Potent LNA oligonucleotides for the inhibition of HIF-1a expression

• US 9,447,138 B2
• Filed: 03/27/2013
• Issued: 09/20/2016
• Est. Priority Date: 11/09/2004
• Status: Expired due to Fees

• Current Assignee: Roche Innovation Center Copenhagen A/S (Roche Holding AG)
• Original Assignee: Roche Innovation Center Copenhagen A/S (Roche Holding AG)
• Inventors: Thrue, Charlotte Albaek, Westergaard, Majken, Rasmussen, Frank Winther, Hansen, Henrik Frydenlund
• Primary Examiner(s): Angell, Jon E
• Application Number:
  US13/851,294
• Publication Number:
  US 20140294897A1
• Time in Patent Office: 1,273 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: C07H 21/04 with deoxyribosyl 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 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

The present disclosure relates to an LNA oligonucleotide consisting of a sequence selected from the group consisting of 5′-(T_x)G_xG_xc_sa_sa_sg_sc_sa_st_sc_sc_sT_xG_xT-3′ and 5′-(G_x)T_xT_xa_sc_st_sg_sc_sc_st_st_sc_sT_xT_xA-3′, wherein capital letters designate a beta-D-oxy-LNA nucleotide analogue, small letters designate a 2-deoxynucleotide, underline designates either a beta-D-oxy-LNA nucleotide analogue or a 2-deoxynucleotide, subscript “s” designates a phosphorothioate link between neighbouring nucleotides/LNA nucleotide analogues, and subscript “x” designates either a phosphorothioate link or a phosphorodiester link between neighbouring nucleotides/LNA nucleotide analogues, and wherein the sequence is optionally extended by up to five 2-deoxynucleotide units. The LNA oligonucleotides are useful for modulating the expression of hypoxia-inducible factor-1a (HIF-1a), e.g. in the treatment of cancer diseases, inhibiting angiogenesis, inducing apoptosis, preventing cellular proliferation, or treating an angiogenic disease, e.g. diabetic retinopathy, macular degeneration (ARMD), psoriasis, rheumatoid arthritis and other inflammatory diseases.

Claims

1. A method of treating an angiogenic disease selected from macular degeneration and diabetic retinopathy, the method comprising administering to a patient in need thereof a therapeutically effective amount of the LNA oligonucleotide

5′

-T_sG_sG_sc_sa_sa_sg_sc_sa_st_sc_sc_sT_sG_sT_sa-3′

(SEQ ID NO;

     1),

wherein the capital letters designate a beta-D-oxy-LNA nucleotide analogue, lower case letters designate a 2-deoxynucleotide, and subscript “

s”

designates a phosphorothioate link between neighboring nucleotides/LNA nucleotide analogues,

or a conjugate of the LNA oligonucleotide or a composition comprising the LNA oligonucleotide or the conjugate thereof.

2. The method of claim 1, wherein the LNA oligonucleotide, the conjugate of the LNA oligonucleotide, or the composition is administered parenterally.

3. The method of claim 1, wherein the LNA oligonucleotide, the conjugate of the LNA oligonucleotide, or the composition is administered intravenously.

4. The method of claim 1, wherein the LNA oligonucleotide, the conjugate of the LNA oligonucleotide, or the composition is administered by bolus injection into a target organ.