Oligomers Having Bicyclic Scaffold Moeities

• US 20180028554A1
• Filed: 07/05/2017
• Published: 02/01/2018
• Est. Priority Date: 07/05/2016
• Status: Abandoned Application

• Current Assignee: BioMarin Technologies B.V.
• Original Assignee: BioMarin Technologies B.V.
• Inventors: Van DEUTEKOM, Judith Christina Theodora, de VISSER, Peter Christian
• Application Number:
  US15/642,270
• Publication Number:
  US 20180028554A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/11 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 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

The current invention provides oligomers with improved characteristics that enhance clinical applicability for treating, ameliorating, preventing a disorder or disease.

Claims

1. An oligomer comprising linked monomers, wherein:

(i) a) at least one monomer has formula I;

11. The oligomer of claim 1, wherein the oligomer comprises the sequence GGAAGAUGGCAU (SEQ ID NO:

6072).

12. The oligomer of claim 1, wherein the oligomer has a length of 16, 17, 18, 19, 20, 21, or 22 nucleotides.

13. The oligomer of claim 1, wherein the oligomer has a length of 16, 18, 20, or 22 nucleotides.

14. The oligomer of claim 1, wherein the oligomer has SEQ ID NO:

453, 455, 456, 453, 455, 456, 459, 461, 462, 465, 467, 468, 471, 473, 474, 483, 486, 525, 531, 538, 539, 540, 543, 545, 546, or 4528-4572.

15. The oligomer of claim 1, wherein the oligomer comprises the sequence GGUAAGUUCNGUCCAAGC (SEQ ID NO:

6073).

16. The oligomer of claim 1, wherein the oligomer is selected from the group consisting of SEQ ID NOs:

4561-4572.

17. The oligomer of claim 1, wherein the oligomer comprises the sequence AAGAUGGCAU (SEQ ID NO:

6085).

18. The oligomer of claim 1, wherein the oligomer is SEQ ID NO:

459.

19. The oligomer of claim 1, wherein the oligomer comprises the sequence UAAGUUCUGUCCAA (SEQ ID NO:

6086).

20. The oligomer of claim 1, wherein the oligomer is SEQ ID NO:

4565.

2. An oligomer having 10 to 33 linked monomer subunits, wherein:

a) at least one monomer has formula I;

3. The oligomer of claim 2, wherein R is unsubstituted alkyl, or CH₃, or ethyl.

4. The oligomer of claim 2, wherein R¹ is CH₃.

5. The oligomer of claim 2, wherein X is F or —

OR.

6. The oligomer of claim 2, wherein X is F or —

OCH₃.

7. The oligomer of claim 2, wherein Z—

Y is a divalent group selected from —

(CH₂)_nO—

, —

CH(CH₃)O— and

—

CH(CH₂OCH₃)O—

.

8. The oligomer of claim 2, wherein Z—

Y is —

CH₂O—

.

9. The oligomer of claim 2, wherein the oligonucleotide comprises the sequence GGAAGAUGGCAU.

10. An oligonucleotide having a length from 10 to 33 nucleotides comprising:

i) only 2′

-substituted monomers linked by phosphorothioate backbone linkages and/or by phosphodiester linkages,

ii) a 5-methylcytosine base, and

iii) at least one monomer comprising a bicyclic nucleic acid (BNA) scaffold modification,

wherein said oligonucleotide is complementary to or binds to or targets or hybridizes with at least a part of dystrophin pre-mRNA exons 2 to 78.

21. An oligonucleotide according to claim 10, wherein said oligonucleotide comprises a continuous stretch of at least 10 and up to 33 nucleotides of at least one of the nucleotide sequences selected from SEQ ID NO:

6065 to 6070, preferably of SEQ ID NO;

6067.

22. An oligonucleotide according to claim 10, wherein said oligonucleotide comprises 1, 2, 3, or 4 monomers that comprise a bicyclic nucleic acid (BNA) scaffold modification, preferably a bridged nucleic acid scaffold modification.

23. An oligonucleotide according to claim 10, wherein at least one bicyclic nucleic acid (BNA) scaffold modification is comprised in a terminal monomer of said oligonucleotide, preferably in the 5′

-terminal monomer of said oligonucleotide, more preferably in both terminal monomers of said oligonucleotide.

24. An oligonucleotide according to claim 10, wherein each occurrence of said bicyclic nucleic acid (BNA) scaffold modification results in a monomer that is independently chosen from the group consisting of

a locked nucleic acid (LNA) monomer, a conformationally restrained nucleotide (CRN) monomer, a xylo-LNA monomer, an α

-L-LNA monomer, a β

-D-LNA monomer, a 2′

-amino-LNA monomer, a 2′

-(alkylamino)-LNA monomer, a 2′

-(acylamino)-LNA monomer, a 2′

-N-substituted-2′

-amino-LNA monomer, a (2′

-O,4′

-C) constrained ethyl (cEt) LNA monomer, a (2′

-O,4′

-C) constrained methoxyethyl (cMOE) BNA monomer, a 2′

,4′

-BNA^NC(N—

H) monomer, a 2′

,4′

-BNA^NC(N-Me) monomer, an ethylene-bridged nucleic acid (ENA) monomer, a 2′

-C-bridged bicyclic nucleotide (CBBN) monomer, and derivatives thereof,

preferably chosen from the group consisting of an LNA monomer, an ENA monomer, a cEt BNA monomer, an oxo-CBBN monomer, a 2′

-amino-LNA monomer, and a cMOE BNA monomer,

more preferably chosen from the group consisting of an LNA monomer, an ENA monomer, a cEt BNA monomer, or a cMOE BNA monomer,

most preferably the BNA scaffold modification results in an LNA monomer.

25. An oligonucleotide according to claim 10, wherein said 2′

-substituted monomer is a 2′

-substituted RNA monomer, a 2′

-F monomer, a 2′

-amino monomer, a 2′

-O-substituted monomer, a 2′

-O-methyl monomer, or a 2′

-O-(2-methoxyethyl) monomer, preferably a 2′

-O-methyl monomer.

26. An oligonucleotide according to claim 10, wherein all cytosine bases are 5-methylcytosine bases, and/or wherein all uracil bases are 5-methyluracil bases.

27. An oligonucleotide according to claim 10, wherein the length of said oligonucleotide is less than 24 nucleotides.

28. An oligonucleotide according to claim 10, wherein said oligonucleotide comprises or consists of a sequence which is complementary to or binds or targets or hybridizes at least a part of an exon recognition sequence (ERS), an exonic splicing silencer (ESS), an intronic splicing silencer (ISS), an SR protein binding site, or another splicing element, signal, or structure.

29. An oligonucleotide according to claim 10, wherein said oligonucleotide induces pre-mRNA splicing modulation, preferably said pre-mRNA splicing modulation alters production or composition of protein, which preferably comprises exon skipping or exon inclusion, wherein said RNA modulation most preferably comprises exon skipping.

30. An oligonucleotide according to claim 10, wherein said oligonucleotide has an improved parameter by comparison to a corresponding oligonucleotide that does not comprise a bicyclic nucleic acid (BNA) scaffold modification.

31. An oligonucleotide according to claim 10, wherein:

a) at least one monomer has formula I;

32. A composition comprising an oligonucleotide as defined in claim 10, preferably wherein said composition comprises at least one excipient that may further aid in enhancing the targeting and/or delivery of said composition and/or said oligonucleotide to a tissue and/or cell and/or into a tissue and/or cell.

33. An oligonucleotide according to claim 10, or a composition according to claim 32 for use as a medicament, preferably for treating, preventing, and/or delaying Duchenne Muscular Dystrophy (DMD).

34. A method for preventing, treating, and/or delaying Duchenne Muscular Dystrophy (DMD), comprising administering to a subject an oligonucleotide as defined in claim 10, or a composition as defined in claim 32.