Granted Patent B2

US 12,203,071 · App. 17/320,139 · Granted Jan 21, 2025

Inventors: Ravi Jagasia (Basel, CH); Lars Joenson (Hørsholm, DK); Søren Rasmussen (Hørsholm, DK); Disa Tehler (Hørsholm, DK); Dorthe Vang Larsen (Hørsholm, DK); Jesper Worm (Hørsholm, DK)

Assignee: Hoffmann-La Roche Inc.

C12N15/113A61P25/00C12N2310/11C12N2310/315C12N2310/3231C12N2310/3341

Abstract

Claims (17)

1. An antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-40 nucleotides in length and comprises a contiguous nucleotide sequence of 12-40 nucleotides in length which are complementary to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript wherein the contiguous nucleotide sequence is selected from:

SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO:110, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:119, SEQ ID NO:125, SEQ ID NO:228, SEQ ID NO:231, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:246; SEQ ID NO:263, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:270, SEQ ID NO:271, SEQ ID NO:272, SEQ ID NO:279, SEQ ID NO:280, SEQ ID NO:293, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:305, SEQ ID NO:311, SEQ ID NO:312, or SEQ ID NO:327;

and further wherein the antisense oligonucleotide progranulin agonist comprises one or more modified nucleosides.

2. The antisense oligonucleotide progranulin agonist of claim 1 , wherein the human progranulin mature mRNA transcript is SEQ ID NO:1.

3. The antisense oligonucleotide progranulin agonist of claim 1 , wherein the human progranulin precursor-mRNA (pre-mRNA) is SEQ ID NO:3949.

4. The antisense oligonucleotide progranulin agonist according to claim 1 , wherein the contiguous nucleotide sequence is the same length as the antisense oligonucleotide.

5. The antisense oligonucleotide progranulin agonist according to claim 1 , wherein the contiguous nucleotide sequence is fully complementary to the human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

6. The antisense oligonucleotide progranulin agonist according to claim 1 , wherein the antisense oligonucleotide progranulin agonist is or comprises an antisense oligonucleotide mixmer or totalmer.

7. An antisense oligonucleotide progranulin agonist of SEQ ID NO 106 and having the structure:

8. An antisense oligonucleotide progranulin agonist wherein the oligonucleotide is the oligonucleotide compound TgGccAggGatCagGG (SEQ ID NO: 106) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

9. An antisense oligonucleotide progranulin agonist according to claim 1 covalently attached to at least one conjugate moiety.

10. An antisense oligonucleotide progranulin agonist according to any one of claim 1 wherein the antisense oligonucleotide progranulin agonist is in the form of a pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising the antisense oligonucleotide progranulin agonist according to claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

12. An in vivo or in vitro method for enhancing the expression of progranulin in a cell which is expressing progranulin, said method comprising administering an antisense oligonucleotide progranulin agonist according to claim 1 , in an effective amount to said cell.

13. An antisense oligonucleotide progranulin agonist according to claim 10 wherein the pharmaceutically acceptable salt is a sodium salt or potassium salt.

14. A pharmaceutical composition according to claim 11 , wherein the pharmaceutical composition comprises an aqueous diluent or solvent.

15. A pharmaceutical composition according to claim 14 wherein the aqueous diluent or solvent is phosphate buffered saline.

Assignments (9)

Priority Claims (2)

Continuity (1)

References Cited (91)