modified nucleobase is a 5-methylcytosine.

10. The compound of claim 2 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

11. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

12. The composition of claim 11 further comprising a colloidal dispersion system.

13. The composition of claim 11 wherein the compound is an antisense oligonucleotide.

14. A method of inhibiting the expression of human serum amyloid A4 in cells or tissues comprising contacting said cells or tissues in vitro with the compound of claim 1 so that expression of human serum amyloid A4 is inhibited.

3. A compound up to 50 nucleobases in length comprising at least an 18 nucleobase portion of SEQ ID NO:

14, 16, 17, 19, 20, 21, 24, 26, 28, 29, 36, 38, 41, 49, 53, 58, 59, 60, 61, 65 or 69 which inhibits the expression of human serum amyloid A4.

15. The compound of claim 3 which is an antisense oligonucleotide.

16. The compound of claim 15 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.

17. The compound of claim 16 wherein the modified internucleoside linkage is a phosphorothioate linkage.

18. The compound of claim 15 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

19. The compound of claim 18 wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

20. The compound of claim 15 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

21. The compound of claim 20 wherein the modified nucleobase is a 5-methylcytosine.

22. The compound of claim 15 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

23. A composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier or diluent.

24. The composition of claim 23 further comprising a colloidal dispersion system.

25. The composition of claim 23 wherein the compound is an antisense oligonucleotide.

26. A method of inhibiting the expression of human serum amyloid A4 in cells or tissues comprising contacting said cells or tissues in vitro with the compound of claim 3 so that expression of human serum amyloid A4 is inhibited.