Amphiregulin gene-specific double-stranded oligonucleotide and composition for preventing and treating fibrosis-related diseases and respiratory diseases, comprising same
Inventors
KIM, TAE-RIM • Yoon, Pyoung Oh • Ko, Youngho • BAE, SEON JOO • Park, Han-Oh • SON, SEUNG SEOB • Park, Jun-hong • YUN, Sung-Il
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Assignees
Member
BioneerBioneer is a biotechnology company specializing in molecular biology, offering solutions in nucleic acid synthesis, molecular diagnostics, protein production, and laboratory automation. The company's expertise covers oligonucleotide chemistry, gene synthesis, sample preparation, molecular diagnostics, and analytical services such as mass spectrometry and sequencing, serving clinical, research, and industrial sectors globally.
Bioneer is a biotechnology company specializing in molecular biology, offering solutions in nucleic acid synthesis, molecular diagnostics, protein production, and laboratory automation. The company's expertise covers oligonucleotide chemistry, gene synthesis, sample preparation, molecular diagnostics, and analytical services such as mass spectrometry and sequencing, serving clinical, research, and industrial sectors globally.
Publication Number
US-12037589-B2
Publication Date
2024-07-16
Expiration Date
Abstract
The present invention relates to a double-stranded oligonucleotide which can highly specifically and efficiently inhibit an amphiregulin expression and, preferably, a double-stranded oligonucleotide comprising a sequence in the form of RNA/RNA, DNA/DNA or DNA/RNA hybrid, a double-stranded oligonucleotide structure comprising the double-stranded oligonucleotide, nanoparticles comprising the double-stranded oligonucleotide structure, and a fibrosis or respiratory disease preventive or therapeutic use thereof.
Core Innovation
The invention relates to a gene-specific double-stranded amphiregulin-inhibiting oligonucleotide in which a DNA sense strand and an RNA antisense strand form a DNA-RNA hybrid. The sense and antisense sequences are defined using complementary strands, with preferred examples including SEQ ID NOs 10 to 12. The oligonucleotides include optional 3′ and/or 5′ chemical and backbone modifications to provide nuclease resistance and reduced immune stimulation.
The invention also defines double-stranded oligonucleotide structural conjugates having a structural arrangement of A-X-R-Y-B, where A is a hydrophilic moiety and B is a hydrophobic moiety. The hydrophilic portion includes PEG or block copolymers, and the hydrophobic portion includes C24 disulfide-containing hydrocarbons and lipids or steroids. The conjugate links the moieties through covalent bonds that can be degradable or non-degradable, with examples including disulfide and other degradable or non-degradable bond types.
The conjugates can further include a ligand and include an amine or polyhistidine to support cellular uptake and endosomal escape. Therapeutic compositions containing the amphiregulin-inhibiting oligonucleotide or the structural conjugates are described for preventing or treating fibrosis and respiratory diseases, including pulmonary fibrosis, idiopathic pulmonary fibrosis, and COPD-related indications. The document also enumerates fibrosis conditions including liver fibrosis, cirrhosis, myelofibrosis, myocardial fibrosis, renal fibrosis, cardiac fibrosis, and radiation-induced fibrosis.
Claims Coverage
The claim set centers on one independent claim directed to a defined structural compound featuring a hydrophilic moiety A, a specified C24 disulfide-containing hydrophobic portion B, covalent bonds or linkers X and Y, and nucleic acid components in the form of a DNA sense strand and an RNA antisense strand that form a DNA-RNA hybrid. Dependent claims refine the identity of the nucleic acid strands, add chemical modifications, specify bond types, add carbohydrate-related conjugation, and include pharmaceutical composition coverage.
Defined amphiregulin-inhibiting DNA-RNA hybrid compound with A-X-Y-B structure
A compound having a structure of Formula (3) or (4) in which A represents hexaethyleneglycol-(—PO3-hexaethyleneglycol)3, B represents C24(C6—S—S—C18), X and Y each independently represent a simple covalent bond or a linker-mediated covalent bond, S is a DNA sense strand and AS is an RNA antisense strand having a sequence complementary thereto, and S and AS form a DNA-RNA hybrid.
DNA sense strand sequence corresponding to a specified SEQ ID NO
The compound specifies that S is a DNA sense strand with a sequence corresponding to SEQ ID NO: 12.
Nucleic-acid chemical modifications of the DNA sense strand and/or RNA antisense strand
The compound defines chemical modifications selected from options involving substitutions on nucleotide sugar structures or modifications to bond types between nucleotides, including options involving PNA, LNA, or UNA.
Non-degradable bond as amide bond or phosphate bond
The compound includes a non-degradable bond, specifically an amide bond or a phosphate bond.
Carbohydrate conjugation to the hydrophilic moiety A
The compound further comprises a hexosamine, sugar, or carbohydrate conjugated to A.
Pharmaceutical composition containing the claimed compound
A pharmaceutical composition that contains, as its active ingredient, the compound specified in claim 1.
Across the claim set, the independent claim requires a defined A/X/Y/B conjugate architecture combined with complementary DNA-RNA hybrid strands. Dependent claims then narrow strand identity via a specific SEQ ID NO, introduce selected chemical modification options, constrain covalent-bond degradability to non-degradable amide or phosphate options, add sugar, hexosamine, or carbohydrate conjugation to A, and extend coverage to pharmaceutical compositions using the claimed compound as the active ingredient.
Stated Advantages
Provides nuclease resistance and reduced immune stimulation.
In vivo reduction of fibrosis markers and reduction of target gene expression in silica- and bleomycin-induced lung fibrosis models and UUO-induced renal fibrosis models.
Reported comparative efficacy outcomes favoring DNA/RNA hybrids, including IC50 measurements in A549 cells for SEQ ID NOs 10 to 12, and reduced innate immune cytokine induction in PBMCs.
Documented Applications
Preventing or treating fibrosis and respiratory diseases, including idiopathic pulmonary fibrosis and COPD-related indications.
Treating pulmonary fibrosis using silica- and bleomycin-induced lung fibrosis models.
Treating renal fibrosis using UUO-induced renal fibrosis model.
Treating other fibrosis conditions explicitly enumerated in the document, including liver fibrosis, cirrhosis, myelofibrosis, myocardial fibrosis, renal fibrosis, cardiac fibrosis, and radiation-induced fibrosis.
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