Oligonucleotide compositions and methods thereof

• US 10,724,035 B2
• Filed: 05/03/2017
• Issued: 07/28/2020
• Est. Priority Date: 05/04/2016
• Status: Active Grant

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: WAVE Life Sciences Ltd.
• Inventors: Vargeese, Chandra, Meena, Svrzikapa, Nenad, Mohapatra, Susovan, Francis, Christopher J., Verdine, Gregory L., Sokolovska, Anna
• Primary Examiner(s): McDonald, Jennifer Pitrak
• Application Number:
  US16/098,836
• Publication Number:
  US 20200056173A1
• Time in Patent Office: 1,182 Days
• Field of Search: None
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/34 Spatial arrangement of the modifications
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/50 Physical structure
• CPC Class Codes: C12N 2320/50 Methods for regulating/modulating their activity

Abstract

Among other things, the present disclosure relates to chirally controlled oligonucleotides of select designs, chirally controlled oligonucleotide compositions, and methods of making and using the same. In some embodiments, a provided chirally controlled oligonucleotide composition provides different cleavage patterns of a nucleic acid polymer than a reference oligonucleotide composition. In some embodiments, a provided chirally controlled oligonucleotide composition provides single site cleavage within a complementary sequence of a nucleic acid polymer. In some embodiments, a chirally controlled oligonucleotide composition has any sequence of bases, and/or pattern or base modifications, sugar modifications, backbone modifications and/or stereochemistry, or combination of these elements, described herein.

Claims

1. An oligonucleotide having the structure of:

mG * SmUmGmCmA * SC * SA * SC * SA * SG * ST * SA * SG * RA * ST * SmGmAmGmG * SmG (SEQ ID NO;

     1467), or a pharmaceutically acceptable salt thereof, wherein;

*S represents a Sp phosphorothioate;

*R represents a Rp phosphorothioate; and

m represents a 2′

-OMe modification to a nucleoside.

2. The oligonucleotide of claim 1, wherein the oligonucleotide is in a salt form.

3. The oligonucleotide of claim 1, wherein the salt is a sodium salt.

4. An oligonucleotide, wherein the oligonucleotide is a sodium salt of:

mG * SmUmGmCmA * SC * SA * SC * SA * SG * ST * SA * SG * RA * ST * SmGmAmGmG * SmG (SEQ ID NO;

     1467), wherein;

*S represents a Sp phosphorothioate;

*R represents a Rp phosphorothioate;

m represents a 2′

-OMe modification to a nucleoside; and

the number of sodium ions in the sodium salt equals the total number of phosphorothioate and phosphate linkages in the oligonucleotide.

5. A chirally controlled composition of an oligonucleotide having the structure of:

mG * SmUmGmCmA * SC * SA * SC * SA * SG * ST * SA * SG * RA * ST * SmGmAmGmG * SmG (SEQ ID NO;

     1467), or a pharmaceutically acceptable salt thereof, wherein;

*S represents a Sp phosphorothioate;

*R represents a Rp phosphorothioate; and

m represents a 2′

-OMe modification to a nucleoside,

wherein the composition is enriched, relative to a substantially racemic preparation of the oligonucleotide for the oligonucleotide.

6. The composition of claim 5, wherein the oligonucleotide is in a salt form.

7. The composition of claim 5, wherein the oligonucleotide is a sodium salt.

8. The composition of claim 7, wherein the number of sodium ions in the sodium salt equals the total number of phosphorothioate and phosphate linkages in the oligonucleotide.

9. A pharmaceutical composition, comprising a therapeutically effective amount of an oligonucleotide and at least one pharmaceutically acceptable inactive ingredient selected from pharmaceutically acceptable diluents, pharmaceutically acceptable excipients, and pharmaceutically acceptable carriers, wherein the oligonucleotide has the structure of:

mG * SmUmGmCmA * SC * SA * SC * SA * SG * ST * SA * SG * RA * ST * SmGmAmGmG * SmG (SEQ ID NO;

     1467), or a pharmaceutically acceptable salt thereof, wherein;

*S represents a Sp phosphorothioate;

*R represents a Rp phosphorothioate; and

m represents a 2′

-OMe modification to a nucleoside.

10. The composition of claim 9, wherein the oligonucleotide is in a salt form.

11. The composition of claim 9, wherein the oligonucleotide is a sodium salt.

12. The composition of claim 9, wherein the number of sodium ions in the sodium salt equals the total number of phosphorothioate and phosphate linkages in the oligonucleotide.