HBV antisense inhibitors

一种反义、反义寡核苷酸的技术，应用在反义寡聚体领域，能够解决限制治疗效果、HBeAg血清转换率HBsAg损失率低等问题

Inactive Publication Date: 2012-10-31
GLAXO GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The nucleoside and nucleotide therapeutics entecavir and tenofovir were successful in reducing viral load, but rates of HBeAg seroconversion and HBsAg loss were even lower than those obtained with IFNα therapeutics
Other similar therapeutics are also used, including lamivudine (3TC), telbivudine (LdT), and adefovir, but for nucleoside / nucleotide therapeutics, in general, the emergence of resistance will Limit Healing Effects

Method used

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  • HBV antisense inhibitors
  • HBV antisense inhibitors
  • HBV antisense inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1: Antisense inhibition of hepatitis B virus expression in HepG2 2.2.15 cells by LNA antisense oligonucleotides

[0161] Locked nucleic acid oligonucleotides were purchased from Exiqon. The total length of the LNA antisense oligonucleotides tested was 16 nucleotides, each had a 4LNA-8nt-4LNA motif, and each contained a central nucleotide (nt) gap segment with 8 consecutively linked 2'-deoxynucleotides. The nt gap segment in each 16-mer ASO is flanked by wing segments on both sides (5' and 3'). Each wing segment in each ASO has 4 consecutively linked nucleotides. Each nucleotide of each wing in each ASO has a locked nucleic acid (LNA) sugar modification. Every internucleotide linkage throughout every LNA antisense oligonucleotide is a phosphorothioate (P=S) linkage, although it is envisioned that certain nucleotides on certain ASOs of the invention Interlinkages can be linkages other than phosphorothioate, including phosphodiester linkages. The LNA motif f...

Embodiment 2

[0169] Example 2: Antisense inhibition of hepatitis B virus or SV40 T antigen expression in HepAD38 (Tet-HBV) cells by LNA antisense oligonucleotides

[0170] An HBV-targeting LNA antisense oligonucleotide was designed with the sequence GAGGCATAGCAGCAGG (SEQ ID NO: 16), which is complementary to the DNA sequence depicted in SEQ ID NO: 4 and GENBANK Accession No. U95551.1, incorporated herein as SEQ ID NO: 16. The total length of the LNA antisense oligonucleotide is 16 nucleotides with a 4-8-4 LNA motif, wherein the ASO has a central gap segment with 8 consecutively linked 2'- deoxynucleotides. The gap segments flank the wing segments on both sides (5' and 3'). Each wing segment has 4 consecutively linked nucleotides. Each nucleotide of each wing has a locked nucleic acid (LNA) sugar modification. Each internucleotide linkage throughout the LNA antisense oligonucleotide is a phosphorothioate (P=S) linkage. Each cytosine of the LNA antisense oligonucleotide is 5-methylcyt...

Embodiment 3

[0177] Example 3: Antisense inhibition of hepatitis B virus or SV40 T antigen expression in THT1 cells by LNA antisense oligonucleotides

[0178] The LNA antisense oligonucleotides described in Example 3 were evaluated for their ability to reduce HBV mRNA in THT1 cells (also called HepG2 2.2.15 cells). These cells were transfected by electroporation with 741 nM, 2,222 nM, 6,667 nM and 20,000 nM antisense oligonucleotides over a period of approximately 24 hours. RNA was isolated from cells and HBV mRNA levels were measured by quantitative real-time PCR. HBV mRNA levels were adjusted according to the total RNA content measured by RIBOGREEN. Data are shown in Table 4 expressed as percent inhibition of mRNA levels compared to untreated cells. As shown in Table 4, the LNA antisense oligonucleotides reduced HBV mRNA levels in a dose-dependent manner.

[0179] Table 4 The dose-dependent antisense suppression of HBV mRNA in HepG2 cells

[0180]

[0181] (B) Evaluation of anti...

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PUM

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Abstract

Antisense oligomers useful for modulating hepatitis B virus infections, and for the treatment of hepatitis B virus (HBV) and hepatitis B virus-related conditions in animals including humans. More particularly, antisense oligomers with modified nucleotides for treatment of HBV in animals, more particularly antisense oligomers comprising 2'O-4'C- methylene-bridged sugars, or nucleotides with other 2'O-4'C bridged sugars, also known as locked nucleic acids (LNA), for treatment of HBV in animals, and more particularly for treatment of HBV in humans.

Description

technical field [0001] The present invention relates to antisense oligonucleotides useful for modulating gene expression and thereby treating diseases, in particular antisense oligonucleotides for treating hepatitis B virus (HBV) and HBV-related disorders in animals, including humans body. More specifically, embodiments of the present invention relate to antisense oligomers having modified nucleosides for use in the treatment of HBV in animals, more specifically, said antisense oligomers comprising Nucleosides of methylene-bridged sugars and nucleosides with other bridged sugars as otherwise described herein, also known as locked nucleic acids (LNAs), for use in the treatment of HBV in animals, more specifically, for Treatment of HBV in humans. Background technique [0002] Hepatitis B is a viral disease that is transmitted parenterally (through contaminants such as blood and blood products, contaminated needles), sexually, and vertically from infected or carrier mothers t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7115A61K31/7125
CPCA61K31/7115A61K31/7125A61P1/16A61P31/00A61P31/12A61P31/20A61P35/00A61P43/00A61K48/00
Inventor R.哈马泰克
Owner GLAXO GRP LTD
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