Oligonucleotide compositions and methods thereof

• US 10,450,568 B2
• Filed: 09/23/2018
• Issued: 10/22/2019
• Est. Priority Date: 10/09/2015
• Status: Expired due to Fees

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: WAVE Life Sciences Ltd.
• Inventors: Butler, David Charles Donnell, Divakaramenon, Sethumadhavan, Francis, Christopher J., Frank-Kamenetsky, Maria David, Iwamoto, Naoki, Lu, Genliang, Marappan, Subramanian, Meena, Vargeese, Chandra, Verdine, Gregory L., Yang, Hailin, Zhang, Jason Jingxin
• Primary Examiner(s): McDonald, Jennifer Pitrak
• Application Number:
  US16/139,091
• Publication Number:
  US 20190008986A1
• Time in Patent Office: 394 Days
• Field of Search: None
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 48/0016 wherein the nucleic acid is delivered as a 'naked' nucleic acid, i.e. not combined with an entity such as a cationic lipid
• CPC Class Codes: A61K 48/0066 Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: C07F 9/59 Hydrogenated pyridine rings
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/343 having patterns, e.g. ==--==--==--
• 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 2320/33 : Alteration of splicing

Abstract

Among other things, the present disclosure relates to designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide altered splicing of a transcript. In some embodiments, provided oligonucleotide compositions have low toxicity. In some embodiments, provided oligonucleotide compositions provide improved protein binding profiles. In some embodiments, provided oligonucleotide compositions have improved delivery. In some embodiments, provided oligonucleotide compositions have improved uptake. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions.

Claims

1. An oligonucleotide having the structure of:

fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*Sf*SfU*SfU*SfU*SfC*SfU (SEQ ID NO;

     773),

or a pharmaceutically acceptable salt thereof, wherein;

f represents a 2′

-F modification to a nucleoside;

S represents a Sp 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 form is a sodium salt.

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

fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*SfU*SfU*SfU*SfC*SfU (SEQ ID NO;

     773), wherein;

f represents a 2′

-F modification to a nucleotide;

*S represents Sp 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:

fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*SfU*SfU*SfU*SfC*SfU (SEQ ID NO;

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

f represents a 2′

-F modification to a nucleoside;

*S represents a Sp 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.

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

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

10. 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.

6. 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:

fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*SfU*SfU*SfU*SfC*SfU (SEQ ID NO;

     773), or pharmaceutically acceptable salt thereof, wherein;

f represents a 2′

-F modification to a nucleoside;

*S represents a Sp phosphorothioate; and

m represents a 2′

-OMe modification to a nucleoside.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a solution.

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

12. The composition of claim 6, wherein the oligonucleotide is a sodium salt.

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