Double-stranded oligo RNA targeted to amphiregulin and pharmaceutical composition comprising same for preventing or treating fibrosis or respiratory diseases
Inventors
Chae, Jeiwook • Yoon, Pyoung Oh • Han, Boram • Kim, Mi Na • Ko, Youngho • Park, Han Oh
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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-10208309-B2
Publication Date
2019-02-19
Expiration Date
Abstract
The present invention relates to a novel siRNA, and a high-efficiency double-stranded oligo RNA structure containing the same, and a nanoparticle containing the high-efficiency double-stranded oligo RNA structure. The double-stranded oligo RNA structure has a structure in which a hydrophilic material and a hydrophobic material are conjugated to both ends of a double-stranded oligo RNA (siRNA) via a simple covalent bond or linker-mediated covalent bond in order to be efficiently delivered into cells, and may be converted into a nanoparticle form in an aqueous solution by hydrophobic interactions of double-stranded oligo RNA structures. It is preferable that the siRNA contained in the double-stranded oligo RNA structure is an siRNA specific for fibrosis or respiratory disease-related gene, particularly, amphiregulin or stratifin.In addition, the present invention relates to a pharmaceutical composition for preventing or treating fibrosis or respiratory diseases, containing an siRNA, a high-efficiency double-stranded oligo RNA structure containing the siRNA, or a nanoparticle containing the high-efficiency double-stranded oligo RNA structure, as an active ingredient.In addition, the present invention relates to a method of preventing or treating fibrosis or respiratory diseases, including administering the pharmaceutical composition for preventing or treating fibrosis or respiratory diseases to a subject in need thereof.
Core Innovation
The invention provides an siRNA with a sense strand comprising a sequence of specific SEQ ID NOs and an antisense strand complementary to the sense strand. For the particular sense strand comprising the sequence of SEQ ID NO: 107, the sense strand contains no more than 19 nucleotides. The siRNA can include strand chemical modifications, and the antisense strand can include a 5′ phosphate, and the disclosed siRNA targets amphiregulin (AR) or stratifin (SFN, 14-3-3 sigma protein, SFN).
The invention further defines a double-stranded oligo RNA structure including a hydrophilic material covalently attached at both ends and a hydrophobic material covalently attached at both ends via covalent bonds, including linker-mediated covalent bonds. The double-stranded oligo RNA structure is expressed as A–X–R–Y–B and related forms, where the hydrophilic material comprises polymers such as PEG and related hydrophilic polymers, and the hydrophobic material comprises lipid, steroid, or hydrocarbon derivatives.
The covalent bonds can be degradable or non-degradable, and the construct is configured to self-assemble in aqueous solution into stable nanoparticles via hydrophobic interactions. The invention provides an amphipathic construct, nanoparticles formed from the self-assembling construct, and pharmaceutical compositions that can be lyophilized, with therapeutic indications including fibrosis and respiratory diseases such as COPD and IPF.
Claims Coverage
The provided claim set includes one independent claim and dependent claims that refine the siRNA and broaden coverage to delivery formats and disease indication contexts. The independent claim defines an siRNA by specific sense-strand SEQ ID NO sequences with an antisense strand complementary thereto, and adds a sequence-length constraint when the sense strand is SEQ ID NO: 107 (no more than 19 nucleotides).
Specific siRNA sequences with complementary antisense and length constraint for SEQ ID NO: 107
An siRNA comprising a sense strand comprising a sequence of SEQ ID NO: 59, 75, 80, 92, 98, 102, or 107, wherein when the sense strand comprises the sequence of SEQ ID NO: 107, the sense strand contains no more than 19 nucleotides; and an antisense strand having a sequence complementary thereto.
Antisense 5′ phosphate end modification and permitted strand chemical modifications
The siRNA additionally allows strand chemical modifications and can include a 5′ phosphate on the antisense.
Double-stranded oligo RNA structure with covalently attached hydrophilic and hydrophobic materials
A double-stranded oligo RNA structure in which the hydrophilic material and the hydrophobic material are covalently attached to both ends via covalent bonds, including linker-mediated covalent bonds, and the bonds can be degradable or non-degradable.
Hydrophilic material molecular weight constraint in the double-stranded oligo RNA structure
A double-stranded oligo RNA structure in which the hydrophilic material has a molecular weight in the range 200 to 10,000.
Nanoparticle comprising the double-stranded oligo RNA structure
A nanoparticle that includes the double-stranded oligonucleotide RNA structure.
Therapeutic targeting of respiratory diseases
A method context directed to respiratory diseases including COPD, asthma, bronchitis, allergic rhinitis, cough and phlegm, bronchiolitis, pharyngitis, tonsillitis, and laryngitis.
Across the provided coverage, the core inventive elements are a defined siRNA sequence set with complementary antisense and an SEQ ID NO: 107 length constraint, strand chemical modifications including antisense 5′ phosphate, and a covalently amphipathic double-stranded oligo RNA construct that forms stable nanoparticles in aqueous solution, with therapeutic contexts focused on fibrosis and respiratory diseases such as COPD and IPF.
Stated Advantages
Strong mRNA knockdown of amphiregulin and stratifin.
Improved delivery and stable nanoparticles via self-assembly in aqueous solution.
Uniformity and inhibition associated with SAMiRNA-derived nanoparticles.
Provides therapeutic indications for fibrosis and respiratory diseases including COPD and IPF.
Documented Applications
Preventing or treating fibrosis and respiratory diseases.
Respiratory diseases including COPD, asthma, bronchitis, allergic rhinitis, cough and phlegm, bronchiolitis, pharyngitis, tonsillitis, and laryngitis.
Fibrosis including IPF, cirrhosis, myelofibrosis, myocardial/renal/pulmonary fibrosis, and lung cancer.
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