Treatment of alpha-L-iduronidase (IDUA) related diseases by inhibition of natural antisense transcript to IDUA

• US 9,873,873 B2
• Filed: 10/28/2015
• Issued: 01/23/2018
• Est. Priority Date: 10/22/2010
• Status: Active Grant

• Current Assignee: CURNA, Inc. (Opko Health, Inc.)
• Original Assignee: CURNA, Inc. (Opko Health, Inc.)
• Inventors: Collard, Joseph, Khorkova Sherman, Olga, Coito, Carlos, Shen, Gang
• Primary Examiner(s): WHITEMAN, BRIAN A
• Application Number:
  US14/925,196
• Publication Number:
  US 20160130584A1
• Time in Patent Office: 818 Days
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/1034 Isolating an individual clone by screening libraries
• 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 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• 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 2320/50 Methods for regulating/modulating their activity
• CPC Class Codes: C12N 2330/10 naturally occurring
• CPC Class Codes: C12Y 302/01076 L-Iduronidase (3.2.1.76)
• CPC Class Codes: G01N 33/5308 for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites

Abstract

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Alpha-L-Iduronidase (IDUA), in particular, by targeting natural antisense polynucleotides of Alpha-L-Iduronidase (IDUA). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of IDUA.

Claims

1. A synthetic, modified oligonucleotide of 10 to 30 nucleotides in length comprising at least one modification wherein the at least one modification is selected from:

at least one modified sugar moiety;

at least one modified intemucleotide linkage;

at least one modified nucleotide, and combinations thereof;

wherein said oligonucleotide is an antisense compound which is 100% complementary to and specifically hybridizes to a target region of a natural antisense polynucleotide of an Alpha-L-Iduronidase (IDUA) gene selected from SEQ ID NO;

2 but excluding a region complementary to SEQ ID NO;

12 and which upregulates the function and/or expression of an Alpha-L-Iduronidase (IDUA) gene in vivo or in vitro as compared to a normal control.

2. The oligonucleotide according to claim 1 wherein said oligonucleotide is 12 to 30 nucleotides in length.

3. The oligonucleotide of claim 1, wherein the at least one modification comprises an intemucleotide linkage selected from the group consisting of:

phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof.

4. The oligonucleotide of claim 1, wherein said oligonucleotide comprises at least one phosphorothioate intemucleotide linkage.

5. The oligonucleotide of claim 1, wherein said oligonucleotide comprises a backbone of phosphorothioate intemucleotide linkages.

6. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified nucleotide, said modified nucleotide selected from:

a peptide nucleic acid, a locked nucleic acid (LNA), analogue, derivative, and a combination thereof.

7. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified nucleotides selected from:

phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and a combination thereof.

8. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified nucleotides selected from:

peptide nucleic acids, locked nucleic acids (LNA), analogues, derivatives, and a combination thereof.

9. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified sugar moiety selected from:

a 2′

-O-methoxyethyl modified sugar moiety, a 2′

-methoxy modified sugar moiety, a 2′

-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and a combination thereof.

10. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified sugar moieties selected from:

a 2′

-O-methoxyethyl modified sugar moiety, a 2′

-methoxy modified sugar moiety, a 2′

-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and a combination thereof.

11. The oligonucleotide of claim 1, wherein the oligonucleotide is of at least about 15 to 30 nucleotides in length.

12. The oligonucleotide of claim 2, wherein the oligonucleotide comprises the sequences set forth as SEQ ID NOS:

10, 11, 17, 19, 20, 21, 22, 23 and 25.

13. A pharmaceutical composition comprising one or more oligonucleotides according to claim 1 and a pharmaceutically acceptable excipient.

15. The composition of claim 13, wherein the oligonucleotides comprise nucleotide sequences set forth as SEQ ID NOS:

10, 11, 17, 19, 20, 21, 22, 23 and 25.

16. The composition of claim 15, wherein the oligonucleotides set forth as SEQ ID NOS:

10, 11, 17, 19, 20, 21, 22, 23 and 25 comprise one or more modifications or substitutions.

17. The composition of claim 16, wherein the one or more modifications are selected from:

phosphorothioate, methylphosphonate, peptide nucleic acid, locked nucleic acid (LNA) molecules, and combinations thereof.

14. A pharmaceutical composition comprising an oligonucleotide having at least about 95% sequence identity as compared to any one of the nucleotide sequences set forth as SEQ ID NOS:

10, 11, 17, 19, 20, 21, 22, 23 and 25 and a pharmaceutically acceptable excipient.