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

Patent metadata

Field	Value
Publication number	US-9447138-B2
Application number	US-201313851294-A
Country	US
Kind code	B2
Filing date	Mar 27, 2013
Priority date	Nov 9, 2004
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

The present disclosure relates to an LNA oligonucleotide consisting of a sequence selected from the group consisting of 5′-( T x )G x G x c s a s a s g s c s a s t s c s c s T x G x T -3′ and 5′-( G x )T x T x a s c s t s g s c s c s t s t s c s T x T x A -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.

First claim

The invention claimed is:

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 s G s G s c s a s a s g s c s a s t s c s c s T s G s T s a-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.

Assignees

• Santaris Pharma As
• Roche Innovation Ct Copenhagen As

Inventors

• Westergaard Majken
• Thrue Charlotte Albaek
• Rasmussen Frank Winther
• Hansen Henrik Frydenlund

Classifications

• C12N2310/315

  Phosphorothioates · CPC title

• C12N15/113 Primary

  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 title

• C07H21/04 Primary

  with deoxyribosyl as saccharide radical · CPC title

• C12N2310/341

  Gapmers, i.e. of the type ===---=== · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title